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Zhang W, Wang Y, Zhang X, Zhang Y, Yu W, Tang H, Yuan WE. Polyzwitterion-branched polycholic acid nanocarriers based oral delivery insulin for long-term glucose and metabolic regulation in diabetes mellitus. J Nanobiotechnology 2025; 23:133. [PMID: 39987096 PMCID: PMC11846306 DOI: 10.1186/s12951-025-03190-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/01/2025] [Indexed: 02/24/2025] Open
Abstract
Diabetes represents a global health crisis that necessitates advancements in prevention, treatment, and management. Beyond glucose regulation, addressing weight management and associated complications is imperative. This study introduces an oral nanoparticle formulation designed to simultaneously control blood glucose, obesity, and metabolic dysfunction. These nanoparticles, based on poly (zwitterion-cholic acid), incorporate a polyzwitterion component to enhance permeation through the mucus layer and prolong drug residence. Furthermore, bile acid polymers not only regulate lipid metabolism but also ameliorate obesity-associated inflammation in adipose and liver tissues. In vivo experiments demonstrated significant hypoglycemic effects in healthy, type I diabetic, and type II diabetic mice. Notably, the nanocarriers significantly reduced body weight gain, ameliorated inflammation in adipose and liver tissues, and modulated lipid metabolism in the liver of db/db mice. Our study elucidates a comprehensive strategy for addressing glycemic control and diabetes-related complications, offering a promising approach for diabetes prevention and treatment.
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Affiliation(s)
- Wenkai Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Yue Wang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Xiangqi Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Yihui Zhang
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Wei Yu
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China
| | - Haozheng Tang
- Department of Bone and Joint Surgery, Department of Orthopedics, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 200001, China
| | - Wei-En Yuan
- Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
- National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China.
- Inner Mongolia Research Institute of Shanghai Jiao Tong University, Hohhot, 010070, China.
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2
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Liu H, Li T, Chen XL, Yu HL, Yu YR. Impact of setting distinct target blood glucose levels on endogenous insulin suppression and pharmacodynamics of insulin preparations. World J Diabetes 2025; 16:101779. [PMID: 39959272 PMCID: PMC11718471 DOI: 10.4239/wjd.v16.i2.101779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/15/2024] [Accepted: 12/05/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Insulin therapy plays a crucial role in managing diabetes. Regulatory guidelines mandate assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of new insulin formulations with euglycemic clamp techniques before entry into the market. Typically, blood glucose (BG) levels are maintained at 5% below baseline to suppress endogenous insulin secretion in healthy volunteers. However, in scenarios where BG baseline is relatively low, maintaining it at 5% below baseline can increase hypoglycemic risk. Consequently, we adjusted to maintain it at 2.5% below a baseline of < 4.00 mmol/L. It remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study insulin. AIM To evaluate and compare the PD and C-peptide status using two different target BG setting methods. METHODS Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart (IAsp) in healthy participants. Target BG was set at 2.5% below baseline for those with a basal BG of < 4.00 mmol/L (group A), and at 5% below baseline for others (group B). The area under the curve (AUC) of IAsp (AUCIAsp, 0-8 h) and GIR from 0 to 8 hours (AUCGIR, 0-8 h) was used to characterize the PK and PD of IAsp, respectively. The C-peptide reduction and PK/PD of IAsp were compared between the two groups. RESULTS Out of 135 subjects, 15 were assigned to group A and 120 to group B; however, group B exhibited higher basal C-peptide (1.59 ± 0.36 vs 1.32 ± 0.42 ng/mL, P = 0.006). Following propensity score matching to adjust for basal C-peptide differences, 71 subjects (15 in group A and 56 in group B) were analyzed. No significant differences were observed in demographics, IAsp dosage, or clamp quality. Group B showed significantly higher baseline (4.35 ± 0.21 vs 3.91 ± 0.09 mmol/L, P < 0.001), target (4.13 ± 0.20 vs 3.81 ± 0.08 mmol/L, P < 0.001), and clamped (4.10 ± 0.17 vs 3.80 ± 0.06 mmol/L, P < 0.001) BG levels. Both groups exhibited comparable C-peptide suppression (32.5% ± 10.0% vs 35.6% ± 12.1%, P = 0.370) and similar IAsp activity (AUCGIR, 0-8 h: 1433 ± 400 vs 1440 ± 397 mg/kg, P = 0.952) under nearly equivalent IAsp exposure (AUCIAsp, 0-8 h: 566 ± 51 vs 571 ± 85 ng/mL × h, P = 0.840). CONCLUSION Maintaining BG at 2.5% below a baseline of < 4.00 mmol/L did not compromise the endogenous insulin suppression nor alter the observed pharmacodynamic effects of the study insulin.
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Affiliation(s)
- Hui Liu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Clinical Trial Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ting Li
- Health Management Center, General Practice Medical Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin-Lei Chen
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hong-Ling Yu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ye-Rong Yu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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3
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Piersanti A, Pacini G, Tura A, D'Argenio DZ, Morettini M. An in-silico modeling approach to separate exogenous and endogenous plasma insulin appearance, with application to inhaled insulin. Sci Rep 2024; 14:10936. [PMID: 38740832 PMCID: PMC11091049 DOI: 10.1038/s41598-024-61293-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 05/03/2024] [Indexed: 05/16/2024] Open
Abstract
The aim of this study was to develop a dynamic model-based approach to separately quantify the exogenous and endogenous contributions to total plasma insulin concentration and to apply it to assess the effects of inhaled-insulin administration on endogenous insulin secretion during a meal test. A three-step dynamic in-silico modeling approach was developed to estimate the two insulin contributions of total plasma insulin in a group of 21 healthy subjects who underwent two equivalent standardized meal tests on separate days, one of which preceded by inhalation of a Technosphere® Insulin dose (22U or 20U). In the 30-120 min test interval, the calculated endogenous insulin component showed a divergence in the time course between the test with and without inhaled insulin. Moreover, the supra-basal area-under-the-curve of endogenous insulin in the test with inhaled insulin was significantly lower than that in the test without (2.1 ± 1.7 × 104 pmol·min/L vs 4.2 ± 1.8 × 104 pmol·min/L, p < 0.01). The percentage of exogenous insulin reaching the plasma, relative to the inhaled dose, was 42 ± 21%. The proposed in-silico approach separates exogenous and endogenous insulin contributions to total plasma insulin, provides individual bioavailability estimates, and can be used to assess the effect of inhaled insulin on endogenous insulin secretion during a meal.
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Affiliation(s)
- Agnese Piersanti
- Department of Information Engineering, Università Politecnica Delle Marche, Via Brecce Bianche 12, Ancona, Italy
| | | | | | - David Z D'Argenio
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Micaela Morettini
- Department of Information Engineering, Università Politecnica Delle Marche, Via Brecce Bianche 12, Ancona, Italy.
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Winn NC, Cottam MA, Bhanot M, Caslin HL, Garcia JN, Arrojo e Drigo R, Hasty AH. Weight Cycling Impairs Pancreatic Insulin Secretion but Does Not Perturb Whole-Body Insulin Action in Mice With Diet-Induced Obesity. Diabetes 2022; 71:2313-2330. [PMID: 35802127 PMCID: PMC9630085 DOI: 10.2337/db22-0161] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 07/03/2022] [Indexed: 01/23/2023]
Abstract
In the setting of obesity and insulin resistance, glycemia is controlled in part by β-cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for β-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared with those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.
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Affiliation(s)
- Nathan C. Winn
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Matthew A. Cottam
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Monica Bhanot
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Heather L. Caslin
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Jamie N. Garcia
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Rafael Arrojo e Drigo
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Alyssa H. Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
- VA Tennessee Valley Healthcare System, Nashville, TN
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5
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Khan D, Moffett RC, Flatt PR, Tarasov AI. Classical and non-classical islet peptides in the control of β-cell function. Peptides 2022; 150:170715. [PMID: 34958851 DOI: 10.1016/j.peptides.2021.170715] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/25/2021] [Accepted: 12/17/2021] [Indexed: 12/25/2022]
Abstract
The dual role of the pancreas as both an endocrine and exocrine gland is vital for food digestion and control of nutrient metabolism. The exocrine pancreas secretes enzymes into the small intestine aiding digestion of sugars and fats, whereas the endocrine pancreas secretes a cocktail of hormones into the blood, which is responsible for blood glucose control and regulation of carbohydrate, protein and fat metabolism. Classical islet hormones, insulin, glucagon, pancreatic polypeptide and somatostatin, interact in an autocrine and paracrine manner, to fine-tube the islet function and insulin secretion to the needs of the body. Recently pancreatic islets have been reported to express a number of non-classical peptide hormones involved in metabolic signalling, whose major production site was believed to reside outside pancreas, e.g. in the small intestine. We highlight the key non-classical islet peptides, and consider their involvement, together with established islet hormones, in regulation of stimulus-secretion coupling as well as proliferation, survival and transdifferentiation of β-cells. We furthermore focus on the paracrine interaction between classical and non-classical islet hormones in the maintenance of β-cell function. Understanding the functional relationships between these islet peptides might help to develop novel, more efficient treatments for diabetes and related metabolic disorders.
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Affiliation(s)
- Dawood Khan
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
| | - R Charlotte Moffett
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Andrei I Tarasov
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
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6
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Lee JS, Han P, Chaudhury R, Khan S, Bickerton S, McHugh MD, Park HB, Siefert AL, Rea G, Carballido JM, Horwitz DA, Criscione J, Perica K, Samstein R, Ragheb R, Kim D, Fahmy TM. Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin. Nat Biomed Eng 2021; 5:983-997. [PMID: 34616050 DOI: 10.1038/s41551-021-00791-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 08/04/2021] [Indexed: 02/08/2023]
Abstract
Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.
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Affiliation(s)
- Jung Seok Lee
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Patrick Han
- Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA
| | - Rabib Chaudhury
- Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA
| | - Shihan Khan
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Sean Bickerton
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Michael D McHugh
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Hyun Bong Park
- Department of Chemistry, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA
| | - Alyssa L Siefert
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | | | | | - David A Horwitz
- Medicine and Molecular Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jason Criscione
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Karlo Perica
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Robert Samstein
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Ragy Ragheb
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Dongin Kim
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA.,Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Tarek M Fahmy
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA. .,Chemical and Environmental Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, CT, USA. .,Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA.
