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1
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Cook JR, Hawkins MA, Pajvani UB. Liver insulinization as a driver of triglyceride dysmetabolism. Nat Metab 2023; 5:1101-1110. [PMID: 37460842 DOI: 10.1038/s42255-023-00843-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/13/2023] [Indexed: 07/26/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly prevalent fellow traveller with the insulin resistance that underlies type 2 diabetes mellitus. However, the mechanistic connection between MAFLD and impaired insulin action remains unclear. In this Perspective, we review data from humans to elucidate insulin's aetiological role in MAFLD. We focus particularly on the relative preservation of insulin's stimulation of triglyceride (TG) biosynthesis despite its waning ability to curb hepatic glucose production (HGP). To explain this apparent 'selective insulin resistance', we propose that hepatocellular processes that lead to TG accumulation require less insulin signal transduction, or 'insulinization,' than do those that regulate HGP. As such, mounting hyperinsulinaemia that barely compensates for aberrant HGP in insulin-resistant states more than suffices to maintain hepatic TG biosynthesis. Thus, even modestly elevated or context-inappropriate insulin levels, when sustained day and night within a heavily pro-lipogenic metabolic milieu, may translate into substantial cumulative TG biosynthesis in the insulin-resistant state.
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Affiliation(s)
- Joshua R Cook
- Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA.
| | - Meredith A Hawkins
- Diabetes Research and Training Center, Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Utpal B Pajvani
- Naomi Berrie Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Columbia University College of Physicians & Surgeons, New York City, NY, USA
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2
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Zhang Y, Shen T, Wang S. Progression from prediabetes to type 2 diabetes mellitus induced by overnutrition. Hormones (Athens) 2022; 21:591-597. [PMID: 36197636 DOI: 10.1007/s42000-022-00399-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 09/19/2022] [Indexed: 12/31/2022]
Abstract
Prediabetes has developed into a global pandemic, its prevalence increasing year by year. Although lifestyle changes are advocated as the basis for prediabetes treatment, some patients fail to choose or adhere to appropriate interventions. The basis for selecting an appropriate intervention is determining the stage and cause of the disease. In this review, we aimed to examine the various types and disease processes of prediabetes caused by overnutrition, the present review supporting the hypothesis that overnutrition-induced hyperinsulinemia precedes insulin resistance (IR) and independently causes β-cell dysfunction. Tissue insulin resistance is the main feature of prediabetes with the crosstalk between tissues promoting the formation of systemic insulin resistance. Finally, both β-cell dysfunction induced by hyperinsulinemia or IR and reduced β-cell mass can lead to abnormal insulin secretion and contribute to development of type 2 diabetes mellitus (T2DM). Hence, overnutrition can cause multiple prediabetes phenotypes resulting in development of T2DM through different trajectories. Future diagnosis and treatment should therefore more carefully consider the disease phenotype and stage of development in patients with prediabetes to reduce the incidence of T2DM.
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Affiliation(s)
- Yuli Zhang
- School of Physical Education & Sports Science, South China Normal University, No.55, West of Zhongshan Ave., Tianhe District, Guangzhou City, 510006, Guangdong Province, China
| | - Tuming Shen
- School of Physical Education & Sports Science, South China Normal University, No.55, West of Zhongshan Ave., Tianhe District, Guangzhou City, 510006, Guangdong Province, China
| | - Songtao Wang
- School of Physical Education & Sports Science, South China Normal University, No.55, West of Zhongshan Ave., Tianhe District, Guangzhou City, 510006, Guangdong Province, China.