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7
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Herzig D, Studer D, Nakas CT, Kuenzli C, Stauffer TP, Hovorka R, Bally L. Effect of fully automated closed-loop insulin delivery using faster aspart versus standard aspart on gluco-regulatory hormones in type 2 diabetes. Diabetes Obes Metab 2021; 23:228-233. [PMID: 32902125 DOI: 10.1111/dom.14185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/07/2020] [Accepted: 08/23/2020] [Indexed: 11/30/2022]
Abstract
We retrospectively assessed gluco-regulatory hormones over 10 h (including two meals) of fully automated closed-loop insulin delivery using faster (FA) versus standard insulin aspart (IAsp) in adults with type 2 diabetes [n = 15, age 59 ± 10 years, body mass index 34.5 ± 9.1 kg/m2 , glycated haemoglobin 7.7 ± 1.2% (60 ± 13 mmol/mol)]. Plasma concentration of human insulin, IAsp, C-peptide, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic peptide and peptide tyrosine tyrosine were measured every 15-30 min. Endogenous insulin secretion was calculated using C-peptide deconvolution and exposures to hormones were compared using their mean plasma concentrations. Ten-hour exposure of IAsp was higher with FA versus IAsp (P = .037) in line with the 10% higher insulin requirements to achieve similar glucose control. No significant difference was found for total insulin exposure and endogenous insulin secretion. Similarly, other gluco-regulatory hormones did not significantly differ. In conclusion, the faster pharmacokinetic profile and slightly higher aspart exposure of FA versus IAsp remained without significant effects on endogenous insulin secretion or other gluco-regulatory hormones. Further studies are warranted to explore the metabolic and endocrine effects of novel insulins with accelerated pharmacokinetic properties.
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Affiliation(s)
- David Herzig
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - David Studer
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
| | - Christos T Nakas
- Laboratory of Biometry, School of Agriculture, University of Thessaly, Nea Ionia, Greece
- University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | | | | | - Roman Hovorka
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
- Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Lia Bally
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
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8
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Rachdaoui N. Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus. Int J Mol Sci 2020; 21:ijms21051770. [PMID: 32150819 PMCID: PMC7084909 DOI: 10.3390/ijms21051770] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/29/2020] [Accepted: 03/02/2020] [Indexed: 12/14/2022] Open
Abstract
Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.
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Affiliation(s)
- Nadia Rachdaoui
- Department of Animal Sciences, Room 108, Foran Hall, Rutgers, the State University of New Jersey, 59 Dudley Rd, New Brunswick, NJ 08901, USA
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9
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Tamarai K, Bhatti JS, Reddy PH. Molecular and cellular bases of diabetes: Focus on type 2 diabetes mouse model-TallyHo. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2276-2284. [PMID: 31082469 DOI: 10.1016/j.bbadis.2019.05.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 12/17/2022]
Abstract
Diabetes is a chronic lifestyle disorder that affects millions of people worldwide. Diabetes is a condition where the body does not produce sufficient insulin or does not use it efficiently. Insulin resistance in diabetes or obesity causes the pancreatic β-cells to increase the insulin output. Diabetes occurs in multiple forms, including type 1, type 2, type 3 and gestational. Type 2 diabetes accounts for ∼90-95% of total affected population and is associated with both impaired insulin production by the β-cells of the pancreas and impaired insulin release in response to high blood glucose levels. Diabetes is tightly linked with genetic mutations and genetic and lifestyle activities, including diet and exercise. Recent epidemiological studies established a close link between the diabetes and progression to Alzheimer's disease. This article summarizes various molecular mechanisms involved in the developments of diabetes, including biochemical characteristics, genetic and molecular links with Alzheimer's disease, β-cell function, and factors associated with diabetes. This will help us in the development of novel therapeutic strategies targeting AD in future.
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Affiliation(s)
- Kavya Tamarai
- Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4(th) Street, Lubbock, TX 79430, United States
| | - Jasvinder Singh Bhatti
- Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4(th) Street, Lubbock, TX 79430, United States; Department of Biotechnology, Sri Guru Gobind Singh College, Chandigarh, India
| | - P Hemachandra Reddy
- Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4(th) Street, Lubbock, TX 79430, United States; Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4(th) Street, MS 9424, Lubbock, TX 79430, United States; Cell Biology & Biochemistry Department, Texas Tech University Health Sciences Center, 3601 4(th) Street, Lubbock, TX 79430, United States; Pharmacology & Neuroscience Department, Texas Tech University Health Sciences Center, 3601 4(th) Street, MS 9424, Lubbock, TX 79430, United States; Neurology Department, Texas Tech University Health Sciences Center, 3601 4(th) Street, MS 9424, Lubbock, TX 79430, United States; Speech, Language and Hearing Sciences Department, Texas Tech University Health Sciences Center, 3601 4(th) Street, MS 9424, Lubbock, TX 79430, United States; Department of Public Health, Graduate School of Biomedical Sciences, 3601 4(th) Street, MS 9424, Lubbock, TX 79430, United States.
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10
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Kaga H, Tamura Y, Takeno K, Kakehi S, Someya Y, Funayama T, Furukawa Y, Suzuki R, Sugimoto D, Kadowaki S, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Giacca A, Kanazawa A, Kawamori R, Watada H. Higher C-Peptide Level During Glucose Clamp Is Associated With Muscle Insulin Resistance in Nonobese Japanese Men. J Endocr Soc 2019; 3:1847-1857. [PMID: 31555755 PMCID: PMC6753586 DOI: 10.1210/js.2019-00167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 07/17/2019] [Indexed: 11/19/2022] Open
Abstract
Context Circulating C-peptide is generally suppressed by exogenous insulin infusion. However, steady-state serum C-peptide (SSSC) levels during hyperinsulinemic-euglycemic clamp in obese subjects are higher than in healthy subjects, which may contribute to hyperinsulinemia to compensate for insulin resistance. Even in healthy subjects, interindividual variations in SSSC levels are present; however, the characteristics of subjects with high SSSC levels in those populations have not been fully elucidated. Objective To investigate the clinical parameters associated with interindividual variations in SSSC levels in apparently healthy, nonobese Japanese men. Design and Participants We studied 49 nonobese (BMI < 25 kg/m2), healthy Japanese men. We evaluated SSSC and insulin sensitivity using hyperinsulinemic-euglycemic clamp with tracer. Intrahepatic lipid (IHL) was measured using proton magnetic resonance spectroscopy. Results We divided subjects into high and low SSSC groups based on the median SSSC value and compared their clinical parameters. Compared with the low SSSC group, the high SSSC group had IHL accumulation, impaired muscle insulin sensitivity, reduced insulin clearance, and hyperinsulinemia during a 75-g oral glucose tolerance test (OGTT). All of these factors were significantly correlated with SSSC. Conclusions In healthy, nonobese men, higher SSSC was associated with impaired muscle insulin sensitivity, IHL accumulation, and hyperinsulinemia during OGTT. These findings suggest that higher endogenous insulin secretion during hyperinsulinemia, along with reduced insulin clearance, may be an early change to maintain metabolic status in the face of moderate muscle insulin resistance, even in healthy, nonobese men.
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Affiliation(s)
- Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kageumi Takeno
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saori Kakehi
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ruriko Suzuki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Daisuke Sugimoto
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Kazunori Shimada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Daida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigeki Aoki
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Adria Giacca
- Departments of Physiology and Medicine, Institute of Medical Science and Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada
| | - Akio Kanazawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan.,Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan
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11
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Pieralice S, Pozzilli P. Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management. Diabetes Metab J 2018; 42:451-464. [PMID: 30565440 PMCID: PMC6300440 DOI: 10.4093/dmj.2018.0190] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 11/14/2018] [Indexed: 12/16/2022] Open
Abstract
Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease characterized by a less intensive autoimmune process and a broad clinical phenotype compared to classical type 1 diabetes mellitus (T1DM), sharing features with both type 2 diabetes mellitus (T2DM) and T1DM. Since patients affected by LADA are initially insulin independent and recognizable only by testing for islet-cell autoantibodies, it could be difficult to identify LADA in clinical setting and a high misdiagnosis rate still remains among patients with T2DM. Ideally, islet-cell autoantibodies screening should be performed in subjects with newly diagnosed T2DM, ensuring a closer monitoring of those resulted positive and avoiding treatment of hyperglycaemia which might increase the rate of β-cells loss. Thus, since the autoimmune process in LADA seems to be slower than in classical T1DM, there is a wider window for new therapeutic interventions that may slow down β-cell failure. This review summarizes the current understanding of LADA, by evaluating data from most recent studies, the actual gaps in diagnosis and management. Finally, we critically highlight and discuss novel findings and future perspectives on the therapeutic approach in LADA.
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Affiliation(s)
- Silvia Pieralice
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
| | - Paolo Pozzilli
- Department of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy
- Centre of Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
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12
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Pozzilli P, Pieralice S. Latent Autoimmune Diabetes in Adults: Current Status and New Horizons. Endocrinol Metab (Seoul) 2018; 33:147-159. [PMID: 29947172 PMCID: PMC6021307 DOI: 10.3803/enm.2018.33.2.147] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 05/23/2018] [Accepted: 05/28/2018] [Indexed: 12/16/2022] Open
Abstract
Autoimmune diabetes is a heterogeneous disease which can arise at any age. Subjects with adult-onset autoimmune diabetes who do not necessitate insulin-therapy for at least 6 months after diagnosis are demarcated as having latent autoimmune diabetes in adults (LADA). This condition is more heterogeneous than young-onset autoimmune diabetes and shares clinical and metabolic characteristics with both type 2 and type 1 diabetes. Patients with LADA are considered by having highly variable β-cell destruction, different degrees of insulin resistance and heterogeneous titre and pattern of islet autoantibody, suggesting different pathophysiological pathways partially explaining the heterogeneous phenotypes of LADA. To date the heterogeneity of LADA does not allow to establish a priori treatment algorithm and no specific guidelines for LADA therapy are available. These subjects are mostly treated as affected by type 2 diabetes, a factor that might lead to the progression to insulin-dependency quickly. A personalised medicine approach is necessary to attain optimal metabolic control and preserve β-cell function to decrease the risk of long-term diabetes complications. Recent data concerning the use of oral antidiabetic agents as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists indicate up-and-coming results in term of protect C-peptide levels and improving glycaemic control. This review summarises current knowledge on LADA, emphasising controversies regarding its pathophysiology and clinical features. Moreover, we discuss data available about novel therapeutic approaches that can be considered for prevention of β-cell loss in LADA.
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Affiliation(s)
- Paolo Pozzilli
- Department of Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy
- Centre of Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary, University of London, London, UK.
| | - Silvia Pieralice
- Department of Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy
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13
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Jensen VF, Mølck AM, Lykkesfeldt J, Bøgh IB. Effect of maternal hypoglycaemia during gestation on materno-foetal nutrient transfer and embryo-foetal development: Evidence from experimental studies focused primarily on the rat. Reprod Toxicol 2018; 77:1-24. [DOI: 10.1016/j.reprotox.2018.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 12/07/2017] [Accepted: 01/30/2018] [Indexed: 01/14/2023]
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14
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Crisman M, Lucchetta L, Luethi N, Cioccari L, Lam Q, Eastwood GM, Bellomo R, Mårtensson J. The effect of insulin administration on c-peptide in critically ill patients with type 2 diabetes. Ann Intensive Care 2017; 7:50. [PMID: 28497374 PMCID: PMC5427062 DOI: 10.1186/s13613-017-0274-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 04/29/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In critically ill patients with permissive hyperglycemia, it is uncertain whether exogenous insulin administration suppresses or enhances c-peptide secretion (a marker of pancreatic beta-cell response). We aimed to explore this effect in patients with type 2 diabetes. METHODS We prospectively enrolled a cohort of 45 critically ill patients with type 2 diabetes managed according to a liberal glucose protocol (target blood glucose 10-14 mmol/l). We recorded the administration of insulin and oral hypoglycemic agents and measured plasma c-peptide as surrogate marker of endogenous insulin secretion on the first two consecutive days in ICU. RESULTS Overall, 20 (44.4%) patients required insulin to achieve target blood glucose. Insulin-treated patients had higher glycated hemoglobin A1c, more premorbid insulin-requiring type 2 diabetes, and greater blood glucose levels but lower c-peptide levels on admission. Premorbid insulin-requiring diabetes was independently associated with lower admission c-peptide, whereas greater plasma creatinine was independently associated with higher levels. Increases in c-peptide were positively correlated with an increase in blood glucose both in patients who did (r = 0.54, P = 0.01) and did not (r = 0.56, P = 0.004) receive insulin. However, insulin administration was independently associated with a greater increase in c-peptide (P = 0.04). This association was not modified by the use of oral insulin secretagogues. CONCLUSIONS C-peptide, a marker of beta-cell response, responds to and is influenced by glycemia and renal function in critically ill patients with type 2 diabetes. In addition, in our cohort, exogenous insulin administration was associated with a greater increase in c-peptide in response to hyperglycemia. Trial Registration Australian New Zealand Clinical Trials Registry (ACTRN12615000216516).
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Affiliation(s)
- Marco Crisman
- Department of Intensive Care, Austin Hospital, The University of Melbourne, 145 Studley Rd, Heidelberg, Melbourne, VIC 3084 Australia
- Department of Anesthesia and Intensive Care, Azienda Ospedaliero-Universitaria “Ospedali Riuniti”, Trieste, Italy
| | - Luca Lucchetta
- Department of Intensive Care, Austin Hospital, The University of Melbourne, 145 Studley Rd, Heidelberg, Melbourne, VIC 3084 Australia
| | - Nora Luethi
- Department of Intensive Care, Austin Hospital, The University of Melbourne, 145 Studley Rd, Heidelberg, Melbourne, VIC 3084 Australia
| | - Luca Cioccari
- Department of Intensive Care, Austin Hospital, The University of Melbourne, 145 Studley Rd, Heidelberg, Melbourne, VIC 3084 Australia
| | - Que Lam
- Department of Pathology, Austin Health, Melbourne, VIC Australia
| | - Glenn M. Eastwood
- Department of Intensive Care, Austin Hospital, The University of Melbourne, 145 Studley Rd, Heidelberg, Melbourne, VIC 3084 Australia
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, The University of Melbourne, 145 Studley Rd, Heidelberg, Melbourne, VIC 3084 Australia
- Department of Epidemiology and Preventive Medicine, Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC Australia
| | - Johan Mårtensson
- Department of Intensive Care, Austin Hospital, The University of Melbourne, 145 Studley Rd, Heidelberg, Melbourne, VIC 3084 Australia
- Section of Anaesthesia and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
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15
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Buzzetti R, Zampetti S, Maddaloni E. Adult-onset autoimmune diabetes: current knowledge and implications for management. Nat Rev Endocrinol 2017; 13:674-686. [PMID: 28885622 DOI: 10.1038/nrendo.2017.99] [Citation(s) in RCA: 165] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Adult-onset autoimmune diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 diabetes mellitus (T1DM). The majority of patients with adult-onset autoimmune diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent autoimmune diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset autoimmune diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset autoimmune diabetes and highlight the similarities and differences with classic T1DM and type 2 diabetes mellitus.
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Affiliation(s)
- Raffaella Buzzetti
- Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy
| | - Simona Zampetti
- Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy
| | - Ernesto Maddaloni
- Department of Medicine, Unit of Endocrinology and Diabetes, University Campus Bio-Medico, Via Álvaro del Portillo 21, 00128, Rome, Italy
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16
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Jensen VFH, Mølck AM, Berthelsen LO, Alifrangis L, Andersen L, Chapman M, Lykkesfeldt J, Bøgh IB. Toxicological Effects during and following Persistent Insulin-Induced Hypoglycaemia in Healthy Euglycaemic Rats. Basic Clin Pharmacol Toxicol 2017; 121:53-66. [DOI: 10.1111/bcpt.12769] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 02/13/2017] [Indexed: 12/27/2022]
Affiliation(s)
- Vivi F. H. Jensen
- Department of Veterinary and Animal Sciences; Section for Experimental Animal Models; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
- Department of Toxicology; Safety Pharm and Pathology; Novo Nordisk A/S; Maaloev Denmark
| | - Anne-Marie Mølck
- Department of Toxicology; Safety Pharm and Pathology; Novo Nordisk A/S; Maaloev Denmark
| | - Line O. Berthelsen
- Department of Toxicology; Safety Pharm and Pathology; Novo Nordisk A/S; Maaloev Denmark
| | - Lene Alifrangis
- Department of Development DMPK; Novo Nordisk A/S; Maaloev Denmark
| | - Lene Andersen
- Department of Diabetes Bioanalysis; Novo Nordisk A/S; Maaloev Denmark
| | | | - Jens Lykkesfeldt
- Department of Veterinary and Animal Sciences; Section for Experimental Animal Models; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - Ingrid B. Bøgh
- Department of Toxicology; Safety Pharm and Pathology; Novo Nordisk A/S; Maaloev Denmark
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17
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N SK, Subhakumari KN. Role of anti-GAD, anti-IA2 antibodies and C-peptide in differentiating latent autoimmune diabetes in adults from type 2 diabetes mellitus. Int J Diabetes Dev Ctries 2015. [DOI: 10.1007/s13410-015-0451-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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18
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Huyett LM, Dassau E, Zisser HC, Doyle FJ. Design and Evaluation of a Robust PID Controller for a Fully Implantable Artificial Pancreas. Ind Eng Chem Res 2015; 54:10311-10321. [PMID: 26538805 PMCID: PMC4627627 DOI: 10.1021/acs.iecr.5b01237] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/06/2015] [Accepted: 06/09/2015] [Indexed: 11/28/2022]
Abstract
Treatment of type 1 diabetes mellitus could be greatly improved by applying a closed-loop control strategy to insulin delivery, also known as an artificial pancreas (AP). In this work, we outline the design of a fully implantable AP using intraperitoneal (IP) insulin delivery and glucose sensing. The design process utilizes the rapid glucose sensing and insulin action offered by the IP space to tune a PID controller with insulin feedback to provide safe and effective insulin delivery. The controller was tuned to meet robust performance and stability specifications. An anti-reset windup strategy was introduced to prevent dangerous undershoot toward hypoglycemia after a large meal disturbance. The final controller design achieved 78% of time within the tight glycemic range of 80-140 mg/dL, with no time spent in hypoglycemia. The next step is to test this controller design in an animal model to evaluate the in vivo performance.
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Affiliation(s)
- Lauren M Huyett
- Department of Chemical Engineering, University of California Santa Barbara , Santa Barbara, California 93106-5080, United States
| | - Eyal Dassau
- Department of Chemical Engineering, University of California Santa Barbara , Santa Barbara, California 93106-5080, United States
| | - Howard C Zisser
- Department of Chemical Engineering, University of California Santa Barbara , Santa Barbara, California 93106-5080, United States
| | - Francis J Doyle
- Department of Chemical Engineering, University of California Santa Barbara , Santa Barbara, California 93106-5080, United States
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19
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Jamaludin UK, Docherty PD, Geoffrey Chase J, Shaw GM. Impact of Haemodialysis on Insulin Kinetics of Acute Kidney Injury Patients in Critical Care. J Med Biol Eng 2015; 35:125-133. [PMID: 25750607 PMCID: PMC4342528 DOI: 10.1007/s40846-015-0015-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 05/02/2014] [Indexed: 01/04/2023]
Abstract
Critically ill patients are occasionally associated with an abrupt decline in renal function secondary to their primary diagnosis. The effect and impact of haemodialysis (HD) on insulin kinetics and endogenous insulin secretion in critically ill patients remains unclear. This study investigates the insulin kinetics of patients with severe acute kidney injury (AKI) who required HD treatment and glycaemic control (GC). Evidence shows that tight GC benefits the onset and progression of renal involvement in precocious phases of diabetic nephropathy for type 2 diabetes. The main objective of GC is to reduce hyperglycaemia while determining insulin sensitivity. Insulin sensitivity (SI) is defined as the body response to the effects of insulin by lowering blood glucose levels. Particularly, this study used SI to track changes in insulin levels during HD therapy. Model-based insulin sensitivity profiles were identified for 51 critically ill patients with severe AKI on specialized relative insulin nutrition titration GC during intervals on HD (OFF/ON) and after HD (ON/OFF). The metabolic effects of HD were observed through changes in SI over the ON/OFF and OFF/ON transitions. Changes in model-based SI at the OFF/ON and ON/OFF transitions indicate changes in endogenous insulin secretion and/or changes in effective insulin clearance. Patients exhibited a median reduction of −29 % (interquartile range (IQR): [−58, 6 %], p = 0.02) in measured SI after the OFF/ON dialysis transition, and a median increase of +9 % (IQR −15 to 28 %, p = 0.7) after the ON/OFF transition. Almost 90 % of patients exhibited decreased SI at the OFF/ON transition, and 55 % exhibited increased SI at the ON/OFF transition. Results indicate that HD commencement has a significant effect on insulin pharmacokinetics at a cohort and per-patient level. These changes in metabolic behaviour are most likely caused by changes in insulin clearance or/and endogenous insulin secretion.