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3
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Sanches A, Guzzoni V, Miranda VCDR, Peressim LB, Rocha S, de Lima PO, Marcondes FK, Tanno AP, Cunha TS. Recreational training improves cardiovascular adaptations, metabolic profile and mental health of elderly women with type-2 diabetes mellitus. Health Care Women Int 2020; 42:1279-1297. [PMID: 33085582 DOI: 10.1080/07399332.2020.1821689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Andrea Sanches
- Physiotherapy Course, Faculty of Americana, Santa Barbara d’Oeste, Sao Paulo, Brazil
| | - Vinicius Guzzoni
- Department of Cellular and Molecular Biology, Federal University of Paraíba, Paraíba, Brazil
| | | | | | - Suellen Rocha
- Physiotherapy Course, Faculty of Americana, Santa Barbara d’Oeste, Sao Paulo, Brazil
| | - Patrícia Oliveira de Lima
- Piracicaba Dental School, Department of Biosciences, University of Campinas, Piracicaba, Sao Paulo, Brazil
| | - Fernanda Klein Marcondes
- Piracicaba Dental School, Department of Biosciences, University of Campinas, Piracicaba, Sao Paulo, Brazil
| | - Ana Paula Tanno
- College of Health Sciences, Methodist University of Piracicaba, Piracicaba, Sao Paulo, Brazil
| | - Tatiana Sousa Cunha
- Science and Technology Institute, Federal University of São Paulo, São Paulo, Brazil
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4
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Muñoz Díaz HA, Lúquez Mindiola AJ, Gómez Aldana AJ. Fisiopatología de la hepatitis C y diabetes mellitus. Hacia la cura de dos epidemias en el siglo XXI. REVISTA COLOMBIANA DE GASTROENTEROLOGÍA 2019; 34:277-287. [DOI: 10.22516/25007440.322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/01/2024]
Abstract
La infección crónica por virus de la hepatitis C (VHC) y la diabetes mellitus (DM) son dos problemas de salud pública que impactan los sistemas de salud, con una alta carga económica global. La infección por VHC produce manifestaciones hepáticas tales como hepatitis, cirrosis y carcinoma hepatocelular; asimismo, se ha involucrado en la patogénesis de manifestaciones extrahepáticas, entre las cuales se ha asociado con alteraciones metabólicas como la DM. Estudios longitudinales y transversales han reportado mayor incidencia y prevalencia de DM en pacientes con infección crónica por VHC. La DM acelera la progresión histológica y clínica en pacientes con infección crónica por VHC y las complicaciones cardiovasculares. Recientemente se ha avanzado en el tratamiento y la introducción de nuevos medicamentos como los antivirales de acción directa, que mejoran el control glucémico en estos pacientes.
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5
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Carvalho AL, Massaro B, Silva LTPE, Salmon CEG, Fukada SY, Nogueira-Barbosa MH, Elias J, Freitas MCF, Couri CEB, Oliveira MC, Simões BP, Rosen CJ, de Paula FJA. Emerging Aspects of the Body Composition, Bone Marrow Adipose Tissue and Skeletal Phenotypes in Type 1 Diabetes Mellitus. J Clin Densitom 2019; 22:420-428. [PMID: 30100221 DOI: 10.1016/j.jocd.2018.06.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 06/22/2018] [Accepted: 06/26/2018] [Indexed: 12/12/2022]
Abstract
Anthropomorphic measures among type 1 diabetic patients are changing as the obesity epidemic continues. Excess fat mass may impact bone density and ultimately fracture risk. We studied the interaction between bone and adipose tissue in type 1 diabetes subjects submitted to two different clinical managements: (I) conventional insulin therapy or (II) autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST). The study comprised 3 groups matched by age, gender, height and weight: control (C = 24), type 1 diabetes (T1D = 23) and type 1 diabetes treated with AHST (T1D-AHST = 9). Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by dual X-ray absorptiometry (DXA). 1H Magnetic resonance spectroscopy was used to assess bone marrow adipose tissue (BMAT) in the L3 vertebra, and abdominal magnetic resonance imaging was used to assess intrahepatic lipids (IHL), visceral (VAT) and subcutaneous adipose tissue (SAT). Individuals conventionally treated for T1D were more likely to be overweight (C = 23.8 ± 3.7; T1D = 25.3 ± 3.4; T1D-AHST = 22.5 ± 2.2 Kg/m2; p > 0.05), but there was no excessive lipid accumulation in VAT or liver. Areal BMD of the three groups were similar at all sites; lumbar spine TBS (L3) was lower in type 1 diabetes (p < 0.05). Neither SAT nor VAT had any association with bone parameters. Bone marrow adipose tissue (BMAT) lipid profiles were similar among groups. BMAT saturated lipids were associated with cholesterol, whereas unsaturated lipids had an association with IGF1. Overweight and normal weight subjects with type 1 diabetes have normal areal bone density, but lower trabecular bone scores. Adipose distribution is normal and BMAT volume is similar to controls, irrespective of clinical treatment.
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Affiliation(s)
- Adriana L Carvalho
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Bianca Massaro
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Luciana T P E Silva
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Carlos E G Salmon
- Department of Physics, Faculty of Philosophy, Sciences and Arts of Ribeirao Preto, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Sandra Y Fukada
- Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Marcello H Nogueira-Barbosa
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Jorge Elias
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Maria C F Freitas
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Carlos E B Couri
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Maria C Oliveira
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Belinda P Simões
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil
| | - Clifford J Rosen
- Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, ME, USA
| | - Francisco J A de Paula
- Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo (USP), Ribeirao Preto, Brazil.
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6
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Tricò D, Natali A, Arslanian S, Mari A, Ferrannini E. Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents. JCI Insight 2018; 3:124912. [PMID: 30568042 DOI: 10.1172/jci.insight.124912] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/06/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.
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Affiliation(s)
- Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Silva Arslanian
- Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Division of Pediatric Endocrinology, Diabetes and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Ele Ferrannini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
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7
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Hepatitis C Virus Infection at Primary Healthcare Level in Abha City, Southwestern Saudi Arabia: Is Type 2 Diabetes Mellitus an Associated Factor? INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:ijerph15112513. [PMID: 30423991 PMCID: PMC6267576 DOI: 10.3390/ijerph15112513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 11/05/2018] [Accepted: 11/08/2018] [Indexed: 12/22/2022]
Abstract
Background: There is an increasing concern about the relation between hepatitis C virus infection (HCV) and type 2 diabetes mellitus (T2DM). The present study aims to determine the prevalence of HCV infection among T2DM patients and non-diabetic patients attending primary healthcare centers (PHCCs) in Abha city, southwestern Saudi Arabia, and to explore the possible association between T2DM and HCV infection. Methods: A cross-sectional study targeting a random sample of T2DM and non-diabetic patients attending PHCCs in Abha City was conducted. Patients were interviewed using a structured questionnaire and screened for HCV infection using fourth-generation ELISA kits. All positive cases were confirmed by qualitative RT-PCR immune assay. Results: The study revealed an overall seroprevalence of HCV infection of 5% (95% CI: 2.9–7.9%). Among T2DM and non-diabetics, a seroprevalence of 8.0% and 2.0% was found, respectively. Using multivariable regression analysis, the only significant associated factor for HCV infection was T2DM (aOR = 4.185, 95% CI: 1.074–16.305). Conclusions: There is strong positive association between T2DM and HCV infection. Yet, the direction of relationship is difficult to establish. Patients with T2DM have higher prevalence of HCV infection than non-diabetic group. It is highly recommended for primary health care providers to screen for HCV infection among T2DM patients and to increase the level of HCV awareness among them.
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8
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Zhao G, Wirth D, Schmitz I, Meyer-Hermann M. A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. Nat Commun 2017; 8:1362. [PMID: 29118381 PMCID: PMC5678123 DOI: 10.1038/s41467-017-01627-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 10/03/2017] [Indexed: 12/15/2022] Open
Abstract
Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch-off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field. Dysregulation of insulin secretion dynamics plays a role in diabetes development. Here, the authors build a mathematical model of hepatic insulin signaling and propose a sequential model of post-meal control of glucose and lipids, according to which delayed aPKC suppression would contribute to selective hepatic insulin resistance.
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Affiliation(s)
- Gang Zhao
- Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Rebenring 56, 38106, Braunschweig, Germany
| | - Dagmar Wirth
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124, Braunschweig, Germany.,Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany
| | - Ingo Schmitz
- Systems-Oriented Immunology and Inflammation Research Group, Department of Immune Control, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124, Braunschweig, Germany.,Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, Leipziger Straße 44, 39120, Magdeburg, Germany
| | - Michael Meyer-Hermann
- Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Rebenring 56, 38106, Braunschweig, Germany. .,Institute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, Spielmannstraße 7, 38106, Braunschweig, Germany.
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Shao J, Zaro JL, Shen WC. Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics. Tissue Barriers 2016; 4:e1156804. [PMID: 27358753 DOI: 10.1080/21688370.2016.1156804] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 02/09/2016] [Accepted: 02/11/2016] [Indexed: 10/22/2022] Open
Abstract
Current subcutaneously (s.c.)-injected insulin (INS) products result in a hyperinsulin exposure to peripheral tissues (skeletal muscle and adipose) while INS hardly accesses to liver after injection. This unphysiological distribution raises risks of hypoglycemia episode and causes weight gain after long term treatment. An ideal INS replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. However, there are 2 factors that limit the ability of s.c. injected INS to restore the liver: peripheral gradient in INS deficient diabetes patients: (1) the transport of INS in capillary endothelium and peripheral tissues from the injection site; and (2) peripheral INS receptor (IR) mediated INS degradation. In this review, the tissue barriers against efficient liver targeting of s.c. injected INS are discussed and current advances in developing hepatoselective insulin therapeutics are introduced.
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Affiliation(s)
- Juntang Shao
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, CA, USA
| | - Jennica L Zaro
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, CA, USA
| | - Wei-Chiang Shen
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California , Los Angeles, CA, USA
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10
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Abstract
Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.