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Affiliation(s)
- Ummu K. Jamaludin
- Faculty of Mechanical Engineering, Universiti Malaysia Pahang, 26600 Pekan, Pahang Malaysia
| | - Paul D. Docherty
- Department of Mechanical Engineering, Centre of Bioengineering, University of Canterbury, Private Bag 4800, Christchurch, 8140 New Zealand
| | - J. Geoffrey Chase
- Department of Mechanical Engineering, Centre of Bioengineering, University of Canterbury, Private Bag 4800, Christchurch, 8140 New Zealand
| | - Geoffrey M. Shaw
- Department of Intensive Care Christchurch School of Medicine and Health Science, PO Box 4345, Christchurch, 8140 New Zealand
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20
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Thabit H, Kumareswaran K, Haidar A, Leelarathna L, Caldwell K, Elleri D, Allen JM, Nodale M, Wilinska ME, Jackson NC, Umpleby AM, Evans ML, Hovorka R. Glucose turnover after replacement of usual therapy by insulin in insulin-naive type 2 diabetes subjects. J Clin Endocrinol Metab 2014; 99:2225-32. [PMID: 24606105 DOI: 10.1210/jc.2013-4519] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
CONTEXT Discontinuation of anti-hyperglycemic oral agents and initiation of insulin is recommended in certain clinical situations for inpatients with type 2 diabetes (T2D). The effects on glucose turnover when these agents are acutely withdrawn are poorly understood and may be of importance when insulin therapy is initiated. OBJECTIVE Our objective was to investigate alterations in glucose turnover after acute withdrawal of noninsulin therapy. DESIGN AND SETTING This was a randomized crossover study at a clinical research facility. PARTICIPANTS Participants included 12 insulin-naive subjects with T2D. METHODS Subjects attended two 24-hour visits. Standard therapy was discontinued and replaced by closed-loop insulin delivery during the intervention visit. Usual anti-hyperglycemic therapy was continued during the control visit. Systemic glucose appearance (Ra) and glucose disposal (Rd) were measured using a tracer dilution technique with iv [6,6-(2)H2]glucose. RESULTS Plasma glucose profiles during both visits were comparable (P = .48). Glucose Ra increased during the day (21.4 [19.5, 23.5] vs 18.6 [17.0, 21.6) μmol/kg/min, P = .019) and decreased overnight (9.7 [8.5, 11.4] vs 11.6 [10.3, 12.9] μmol/kg/min, P = .004) when the usual therapy was discontinued and replaced with insulin. Increased daytime glucose Rd (21.2 [19.4, 23.9] vs 18.8 [18.3, 21.7] μmol/kg/min, P = .002) and decreased overnight Rd (10.4 [9.1, 12.0] vs 11.8 [10.7, 13.7] μmol/kg/min, P = .005) were observed when the usual therapy was discontinued, whereas daytime peripheral insulin sensitivity was reduced (47.8 [24.8, 66.1] vs 62.5 [34.8, 75.8] nmol/kg/min per pmol/L, P = .034). CONCLUSION In T2D, acute discontinuation of anti-hyperglycemic therapy and replacement with insulin increases postprandial Ra and reduces peripheral insulin sensitivity. Insulin dose initiation may need to compensate for these alterations.
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Affiliation(s)
- H Thabit
- Metabolic Research Laboratories (H.T., K.K., L.L., K.C., D.E., J.M.A., M.N., M.E.W., M.L.E., R.H.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, and Department of Paediatrics (D.E., J.M.A., M.E.W., R.H.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Centre for Intelligent Machines (A.H.), McGill University, Montreal, Quebec H3A 0E9, Canada; and Postgraduate Medical School (N.C.J., A.M.U.), University of Surrey, Guildford GU2 7TE, United Kingdom
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21
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Lazarenko R, Geisler J, Bayliss D, Larner J, Li C. D-chiro-inositol glycan stimulates insulin secretion in pancreatic β cells. Mol Cell Endocrinol 2014; 387:1-7. [PMID: 24530497 PMCID: PMC4366192 DOI: 10.1016/j.mce.2014.02.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 01/30/2014] [Accepted: 02/07/2014] [Indexed: 12/25/2022]
Abstract
Insulin has been shown to act on pancreatic β cells to regulate its own secretion. Currently the mechanism underlying this effect is unclear. INS-2, a novel inositol glycan pseudo-disaccharide containing D-chiro-inositol and galactosamine, has been shown to function as an insulin mimetic and a putative insulin mediator. In the present study we found that INS-2 stimulates insulin secretion in MIN6 β cells and potentiates glucose stimulated insulin secretion in isolated mouse islets. Importantly, INS-2 failed to potentiate insulin secretion induced by tolbutamide, which stimulates insulin release by closing ATP sensitive potassium channels (KATP). Electrophysiological studies showed that INS-2 inhibited sulfonylurea-sensitive KATP conductance. The effect of INS-2 on inhibiting KATP channel is mediated by protein phosphatase 2C (PP2C), as knocking down PP2C expression in MIN6 cells by PP2C small hairpin RNA completely abolished the effect of INS-2 on KATP and consequently attenuated INS-2 induced insulin secretion. In conclusion, the present study identifies a novel mechanism involving PP2C in regulating KATP channel activity and consequently insulin secretion.
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Affiliation(s)
- Roman Lazarenko
- Department of Pharmacology, University of Virginia Health System, Charlottesville, VA, United States
| | - Jessica Geisler
- Department of Pharmacology, University of Virginia Health System, Charlottesville, VA, United States
| | - Douglas Bayliss
- Department of Pharmacology, University of Virginia Health System, Charlottesville, VA, United States
| | - Joseph Larner
- Department of Pharmacology, University of Virginia Health System, Charlottesville, VA, United States
| | - Chien Li
- Department of Pharmacology, University of Virginia Health System, Charlottesville, VA, United States.
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22
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Docherty PD, Chase JG. An in-silico proof-of-concept investigation of a combined glucose-insulin bolus quick dynamic insulin sensitivity test. Biomed Signal Process Control 2014. [DOI: 10.1016/j.bspc.2012.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Cernea S, Dobreanu M. Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. Biochem Med (Zagreb) 2013; 23:266-80. [PMID: 24266296 PMCID: PMC3900074 DOI: 10.11613/bm.2013.033] [Citation(s) in RCA: 133] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Diabetes is a complex, heterogeneous condition that has beta cell dysfunction at its core. Many factors (e.g. hyperglycemia/glucotoxicity, lipotoxicity, autoimmunity, inflammation, adipokines, islet amyloid, incretins and insulin resistance) influence the function of pancreatic beta cells. Chronic hyperglycaemia may result in detrimental effects on insulin synthesis/secretion, cell survival and insulin sensitivity through multiple mechanisms: gradual loss of insulin gene expression and other beta-cell specific genes; chronic endoplasmic reticulum stress and oxidative stress; changes in mitochondrial number, morphology and function; disruption in calcium homeostasis. In the presence of hyperglycaemia, prolonged exposure to increased free fatty acids result in accumulation of toxic metabolites in the cells (“lipotoxicity”), finally causing decreased insulin gene expression and impairment of insulin secretion. The rest of the factors/mechanisms which impact on the course of the disease are also discusses in detail. The correct assessment of beta cell function requires a concomitant quantification of insulin secretion and insulin sensitivity, because the two variables are closely interrelated. In order to better understand the fundamental pathogenetic mechanisms that contribute to disease development in a certain individual with diabetes, additional markers could be used, apart from those that evaluate beta cell function. The aim of the paper was to overview the relevant mechanisms/factors that influence beta cell function and to discuss the available methods of its assessment. In addition, clinical considerations are made regarding the therapeutical options that have potential protective effects on beta cell function/mass by targeting various underlying factors and mechanisms with a role in disease progression.
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Affiliation(s)
- Simona Cernea
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş, Romania.
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24
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O'Grady MJ, Retterath AJ, Keenan DB, Kurtz N, Cantwell M, Spital G, Kremliovsky MN, Roy A, Davis EA, Jones TW, Ly TT. The use of an automated, portable glucose control system for overnight glucose control in adolescents and young adults with type 1 diabetes. Diabetes Care 2012; 35:2182-7. [PMID: 22875230 PMCID: PMC3476913 DOI: 10.2337/dc12-0761] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2012] [Accepted: 05/26/2012] [Indexed: 02/03/2023]
Abstract
OBJECTIVE A key milestone in progress towards providing an efficacious and safe closed-loop artificial pancreas system for outpatient use is the development of fully automated, portable devices with fault detection capabilities to ensure patient safety. The ability to remotely monitor the operation of the closed-loop system would facilitate future physician-supervised home studies. RESEARCH DESIGN AND METHODS This study was designed to investigate the efficacy and safety of a fully automated, portable, closed-loop system. The Medtronic Portable Glucose Control System (PGCS) consists of two subcutaneous glucose sensors, a control algorithm based on proportional-integral-derivative with insulin feedback operating from a BlackBerry Storm smartphone platform, Bluetooth radiofrequency translator, and an off-the-shelf Medtronic Paradigm Veo insulin pump. Participants with type 1 diabetes using insulin pump therapy underwent two consecutive nights of in-clinic, overnight, closed-loop control after a baseline open-loop assessment. RESULTS Eight participants attended for 16 overnight studies. The PGCS maintained mean overnight plasma glucose levels of 6.4 ± 1.7 mmol/L (115 ± 31 mg/dL). The proportion of time with venous plasma glucose <3.9, between 3.9 and 8 (70 and 144 mg/dL), and >8 mmol/L was 7, 78, and 15%, respectively. The proportion of time the sensor glucose values were maintained between 3.9 and 8 mmol/L was greater for closed-loop than open-loop (84.5 vs. 46.7%; P < 0.0001), and time spent <3.3 mmol/L was also reduced (0.9 vs. 3%; P < 0.0001). CONCLUSIONS These results suggest that the PGCS, an automated closed-loop device, is safe and effective in achieving overnight glucose control in patients with type 1 diabetes.
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Affiliation(s)
- Michael J. O'Grady
- Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
- Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia
| | - Adam J. Retterath
- Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia
| | | | | | | | | | | | | | - Elizabeth A. Davis
- Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
- Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia
- School of Paediatrics and Child Health, The University of Western Australia, Perth, Western Australia, Australia
| | - Timothy W. Jones
- Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
- Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia
- School of Paediatrics and Child Health, The University of Western Australia, Perth, Western Australia, Australia
| | - Trang T. Ly
- Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
- Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia
- School of Paediatrics and Child Health, The University of Western Australia, Perth, Western Australia, Australia
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Ruiz JL, Sherr JL, Cengiz E, Carria L, Roy A, Voskanyan G, Tamborlane WV, Weinzimer SA. Effect of insulin feedback on closed-loop glucose control: a crossover study. J Diabetes Sci Technol 2012; 6:1123-30. [PMID: 23063039 PMCID: PMC3570847 DOI: 10.1177/193229681200600517] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Closed-loop (CL) insulin delivery systems utilizing proportional-integral-derivative (PID) controllers have demonstrated susceptibility to late postprandial hypoglycemia because of delays between insulin delivery and blood glucose (BG) response. An insulin feedback (IFB) modification to the PID algorithm has been introduced to mitigate this risk. We examined the effect of IFB on CL BG control. METHODS Using the Medtronic ePID CL system, four subjects were studied for 24 h on PID control and 24 h during a separate admission with the IFB modification (PID + IFB). Target glucose was 120 mg/dl; meals were served at 8:00 AM, 1:00 PM, and 6:00 PM and were identical for both admissions. No premeal manual boluses were given. Reference BG excursions, defined as incremental glucose rise from premeal to peak, and postprandial BG area under the curve (AUC; 0-5 h) were compared. Results are reported as mean ± standard deviation. RESULTS The PID + IFB control resulted in higher mean BG levels compared with PID alone (153 ± 54 versus 133 ± 56 mg/dl; p < .0001). Postmeal BG excursions (114 ± 28 versus 114 ± 47 mg/dl) and AUCs (285 ± 102 versus 255 ± 129 mg/dl/h) were similar under both conditions. Total insulin delivery averaged 57 ± 20 U with PID versus 45 ± 13 U with PID + IFB (p = .18). Notably, eight hypoglycemic events (BG < 60 mg/dl) occurred during PID control versus none during PID + IFB. CONCLUSIONS Addition of IFB to the PID controller markedly reduced the occurrence of hypoglycemia without increasing meal-related glucose excursions. Higher average BG levels may be attributable to differences in the determination of system gain (Kp) in this study. The prevention of postprandial hypoglycemia suggests that the PID + IFB algorithm may allow for lower target glucose selection and improved overall glycemic control.
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Affiliation(s)
- Jessica L Ruiz
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8064, USA
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Poudel RR. Latent autoimmune diabetes of adults: From oral hypoglycemic agents to early insulin. Indian J Endocrinol Metab 2012; 16 Suppl 1:S41-S46. [PMID: 22701843 PMCID: PMC3354922 DOI: 10.4103/2230-8210.94257] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Approximately 10% of phenotypic type 2 diabetics have islet autoantibodies and are referred to as having latent autoimmune diabetes of adults (LADA), and they land on early sulfonylurea failure and require insulin. Diagnosing LADA has treatment implications because of high risk of progression to insulin dependency. But often there is delay in insulin therapy, as there are no recommendations for islet antibody testing in adult-onset diabetes currently. LADA clinical risk score can identify adults at high risk who may benefit from antibody testing. The optimal treatment of LADA is not established. Early insulin therapy helps to achieve good metabolic control and better long-term outcomes by preserving β-cells and endogenous C-peptide secretion. Sulfonylureas are better avoided as they exhaust β-cells; glitazones and exenatide have favorable outcomes, whereas metformin needs to be used with caution. Understanding LADA will also bring new windows in managing type 1 diabetes. Information acquisition was done by reviewing the medical literature published since 1987, with particular attention to the natural history, genetic factors, and treatment of LADA.
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Affiliation(s)
- Resham R. Poudel
- Department of Internal Medicine, Institute of Medicine, Kathmandu, Nepal
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27
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Halperin F, Lopez X, Manning R, Kahn CR, Kulkarni RN, Goldfine AB. Insulin augmentation of glucose-stimulated insulin secretion is impaired in insulin-resistant humans. Diabetes 2012; 61:301-9. [PMID: 22275085 PMCID: PMC3266415 DOI: 10.2337/db11-1067] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin's effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, and 8 healthy control subjects were studied on two occasions. The insulin secretory response was assessed by the administration of dextrose for 80 min following a 4-h clamp with either saline infusion (sham) or an isoglycemic-hyperinsulinemic clamp using B28-Asp-insulin (which can be distinguished immunologically from endogenous insulin) that raised insulin concentrations to high physiologic concentrations. Pre-exposure to insulin augmented GSIS in healthy persons. This effect was attenuated in insulin-resistant cohorts, both those with IGT and those with T2D. Insulin potentiates glucose-stimulated insulin secretion in insulin-resistant subjects to a lesser degree than in normal subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo with therapeutic implications.
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Affiliation(s)
- Florencia Halperin
- Joslin Diabetes Center, Boston, Massachusetts
- Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Ximena Lopez
- Joslin Diabetes Center, Boston, Massachusetts
- Brigham and Women’s Hospital, Boston, Massachusetts
- University of Texas Southwestern Medical Center, Dallas, Texas
| | | | - C. Ronald Kahn
- Joslin Diabetes Center, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Rohit N. Kulkarni
- Joslin Diabetes Center, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Allison B. Goldfine
- Joslin Diabetes Center, Boston, Massachusetts
- Brigham and Women’s Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Corresponding author: Allison B. Goldfine,
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Steil GM, Palerm CC, Kurtz N, Voskanyan G, Roy A, Paz S, Kandeel FR. The effect of insulin feedback on closed loop glucose control. J Clin Endocrinol Metab 2011; 96:1402-8. [PMID: 21367930 PMCID: PMC3085208 DOI: 10.1210/jc.2010-2578] [Citation(s) in RCA: 162] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
CONTEXT Initial studies of closed-loop proportional integral derivative control in individuals with type 1 diabetes showed good overnight performance, but with breakfast meal being the hardest to control and requiring supplemental carbohydrate to prevent hypoglycemia. OBJECTIVE The aim of this study was to assess the ability of insulin feedback to improve the breakfast-meal profile. DESIGN AND SETTING We performed a single center study with closed-loop control over approximately 30 h at an inpatient clinical research facility. PATIENTS Eight adult subjects with previously diagnosed type 1 diabetes participated. INTERVENTION Subjects received closed-loop insulin delivery with supplemental carbohydrate as needed. MAIN OUTCOME MEASURES Outcome measures were plasma insulin concentration, model-predicted plasma insulin concentration, 2-h postprandial and 3- to 4-h glucose rate-of-change following breakfast after 1 d of closed-loop control, and the need for supplemental carbohydrate in response to nadir hypoglycemia. RESULTS Plasma insulin levels during closed loop were well correlated with model predictions (R = 0.86). Fasting glucose after 1 d of closed loop was not different from nighttime target (118 ± 9 vs. 110 mg/dl; P = 0.38). Two-hour postbreakfast glucose was 132 ± 16 mg/dl with stable values 3-4 h after the meal (0.03792 ± 0.0884 mg/dl · min, not different from 0; P = 0.68) and at target (97 ± 6 mg/dl, not different from 90; P = 0.28). Three subjects required supplemental carbohydrates after breakfast on d 2 of closed loop. CONCLUSIONS/INTERPRETATION Insulin feedback can be implemented using a model estimate of concentration. Proportional integral derivative control with insulin feedback can achieve a desired breakfast response but still requires supplemental carbohydrate to be delivered in some instances. Studies assessing more optimal control configurations and safeguards need to be conducted.
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Affiliation(s)
- Garry M Steil
- Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
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Pretty CG, Docherty PD, Lin J, Pfeifer L, Jamaludin U, Shaw GM, Le Compte AJ, Chase JG. Endogenous insulin secretion and suppression during and after sepsis in critically ill patients: implications for tight glycemic control protocols. Crit Care 2011. [PMCID: PMC3068318 DOI: 10.1186/cc9809] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Anderwald C, Tura A, Grassi A, Krebs M, Szendroedi J, Roden M, Bischof MG, Luger A, Pacini G. Insulin infusion during normoglycemia modulates insulin secretion according to whole-body insulin sensitivity. Diabetes Care 2011; 34:437-41. [PMID: 21216852 PMCID: PMC3024363 DOI: 10.2337/dc10-1137] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Glucose is the major stimulus for insulin release. Time course and amount of insulin secreted after glycemic stimulus are different between type 2 diabetes mellitus (T2DM) patients and healthy subjects. In rodents, it was demonstrated that insulin can modulate its own release. Previous studies in humans yielded contrasting results: Insulin was shown to have an enhancing effect, no effect, or a suppressive effect on its own secretion. Thus, we aimed to evaluate short-term effects of human insulin infusion on insulin secretion during normoglycemia in healthy humans and T2DM subjects of both sex. RESEARCH DESIGN AND METHODS Hyperinsulinemic-isoglycemic clamps with whole-body insulin-sensitivity (M) and C-peptide measurements for insulin secretion modeling were performed in 65 insulin-sensitive (IS) subjects (45 ± 1 year, BMI: 24.8 ± 0.5 kg/m(2)), 17 insulin-resistant (IR) subjects (46 ± 2 years, 28.1 ± 1.3 kg/m(2)), and 20 T2DM patients (56 ± 2 years, 28.0 ± 0.8 kg/m(2); HbA(1c) = 6.7 ± 0.1%). RESULTS IS subjects (M = 8.8 ± 0.3 mg · min(-1) · kg(-1)) had higher (P < 0.00001) whole-body insulin sensitivity than IR subjects (M = 4.0 ± 0.2) and T2DM patients (M = 4.3 ± 0.5). Insulin secretion profiles during clamp were different (P < 0.00001) among the groups, increasing in IS subjects (slope: 0.56 ± 0.11 pmol/min(2)) but declining in IR (-0.41 ± 0.14) and T2DM (-0.87 ± 0.12, P < 0.00002 IR and T2DM vs. IS) subjects. Insulin secretion changes during clamp directly correlated with M (r = 0.6, P < 0.00001). CONCLUSIONS Insulin release during normoglycemia can be modulated by exogenous insulin infusion and directly depends on whole-body insulin sensitivity. Thus, in highly sensitive subjects, insulin increases its own secretion. On the other hand, a suppressive effect of insulin on its own secretion occurs in IR and T2DM subjects.
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Affiliation(s)
- Christian Anderwald
- Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, Italy.
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Insulin/phosphoinositide 3-kinase pathway accelerates the glucose-induced first-phase insulin secretion through TrpV2 recruitment in pancreatic β-cells. Biochem J 2010; 432:375-86. [PMID: 20854263 DOI: 10.1042/bj20100864] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Functional insulin receptor and its downstream effector PI3K (phosphoinositide 3-kinase) have been identified in pancreatic β-cells, but their involvement in the regulation of insulin secretion from β-cells remains unclear. In the present study, we investigated the physiological role of insulin and PI3K in glucose-induced biphasic insulin exocytosis in primary cultured β-cells and insulinoma Min6 cells using total internal reflection fluorescent microscopy. The pretreatment of β-cells with insulin induced the rapid increase in intracellular Ca2+ levels and accelerated the exocytotic response without affecting the second-phase insulin secretion. The inhibition of PI3K not only abolished the insulin-induced rapid development of the exocytotic response, but also potentiated the second-phase insulin secretion. The rapid development of Ca2+ and accelerated exocytotic response induced by insulin were accompanied by the translocation of the Ca2+-permeable channel TrpV2 (transient receptor potential V2) in a PI3K-dependent manner. Inhibition of TrpV2 by the selective blocker tranilast, or the expression of shRNA (short-hairpin RNA) against TrpV2 suppressed the effect of insulin in the first phase, but the second phase was not affected. Thus our results demonstrate that insulin treatment induced the acceleration of the exocytotic response during the glucose-induced first-phase response by the insertion of TrpV2 into the plasma membrane in a PI3K-dependent manner.