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11
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Matteucci E, Giampietro O, Covolan V, Giustarini D, Fanti P, Rossi R. Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery. Drug Des Devel Ther 2015; 9:3109-18. [PMID: 26124635 PMCID: PMC4476457 DOI: 10.2147/dddt.s79322] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Insulin is a life-saving medication for people with type 1 diabetes, but traditional insulin replacement therapy is based on multiple daily subcutaneous injections or continuous subcutaneous pump-regulated infusion. Nonphysiologic delivery of subcutaneous insulin implies a rapid and sustained increase in systemic insulin levels due to the loss of concentration gradient between portal and systemic circulations. In fact, the liver degrades about half of the endogenous insulin secreted by the pancreas into the venous portal system. The reverse insulin distribution has short- and long-term effects on glucose metabolism. Thus, researchers have explored less-invasive administration routes based on innovative pharmaceutical formulations, which preserve hormone stability and ensure the therapeutic effectiveness. This review examines some of the recent proposals from clinical and material chemistry point of view, giving particular attention to patients' (and diabetologists') ideal requirements that organic chemistry could meet.
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Affiliation(s)
- Elena Matteucci
- Department of Clinical and Experimental Medicine, University of Pisa, Siena, Italy
| | - Ottavio Giampietro
- Department of Clinical and Experimental Medicine, University of Pisa, Siena, Italy
| | - Vera Covolan
- Department of Chemistry and Industrial Chemistry, University of Pisa, Siena, Italy
| | - Daniela Giustarini
- Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Siena, Italy
| | - Paolo Fanti
- Division of Nephrology, University of Texas Health Science Center San Antonio, South Texas Veteran Health Care System, San Antonio, Texas, USA
| | - Ranieri Rossi
- Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Siena, Italy
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12
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Glucose-driven chemo-mechanical autonomous drug-release system with multi-enzymatic amplification toward feedback control of blood glucose in diabetes. Biosens Bioelectron 2015; 67:315-20. [PMID: 25223550 DOI: 10.1016/j.bios.2014.08.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 08/11/2014] [Accepted: 08/14/2014] [Indexed: 01/27/2023]
Abstract
A second-generation novel chemo-mechanical autonomous drug release system, incorporating various improvements over our first-generation system, was fabricated and evaluated. Enhanced oxygen uptake by the enzyme membrane of the organic engine was facilitated by optimizing the quantity of enzyme immobilizer, PVA-SbQ, and by hydrophobizing the membrane surface. Various quantities of PVA-SbQ were evaluated in the organic engine by measuring the decompression rate, with 1.5 mg/cm(2) yielding optimum results. When fluororesin was used as a hydrophobizing coating, the time to reach the peak decompression rate was shortened 2.3-fold. The optimized elements of the system were evaluated as a unit, first in an open loop and then in a closed loop setting, using a mixture of glucose solution (25 mmol/L), ATP and MgCI2 with glucose hexokinase enzyme (HK) as a glucose reducer. In conclusion, feedback-control of physiologically relevant glucose concentration was demonstrated by the second-generation drug release system without any requirement for external energy.
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13
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Antonelli A, Ferrari SM, Giuggioli D, Di Domenicantonio A, Ruffilli I, Corrado A, Fabiani S, Marchi S, Ferri C, Ferrannini E, Fallahi P. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J Diabetes 2014; 5:586-600. [PMID: 25317237 PMCID: PMC4138583 DOI: 10.4239/wjd.v5.i5.586] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/10/2014] [Accepted: 07/12/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.
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14
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Abstract
Treatment of type 1 diabetes mellitus (T1DM) requires lifelong administration of exogenous insulin. The primary goal of treatment of T1DM in children and adolescents is to maintain near-normoglycemia through intensive insulin therapy, avoid acute complications, and prevent long-term microvascular and macrovascular complications, while facilitating as close to a normal life as possible. Effective insulin therapy must, therefore, be provided on the basis of the needs, preferences, and resources of the individual and the family for optimal management of T1DM. To achieve target glycemic control, the best therapeutic option for patients with T1DM is basal-bolus therapy either with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). Many formulations of insulin are available to help simulate endogenous insulin secretion as closely as possible in an effort to eliminate the symptoms and complications of hyperglycemia, while minimizing the risk of hypoglycemia secondary to therapy. When using MDI, basal insulin requirements are given as an injection of long- or intermediate-acting insulin analogs, while meal-related glucose excursions are controlled with bolus injections of rapid-acting insulin analogs. Alternatively, CSII can be used, which provides a 24-h preselected but adjustable basal rate of rapid-acting insulin, along with patient-activated mealtime bolus doses, eliminating the need for periodic injections. Both MDI treatment and CSII therapy must be supported by comprehensive education that is appropriate for the individual needs of the patient and family before and after initiation. Current therapies still do not match the endogenous insulin profile of pancreatic β-cells, and all still pose risks of suboptimal control, hypoglycemia, and ketosis in children and adolescents. The safety and success of a prescribed insulin regimen is, therefore, dependent on self-monitoring of blood glucose and/or a continuous glucose monitoring system to avoid critical hypoglycemia and glucose variability. Regardless of the mode of insulin therapy, doses should be adapted on the basis of the daily pattern of blood glucose, through regular review and reassessment, and patient factors such as exercise and pubertal status. New therapy options such as sensor-augmented insulin pump therapy, which integrates CSII with a continuous glucose sensor, along with emerging therapies such as the artificial pancreas, will likely continue to improve safe insulin therapy in the near future.