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Rowe PA, Campbell-Thompson ML, Schatz DA, Atkinson MA. The pancreas in human type 1 diabetes. Semin Immunopathol 2010; 33:29-43. [PMID: 20495921 PMCID: PMC3022158 DOI: 10.1007/s00281-010-0208-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Accepted: 04/13/2010] [Indexed: 11/24/2022]
Abstract
Type 1 diabetes (T1D) is considered a disorder whose pathogenesis is autoimmune in origin, a notion drawn in large part from studies of human pancreata performed as far back as the 1960s. While studies of the genetics, epidemiology, and peripheral immunity in T1D have been subject to widespread analysis over the ensuing decades, efforts to understand the disorder through analysis of human pancreata have been far more limited. We have reviewed the published literature pertaining to the pathology of the human pancreas throughout all stages in the natural history of T1D. This effort uncovered a series of findings that challenge many dogmas ascribed to T1D and revealed data suggesting the marked heterogeneity in terms of its pathology. An improved understanding and appreciation for pancreatic pathology in T1D could lead to improved disease classification, an understanding of why the disorder occurs, and better therapies for disease prevention and management.
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Affiliation(s)
- Patrick A Rowe
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA
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Monte SV, Schentag JJ, Adelman MH, Paladino JA. Glucose supply and insulin demand dynamics of antidiabetic agents. J Diabetes Sci Technol 2010; 4:365-81. [PMID: 20307399 PMCID: PMC2864174 DOI: 10.1177/193229681000400219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND For microvascular outcomes, there is compelling historical and contemporary evidence for intensive blood glucose reduction in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). There is also strong evidence to support macrovascular benefit with intensive blood glucose reduction in T1DM. Similar evidence remains elusive for T2DM. Because cardiovascular outcome trials utilizing conventional algorithms to attain intensive blood glucose reduction have not demonstrated superiority to less aggressive blood glucose reduction (Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; and Veterans Affairs Diabetes Trial), it should be considered that the means by which the blood glucose is reduced may be as important as the actual blood glucose. METHODS By identifying quantitative differences between antidiabetic agents on carbohydrate exposure (CE), hepatic glucose uptake (HGU), hepatic gluconeogenesis (GNG), insulin resistance (IR), peripheral glucose uptake (PGU), and peripheral insulin exposure (PIE), we created a pharmacokinetic/pharmacodynamic model to characterize the effect of the agents on the glucose supply and insulin demand dynamic. Glucose supply was defined as the cumulative percentage decrease in CE, increase in HGU, decrease in GNG, and decrease in IR, while insulin demand was defined as the cumulative percentage increase in PIE and PGU. With the glucose supply and insulin demand effects of each antidiabetic agent summated, the glucose supply (numerator) was divided by the insulin demand (denominator) to create a value representative of the glucose supply and insulin demand dynamic (SD ratio). RESULTS Alpha-glucosidase inhibitors (1.25), metformin (2.20), and thiazolidinediones (TZDs; 1.25-1.32) demonstrate a greater effect on glucose supply (SD ratio >1), while secretagogues (0.69-0.81), basal insulins (0.77-0.79), and bolus insulins (0.62-0.67) demonstrate a greater effect on insulin demand (SD ratio <1). CONCLUSION Alpha-glucosidase inhibitors, metformin, and TZDs demonstrate a greater effect on glucose supply, while secretagogues, basal insulin, and bolus insulin demonstrate a greater effect on insulin demand. Because T2DM cardiovascular outcome trials have not demonstrated macrovascular benefit with more aggressive blood glucose reduction when using conventional algorithms that predominantly focus on insulin demand, it would appear logical to consider a model that incorporates both the extent of blood glucose lowering (hemoglobin A1c) and the means by which the blood glucose was reduced (SD ratio) when considering macrovascular outcomes.
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Cernea S, Buzzetti R, Pozzilli P. Beta-cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care 2009; 32 Suppl 2:S246-52. [PMID: 19875559 PMCID: PMC2811444 DOI: 10.2337/dc09-s317] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Simona Cernea
- Department of Endocrinology & Diabetes, University Campus Bio-Medico, Rome, Italy
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35
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Haugaard SB, Andersen O, Hansen BR, Andersen UB, Vølund A, Iversen J, Nielsen JO, Madsbad S. In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance. Metabolism 2005; 54:171-9. [PMID: 15690310 DOI: 10.1016/j.metabol.2004.08.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic, human immunodeficiency virus (HIV)-infected patients with and without lipodystrophy. We studied 18 HIV-infected patients with lipodystrophy (LIPO) on antiretroviral therapy and 25 HIV-infected patients without lipodystrophy (controls) of whom 18 were on antiretroviral therapy and 7 were not. Posthepatic insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU.m-2 .min-1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting insulin (130%, P < .001), impaired insulin sensitivity index (M value, -29%, P < .001), and reduced MCRi (-17%, P < .01). Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P < .02 and r = -0.68, P < .002) and positively with M value (r = 0.63, P < .01 and r = 0.65, P < .004). In controls, MCRi correlated inversely with fasting insulin (r = -0.47, P < .02) and positively with M value (r = 0.57, P < .004); however, the correlations between HEXi and these parameters were insignificant (P > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy.
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Affiliation(s)
- Steen B Haugaard
- Department of Infectious Diseases, Hvidovre University Hospital, DK 2650 Hvidovre, Copenhagen, Denmark.
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Haugaard SB, Andersen O, Storgaard H, Dela F, Holst JJ, Iversen J, Nielsen JO, Madsbad S. Insulin secretion in lipodystrophic HIV-infected patients is associated with high levels of nonglucose secretagogues and insulin resistance of beta-cells. Am J Physiol Endocrinol Metab 2004; 287:E677-85. [PMID: 15149949 DOI: 10.1152/ajpendo.00009.2004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We examined whether plasma concentrations of nonglucose insulin secretagogues are associated with prehepatic insulin secretion rates (ISR) in nondiabetic, insulin-resistant, human immunodeficiency virus (HIV)-infected, lipodystrophic patients (LIPO). Additionally, the negative feedback of insulin on ISR was evaluated. ISR were estimated by deconvolution of plasma C-peptide concentrations during fasting (basal) and during the last 30 min of a 120-min euglycemic insulin clamp (40 mU.m(-2).min(-1)). Eighteen normoglycemic LIPO were compared with 25 normoglycemic HIV-infected patients without lipodystrophy (controls). Thirty minutes before start of the clamp, a bolus of glucose was injected intravenously to stimulate endogenous insulin secretion. Insulin sensitivity index (SiRd) was estimated from glucose tracer analysis. LIPO displayed increased basal ISR (69%), clamp ISR (114%), basal insulin (130%), and clamp insulin (32%), all P < or = 0.001, whereas SiRd was decreased (57%, P < 0.001). In LIPO, ISRbasal correlated significantly with basal insulin, alanine, and glucagon (all r > 0.65, P < 0.01), but not with glucose. In control subjects, ISR(basal) correlated significantly with insulin, glucagon, and glucose (all r > 0.41, P < 0.05), but not with alanine. In LIPO, ISRclamp correlated significantly with clamp free fatty acids (FFA), alanine, triglyceride, and glucagon (all r > 0.51, P < 0.05). In control subjects, ISRclamp correlated with clamp triglyceride (r = 0.45, P < 0.05). Paradoxically, in LIPO, ISRclamp correlated positively with clamp insulin (r = 0.68, P < 0.01), which suggests an absent negative feedback of insulin on ISR. Our data support evidence that lipodystrophic, nondiabetic, HIV-infected patients exhibit increased ISR, which can be partially explained by an impaired negative feedback of insulin on beta-cells and an increased stimulation of ISR by FFA, alanine, triglyceride, and glucagon.
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Affiliation(s)
- Steen B Haugaard
- Department of Infectious Diseases, Hvidovre University Hospital, DK 2650, Copenhagen, Denmark.
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Zawalich WS, Tesz GJ, Zawalich KC. Are 5-hydroxytryptamine-preloaded beta-cells an appropriate physiologic model system for establishing that insulin stimulates insulin secretion? J Biol Chem 2001; 276:37120-3. [PMID: 11479304 DOI: 10.1074/jbc.m105008200] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The release and oxidation of 5-hydroxytryptamine from 5-hydroxytryptamine-preloaded beta-cells has been used as a surrogate marker for insulin secretion. Findings made using this methodology have been used to support the concept that insulin stimulates its own release. In the present studies, the effects of 5-hydroxytryptamine on stimulated insulin secretion from isolated perifused rat islets was determined. When added together with stimulatory glucose, 5-hydroxytryptamine (0.5 mm) significantly reduced both phases of 8 mm glucose-induced secretion and reduced the first phase of 15 mm glucose-induced release by 60% without any effect on sustained insulin release rates. Preloading of beta-cells with 0.5 mm 5-hydroxytryptamine for 3 h resulted in a more severe impairment of 15 mm glucose-induced secretion. First and second phase release rates were reduced by 70 and 55%, respectively. In addition, this pretreatment protocol also abolished 200 microm tolbutamide-induced insulin secretion from perifused islets. These findings confirm that 5-hydroxytryptamine is a powerful inhibitor of stimulated insulin secretion. The responses of 5-hydroxytryptamine-preloaded beta-cells may not accurately reflect the biochemical events occurring during the physiologic regulation of insulin secretion. The suggestion that insulin stimulates its own secretion based exclusively on amperometric measurements should be reconsidered.
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Affiliation(s)
- W S Zawalich
- Yale University School of Nursing, New Haven, Connecticut 06536-0740, USA.
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Paraskevas S, Aikin R, Maysinger D, Lakey JR, Cavanagh TJ, Agapitos D, Wang R, Rosenberg L. Modulation of JNK and p38 stress activated protein kinases in isolated islets of Langerhans: insulin as an autocrine survival signal. Ann Surg 2001; 233:124-33. [PMID: 11141234 PMCID: PMC1421175 DOI: 10.1097/00000658-200101000-00018] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The objective of this study was to determine the effects of islet isolation and cytokine exposure on e-JUN NH2 terminal kinase (JNK) and p38 activation and whether insulin or the p38 inhibitor PD169316 could modify the response. SUMMARY BACKGROUND DATA Islet transplantation exposes the cells of the graft to a variety of stressful stimuli that could promote beta-cell death and lead to graft failure. METHODS Islets from canine (n = 12) and cadaveric human (n = 6) pancreata were isolated and purified. Islets were cultured in CMRL 1066 with and without 100 ng/ml insulin. The response to cytokine stimulation with tumor necrosis factor (TNF)alpha and IL-1 beta and the p38 inhibitor PD169316 was also observed. Islet lysates were analyzed by Western blotting for total and phosphorylated JNK and p38 content. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL) assay and by a specific cell death enzyme-linked immunosorbant assay (ELISA). RESULTS In unstimulated islets, JNK activity was highest immediately following isolation, declining over 3 days to a low baseline level. The activity of p38 was lowest immediately after isolation, increasing progressively with time. The addition of insulin resulted in a more rapid decline in JNK activity, as opposed to p38, which showed no decrease in phosphorylation in response to insulin. In the cytokine stimulation studies, IL-1 beta stimulated p38 activation in a dose dependent manner, while JNK was relatively unaffected. PD169316 (100 microg/ml) was able to inhibit p38 activation in response to the isolation procedure as well as cytokine stimulation. Apoptotic activity was highest 24 hours after isolation, and was significantly reduced when islets were maintained in insulin-supplemented medium. CONCLUSIONS Inhibition of the stress-activated protein kinase (SAPK) pathways may be important for the maintenance of islet cell survival following islet isolation for transplantation. This study supports an autocrine role of insulin in this process.