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Affiliation(s)
- Faisal S Malik
- Division of Endocrinology and Diabetes, Department of Pediatrics, University of Washington and Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, WA, 98105, USA
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15
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Abstract
PURPOSE OF REVIEW To highlight the recent advances in closed-loop research, the development and progress towards utilizing closed loop outside of the clinical research setting and at patients' homes. RECENT FINDINGS In spite of the modern insulin therapy in type 1 diabetes, hypoglycaemia is still a major limiting factor. This often leads to suboptimal glycaemic control and risk of diabetes complications. Closed loop has been shown to improve glycaemic control whilst avoiding hypoglycaemia. Incremental progress has been made in this field, from the use of automated systems and bihormonal closed-loop systems in clinical research facility settings under close supervision to the use of ambulatory closed-loop prototype at patients' homes in free-living conditions. Different population of patients with type 1 diabetes and control algorithm approaches have been studied, assessing the efficacy and safety. Transitional and home studies present different challenges at achieving better glycaemic outcome with closed loop. Improved glucose sensor reliability may accelerate the clinical use and faster insulin analogues increase the clinical utility. SUMMARY Results and experience with closed-loop insulin delivery have been encouraging, leading the way for future improvements and development in the field, to make closed loop suitable for use in clinical practice.
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Affiliation(s)
- Hood Thabit
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
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Badeau RM, Honka MJ, Lautamäki R, Stewart M, Kangas AJ, Soininen P, Ala-Korpela M, Nuutila P. Systemic metabolic markers and myocardial glucose uptake in type 2 diabetic and coronary artery disease patients treated for 16 weeks with rosiglitazone, a PPARγ agonist. Ann Med 2014; 46:18-23. [PMID: 24266715 DOI: 10.3109/07853890.2013.853369] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Treatment with rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, in type 2 diabetic mellitus (T2DM) patients is under scrutiny because it affects adversely cardiovascular outcomes. In T2DM patients, with existing coronary heart disease, short-term treatment with rosiglitazone increases myocardial glucose uptake (MGU). Serum metabolic and lipoprotein subclass changes, which may be associated with this rosiglitazone-induced improvement, are unknown. METHODS Patients with both T2DM and coronary heart disease were separated into placebo (n = 26) and treatment (rosiglitazone 4-8 mg; n = 25) groups. After 16 weeks of treatment, serum NMR metabolomics was used to measure circulating low-molecular-weight metabolites and lipoprotein subclasses and lipids that are associated with T2DM before and after the treatment. Significant metabolic measure changes after rosiglitazone treatment were correlated to MGU values assessed with [(18)F]fluorodeoxyglucose positron emission tomography. RESULTS Compared to placebo, the treatment significantly increased circulating glutamine and decreased lactate concentrations. Circulating lactate concentrations showed a significant inverse association with MGU after rosiglitazone treatment. CONCLUSION In T2DM patients with existing coronary heart disease, short-term rosiglitazone treatment caused minor improvements in metabolism: serum lactate and glutamine concentrations changed, reflecting improvements in insulin sensitivity, and circulating lactate concentrations inversely correlated to increases in myocardial glucose uptake.
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Affiliation(s)
- Robert M Badeau
- Turku PET Centre, University of Turku and Turku University Hospital , Turku , Finland
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de Paula FJA, Rosen CJ. Bone Remodeling and Energy Metabolism: New Perspectives. Bone Res 2013; 1:72-84. [PMID: 26273493 DOI: 10.4248/br201301005] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 01/30/2013] [Indexed: 12/27/2022] Open
Abstract
Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications.
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Affiliation(s)
- Francisco J A de Paula
- Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo , Brazil
| | - Clifford J Rosen
- Center for Clinical and Translational Research, Maine Medical Center Research Institute , USA
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