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Affiliation(s)
- S Paraskevas
- Departments of Surgery, the Montreal General Hospital Research Institute and McGill University, Montreal, Quebec, Canada
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39
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van der Merwe MT, Crowther NJ, Schlaphoff GP, Gray IP, Joffe BI, Lönnroth PN. Evidence for insulin resistance in black women from South Africa. Int J Obes (Lond) 2000; 24:1340-6. [PMID: 11093297 DOI: 10.1038/sj.ijo.0801416] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The rate of glucose disposal was determined in 10 black and 10 white obese nondiabetic urban women from South Africa to assess insulin resistance. DESIGN AND METHODS Euglycemic hyperinsulinemic clamp and body composition analysis. RESULTS Age, body mass index (BMI), anthropometric measurements and body composition were similar in both groups of women. A five-level computed tomography (CT) scan showed a similar mean subcutaneous fat mass in both groups of women (black obese women 555 +/- 9.0 vs white obese women 532 +/- 6.0 cm2), but less visceral fat in black obese women (90 +/- 3.0 vs 121 +/- 3.1 cm2; P< 0.05). Black obese women had higher fasting free fatty acid (997 +/- 69 vs 678 +/- 93 micromol/l; P < 0.05) and lactate concentrations (1,462 +/- 94 vs 1,038 +/- 39 micromol/l; P < 0.05), but lower fasting insulin levels (87 +/- 12 vs 155 +/- 9 pmol/l; P < 0.001). Black obese women also had a more favorable HDL: total cholesterol ratio (30.5% vs 23.0%; P< 0.04). The mean glucose disposal rate (M) and disposal expressed as glucose sensitivity index (M/I) were reduced in the black obese women vs white obese women (M: 7.1 +/- 0.8 vs 13.7 +/- 1.0 mmol/kg min(-1) x 100; P< 0.01, and M/I: 0.12 +/- 0.01 vs 0.24 +/- 0.02 mmol/kg x min(-1)/pmol/1 x 1,000; P < 0.01). Only black obese women showed a significant decrease in C-peptide levels during the clamp (2.9 +/- 0.22 vs 1.2 +/- 0.12 nmol/l; P<0.001). During the euglycemic period, the black obese women had higher lactate levels at all time points, but only the white obese women had increased lactate levels (918 +/- 66 to 1,300 +/- 53 micromol/l; P< 0.05). CONCLUSION Black obese women demonstrate a higher degree of insulin resistance, despite less visceral fat and a higher HDL: total-cholesterol ratio. In addition, endogenous beta-cell secretory function in black obese women appears to be more sensitive to the suppressive effect of exogenous insulin administration. The significant increase in lactate levels in white obese women confirms that they are more insulin sensitive.
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Affiliation(s)
- M T van der Merwe
- Carbohydrate and Lipid Metabolism Research Group, University of Witwatersrand Medical School, Johannesburg, South Africa.
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40
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Rosmalen JG, Homo-Delarche F, Durant S, Kap M, Leenen PJ, Drexhage HA. Islet abnormalities associated with an early influx of dendritic cells and macrophages in NOD and NODscid mice. J Transl Med 2000; 80:769-77. [PMID: 10830787 DOI: 10.1038/labinvest.3780080] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
In the nonobese diabetic (NOD) mouse model for type 1 diabetes, the inflammatory infiltration of islets starts with an influx of dendritic cells (DC) and macrophages (Mphi) at approximately 4 weeks of age. Around this time, NOD mice show endocrine abnormalities, indicated by a transient hyperinsulinemia that lasts until 8 weeks of age. Subsequently, they develop abnormally large islets of Langerhans, here designated as "mega-islets." NODscid mice, which lack functional lymphocytes, also exhibit transient hyperinsulinemia, but to a lesser extent. First, to determine the role of lymphocytes in the morphological islet abnormalities, we compared 6-week-old (prediabetic) NOD and NODscid females regarding mega-islet development and accumulation of antigen-presenting cells (APC), particularly CD11c+ DC and ERMP23+ Mphi. In NODscid mice, early APC infiltration and mega-islets were present, but less marked compared with NOD mice, thus suggesting a role of lymphocytes in mega-islet formation. In both NOD and NODscid mice, the APC infiltration was predominantly found around the mega-islets, suggesting a relationship between both parameters. Second, to analyze the role of beta-cell hyperactivity in mega-islet formation, we studied the effect of short-term prophylactic insulin treatment on these parameters. Prophylactic insulin treatment decreased the percentages of mega-islets in both NOD and NODscid mice, indicating that beta-cell hyperactivity is also involved in mega-islet formation. In conclusion, mega-islet formation in mice with the NOD genetic background takes place under the influence of both beta-cell hyperactivity and leukocytes.
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Affiliation(s)
- J G Rosmalen
- Department of Immunology, Erasmus University, Rotterdam, The Netherlands.
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41
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Simon T, Marcus A, Royce CL, Chao F, Mendez T, Fink AS. Hyperglycemia alone does not inhibit secretin-induced pancreatic bicarbonate secretion. Pancreas 2000; 20:277-81. [PMID: 10766454 DOI: 10.1097/00006676-200004000-00009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Administration of exogenous insulin (INS) inhibits secretin-stimulated pancreatic bicarbonate (HCO3) output via a dose-dependent, neurally mediated mechanism. To determine whether this effect was due to systemic hyperinsulinemia or to reduced endogenous insulin production, we examined the effect of hyperglycemia on secretin-stimulated pancreatic secretion. Chronic pancreatic fistulae were created in six dogs. After 30 minutes of equilibration, a computer-assisted hyperglycemic clamp protocol was used to maintain glucose (GLU) levels 100 or 150 mg/dL above basal in clamp animals; control animals received volume- and rate-matched infusions of 0.9% saline. One hour after beginning the clamp period, intravenous secretin dose-response (16-125 ng/kg/h) was begun, doubling the dose every half hour. Unstimulated (0-30 minutes) HCO3, GLU, and INS levels did not differ between groups. INS and GLU levels in clamp animals were significantly elevated during clamp (30-90 minutes) and stimulated (90-210 minutes) periods. For the same periods, HCO3 secretion was not significantly changed despite profound hyperinsulinemia. We conclude that systemic hyperinsulinemia alone does not inhibit secretin-stimulated HCO3 output. Since exogenous INS exerts feedback regulation on the pancreas, we propose that suppression of endogenous INS secretion mediates the previously reported inhibitory response.
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Affiliation(s)
- T Simon
- Atlanta Veteran Affairs Medical Center, and Department of Surgery, Emory University, Georgia 30033, USA
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42
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Kim CH, Park JY, Shong YK, Hong SK, Kim GS, Lee KU. Suppression of endogenous insulin secretion by exogenous insulin in patients with insulinoma. Clin Endocrinol (Oxf) 2000; 52:87-92. [PMID: 10651758 DOI: 10.1046/j.1365-2265.2000.00869.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Previous studies have demonstrated that endogenous insulin secretion is not suppressed by exogenous insulin in patients with insulinoma. In this study we examined whether insulin secretion in insulinoma patients is suppressed by exogenous insulin during hypoglycaemia. SUBJECTS AND METHODS Sixteen insulinoma patients (5 men and 11 women) and 10 normal subjects were studied. Hyperinsulinaemic glucose clamp studies were performed at both euglycaemia (4.5 mmol/l glucose) and hypoglycaemia (2.5 mmol/l glucose). RESULTS In normal subjects, plasma C-peptide levels were suppressed by 66% during the euglycaemic hyperinsulinaemic clamps (P < 0.01). In contrast, in insulinoma patients, plasma C-peptide levels increased by 25% during the clamps (P < 0.05). In the hypoglycaemic hyperinsulinaemic clamps, plasma C-peptide levels were nearly completely (91%) suppressed in normal subjects and partially (39%) suppressed in patients with insulinoma (P < 0.01). The decrease in C-peptide levels during the hypoglycaemic clamps was > 30% in 12 (75%) of 16 insulinoma patients and > 50% in 8 (50%) patients. CONCLUSIONS This study demonstrated that in patients with insulinoma, insulin secretion was not suppressed by exogenous insulin during euglycaemia but was suppressed during hypoglycaemia, although the degree of suppression was less than that in normal subjects. Our results suggest that the feedback regulation of insulin secretion by exogenous insulin is partially retained in patients with insulinoma.
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Affiliation(s)
- C H Kim
- Department of Internal Medicine, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea
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Aspinwall CA, Lakey JR, Kennedy RT. Insulin-stimulated insulin secretion in single pancreatic beta cells. J Biol Chem 1999; 274:6360-5. [PMID: 10037726 DOI: 10.1074/jbc.274.10.6360] [Citation(s) in RCA: 161] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Functional insulin receptors are known to occur in pancreatic beta cells; however, except for a positive feedback on insulin synthesis, their physiological effects are unknown. Amperometric measurements at single, primary pancreatic beta cells reveal that application of exogenous insulin in the presence or absence of nonstimulatory concentrations of glucose evokes exocytosis mediated by the beta cell insulin receptor. Insulin also elicits increases in intracellular Ca2+ concentration in beta cells but has minimal effects on membrane potential. Conditions where the insulin receptor is blocked or cell surface concentration of free insulin is reduced during exocytosis diminishes secretion induced by other secretagogues, providing evidence for direct autocrine action of insulin upon secretion from the same cell. These results indicate that the beta cell insulin receptor can mediate positive feedback for insulin secretion. The presence of a positive feedback mechanism for insulin secretion mediated by the insulin receptor provides a potential link between impaired insulin secretion and insulin resistance.
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Affiliation(s)
- C A Aspinwall
- Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, USA
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44
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Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999; 96:329-39. [PMID: 10025399 DOI: 10.1016/s0092-8674(00)80546-2] [Citation(s) in RCA: 857] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Dysfunction of the pancreatic beta cell is an important defect in the pathogenesis of type 2 diabetes, although its exact relationship to the insulin resistance is unclear. To determine whether insulin signaling has a functional role in the beta cell we have used the Cre-loxP system to specifically inactivate the insulin receptor gene in the beta cells. The resultant mice exhibit a selective loss of insulin secretion in response to glucose and a progressive impairment of glucose tolerance. These data indicate an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggest that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type 2 diabetes.
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Affiliation(s)
- R N Kulkarni
- Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
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45
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Lienhardt A, Rakotoambinina B, Colomb V, Souissi S, Sadoun E, Goulet O, Robert JJ, Ricour C. Insulin secretion and sensitivity in children on cyclic total parenteral nutrition. JPEN J Parenter Enteral Nutr 1998; 22:382-6. [PMID: 9829612 DOI: 10.1177/0148607198022006382] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Some children receiving total parenteral nutrition (TPN) have abnormal glucose tolerance. METHODS Insulin secretion and sensitivity were studied in 12 patients, aged 5.7 to 19.4 years, receiving cyclic nocturnal TPN. Insulin secretion was measured during an IV glucose tolerance test (IVGTT; 0.5 g/kg) followed by a hyperglycemic clamp (plasma glucose at 10 mmol/L). Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp (insulin infusion = 1 mU/kg/min). RESULTS Patients with normal glucose tolerance receiving TPN had an insulin response to IVGTT similar to that of normal children of the same age. Insulin levels of TPN patients were higher than those in healthy young adults during the hyperglycemic clamp. Whole body glucose disposal was greater in younger than in older children (range, 7.1 to 25.2 mg/kg/min), and this inverse correlation with age was statistically significant (p < .01). Two patients with abnormal glucose tolerance showed a decreased capacity to release insulin, whereas insulin sensitivity was unchanged in one of these two patients. Two patients treated with prednisone or octreotide had insulin levels similar to those of normal TPN children. CONCLUSIONS The insulin response to sustained hyperglycemia was stronger in children with normal glucose tolerance on cyclic TPN. Patients with a limited capacity to release insulin, either constitutional or acquired, may not be able to produce enough insulin in these conditions and develop glucose intolerance during TPN. Insulin sensitivity was not a key factor in the alteration of glucose tolerance.
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Affiliation(s)
- A Lienhardt
- Department of Pediatric and Adolescent Diabetes, INSERM U30, Hôpital Necker-Enfants Malades, Paris, France
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46
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Klimes I, Mitková A, Gasperíková D, Ukropec J, Líska B, Bohov P, Stanek J, Seböková E. The effect of the new oral hypoglycemic agent A-4166 on glucose turnover in the high fat diet-induced and/or in the hereditary insulin resistance of rats. Arch Physiol Biochem 1998; 106:325-32. [PMID: 10417860 DOI: 10.1076/apab.106.4.325.4370] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.
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Affiliation(s)
- I Klimes
- Diabetes and Nutrition Research Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
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47
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Xu G, Howland J, Rothenberg PL. Insulin and secretagogues differentially regulate fluid-phase pinocytosis in insulin-secreting beta-cells. Biochem J 1996; 318 ( Pt 2):623-9. [PMID: 8809056 PMCID: PMC1217666 DOI: 10.1042/bj3180623] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The physiological role of the beta-cell insulin receptor is unknown. To evaluate a candidate function, the insulin regulation of fluid-phase pinocytosis was investigated in a clonal insulinoma cell line (beta TC6-F7) and, for comparison, also in Chinese hamster ovary cells transfected with the human insulin receptor (CHO-T cells). In CHO-T cells, the net rate of fluid-phase pinocytosis was rapidly increased 3-4-fold over the basal rate by 100 nM insulin, with half-maximal stimulation at 2 nM insulin, as assayed by cellular uptake of horseradish peroxidase from the medium. Wortmannin, an inhibitor of phosphatidylinositol (PI)-3-kinase, blocked insulin-stimulated pinocytosis with an IC50 of 7.5 nM without affecting the basal rate of pinocytosis. In insulin-secreting beta TC6-F7 cells, the secretagogues glucose and carbachol (at maximally effective concentrations of 15 mM and 0.5 mM respectively) augmented fluid-phase pinocytosis 1.65-fold over the basal rate. Wortmannin also inhibited secretagogue-stimulated pinocytosis in these beta-cells with an IC50 of 7 nM but did not affect the basal rate of pinocytosis measured in the absence of secretagogues. Wortmannin did not influence either basal or secretagogue-induced insulin secretion. Although these beta TC6-F7 cells have cell-surface insulin receptors, adding exogenous insulin or insulin-like growth factor 1 did not affect their rate of fluid-phase pinocytosis, either in the absence or presence of secretagogues. From these observations, we conclude that: (1) in both insulin-secreting beta-cells and in conventional, insulin-responsive CHO-T cells, a common, wortmannin-sensitive reaction, which probably involves PI-3-kinase, regulates fluid-phase pinocytosis; (2) the insulin-receptor signal transduction pathway is dissociated from the regulation of fluid-phase pinocytosis in the insulin-secreting beta-cell line we studied; and (3) the enhancement of fluid-phase pinocytosis associated with secretagogue-induced insulin release in beta TC6-F7 cells is not attributable to autocrine activation of beta-cell surface insulin receptors.
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Affiliation(s)
- G Xu
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, U.S.A
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Marchetti P, Scharp DW, McLear M, Finke EH, Olack B, Swanson C, Giannarelli R, Navalesi R, Lacy PE. Insulin inhibits its own secretion from isolated, perifused human pancreatic islets. Acta Diabetol 1995; 32:75-7. [PMID: 7579537 DOI: 10.1007/bf00569560] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
It is still a controversial question whether insulin suppresses its own secretion. We prepared pure human islets from three pancreases by collagenase digestion and density gradient purification. Aliquots of 200 islet equivalents (IE, 150-microns sized-islets) were sequentially perifused at 37 degrees C with 3.3 mmol/l glucose (3.3G, 40 min), 16.7 mmol/l glucose (16.7G, 30 min) and again 3.3G (30 min) after 24 h, 37 degrees C culture in CMRL 1066 medium with or without the addition of either 200 or 400 microU/ml human insulin in the incubation medium (6 replicates each). Insulin secretion was assessed by C-peptide (Cp) measurement in the perifusate. Without added insulin (C) and with 200 (Ins200) or 400 (Ins400) microU/ml added insulin, basal Cp release was 0.12 +/- 0.03, 0.14 +/- 0.02 and 0.14 +/- 0.04 ng/ml, respectively. At 16.7G, the first-phase secretion peak (expressed as Cp value) was significantly lower with Ins200 (0.47 +/- 0.13 ng/ml, P < 0.02) and Ins400 (0.68 +/- 0.15 ng/ml, P < 0.05) than C (0.83 +/- 0.15 ng/ml). The second-phase secretion peak was also significantly (P < 0.05) reduced with added insulin (Ins200: 0.47 +/- 0.08 ng/ml; Ins400: 0.45 +/- 0.07 ng/ml) than in its absence (C: 0.65 +/- 0.09 ng/ml). Accordingly, total Cp secretion was lower with Ins200 (10.6 +/- 2.3 ng/ml, P = 0.03) and Ins400 (11.8 +/- 2.3 ng/ml) than with C (16.0 +/- 2.2 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- P Marchetti
- Department of Metabolic Diseases, University of Pisa, Italy
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49
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Eliasson B, Björnsson E, Urbanavicius V, Andersson H, Fowelin J, Attvall S, Abrahamsson H, Smith U. Hyperinsulinaemia impairs gastrointestinal motility and slows carbohydrate absorption. Diabetologia 1995; 38:79-85. [PMID: 7744232 DOI: 10.1007/bf02369356] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Experimental euglycaemic hyperinsulinaemia (insulin levels 46 +/- 4 mU/l) impaired the post-absorptive gastrointestinal motility in healthy individuals; the effect being particularly pronounced in the upper gastrointestinal tract (stomach and proximal duodenum). The postprandial gastric emptying, measured with a standardized 99mTc labelled meal, was also significantly delayed (t50 increased by 38% or 32 min). This was combined with a slower carbohydrate absorption (delay in peak blood glucose level about 40 min). Furthermore, during experimental hyperinsulinaemia higher blood glucose levels were seen at 120 min than at 60 min after food ingestion. This was not seen in any subject in the control study where only 0.9% NaCl was infused. Blood levels of the motility-stimulating hormone, motilin, were significantly lower during experimental hyperinsulinaemia. Thus, experimental hyperinsulinaemia impairs the gastrointestinal motility in both the postabsorptive and postprandial states. This effect is combined with a delayed carbohydrate absorption. Hyperinsulinaemia per se may thus lead to alterations in carbohydrate absorption and can also contribute to the gastrointestinal disturbances in diabetes.
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Affiliation(s)
- B Eliasson
- Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Göteborg University, Sahlgrenska University Hospital, Gothenburg, Sweden
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50
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Rotella CM, Cresci B, Mannucci E, Rizzello SM, Colzi G, Galli G, Giannini S, Messeri G, Piani F, Vannini R. Short cycles of very low calorie diet in the therapy of obese type II diabetes mellitus. J Endocrinol Invest 1994; 17:171-9. [PMID: 8051339 DOI: 10.1007/bf03347709] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Very Low Calorie Diet (VLCD) is known to induce not only weight loss, but also an improvement of metabolic control, in obese type II diabetics. In order to evaluate the therapeutical efficacy of cycles of VLCD shorter than those previously described, 29 obese type II diabetics and 31 obese nondiabetic subjects were entered as inpatients and prescribed a 450 kcal/day diet for 15 days. Metabolic results obtained were similar to those achieved with longer cycles of VLCD, showing that 15 days are sufficient to induce a BMI decrease in diabetic (BMI from 35.3 +/- 4.8 to 33.3 +/- 4.6 after VLCD) and nondiabetic patients (BMI from 40.5 +/- 7.4 to 38.1 +/- 7.2 after VLCD), a desired fall of blood glucose levels and the decrease of daily insulin needs in insulin-treated patients. Glucagon tests were performed before and after VLCD in order to study possible modifications of insulin secretion. Although we did not observe any significant increase of C-peptide basal or peak levels (nM/ml) either in diabetic (basal levels before VLDC: 1.2 +/- 0.4 and peak levels 2.4 +/- 0.7; basal after VLCD 1.23 +/- 0.6 and peak 2.6 +/- 0.7) and nondiabetic patients (basal levels before VLDC 1.0 +/- 0.3 and peak levels 2.5 +/- 0.4; basal after VLCD 0.9 +/- 0.3 and peak 2.4 +/- 0.6). The rise of the C-peptide/glycemia ratio is an index of an improvement of insulin biological activity, which could be partly responsible for the therapeutical effects of VLCD.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- C M Rotella
- Department of Clinical Pathophysiology, University of Florence, Italy
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