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Golovinskaia O, Wang CK. The hypoglycemic potential of phenolics from functional foods and their mechanisms. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2022.10.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Liu FS, Wang S, Guo XS, Ye ZX, Zhang HY, Li Z. State of art on the mechanisms of laparoscopic sleeve gastrectomy in treating type 2 diabetes mellitus. World J Diabetes 2023; 14:632-655. [PMID: 37383590 PMCID: PMC10294061 DOI: 10.4239/wjd.v14.i6.632] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 04/01/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Obesity and type-2 diabetes mellitus (T2DM) are metabolic disorders. Obesity increases the risk of T2DM, and as obesity is becoming increasingly common, more individuals suffer from T2DM, which poses a considerable burden on health systems. Traditionally, pharmaceutical therapy together with lifestyle changes is used to treat obesity and T2DM to decrease the incidence of comorbidities and all-cause mortality and to increase life expectancy. Bariatric surgery is increasingly replacing other forms of treatment of morbid obesity, especially in patients with refractory obesity, owing to its many benefits including good long-term outcomes and almost no weight regain. The bariatric surgery options have markedly changed recently, and laparoscopic sleeve gastrectomy (LSG) is gradually gaining popularity. LSG has become an effective and safe treatment for type-2 diabetes and morbid obesity, with a high cost-benefit ratio. Here, we review the me-chanism associated with LSG treatment of T2DM, and we discuss clinical studies and animal experiments with regard to gastrointestinal hormones, gut microbiota, bile acids, and adipokines to clarify current treatment modalities for patients with obesity and T2DM.
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Affiliation(s)
- Fa-Shun Liu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Song Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xian-Shan Guo
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
| | - Zhen-Xiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Hong-Ya Zhang
- Central Laboratory, Yangpu District Control and Prevention Center, Shanghai 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
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Zakaria EM, Tawfeek WM, Hassanin MH, Hassaballah MY. Cardiovascular protection by DPP-4 inhibitors in preclinical studies: an updated review of molecular mechanisms. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:1357-1372. [PMID: 35945358 PMCID: PMC9568460 DOI: 10.1007/s00210-022-02279-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 07/26/2022] [Indexed: 11/29/2022]
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors are a class of antidiabetic medications that cause glucose-dependent increase in incretins in diabetic patients. One of the two incretins, glucagon-like peptide-1 (GLP-1), beside its insulinotropic activity, has been studied for extra pancreatic effects. Most of DPP4 inhibitors (DPP4i) have been investigated in in vivo and in vitro models of diabetic and nondiabetic cardiovascular diseases including heart failure, hypertension, myocardial ischemia or infarction, atherosclerosis, and stroke. Results of preclinical studies proved prominent therapeutic potential of DPP4i in cardiovascular diseases, regardless the presence of diabetes. This review aims to present an updated summary of the cardiovascular protective and therapeutic effects of DPP4 inhibitors through the past 5 years focusing on the molecular mechanisms beneath these effects. Additionally, based on the results summary presented here, future studies may be conducted to elucidate or illustrate some of these findings which can add clinical benefits towards management of diabetic cardiovascular complications.
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Affiliation(s)
- Esraa M Zakaria
- Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Walaa M Tawfeek
- Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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Strunz PP, Vuille-Dit-Bille RN, R Fox M, Geier A, Maggiorini M, Gassmann M, Fruehauf H, Lutz TA, Goetze O. Effect of high altitude on human postprandial 13 C-octanoate metabolism, intermediary metabolites, gastrointestinal peptides, and visceral perception. Neurogastroenterol Motil 2022; 34:e14225. [PMID: 34342373 DOI: 10.1111/nmo.14225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/08/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVE At high altitude (HA), acute mountain sickness (AMS) is accompanied by neurologic and upper gastrointestinal symptoms (UGS). The primary aim of this study was to test the hypothesis that delayed gastric emptying (GE), assessed by 13 C-octanoate breath testing (OBT), causes UGS in AMS. The secondary aim was to assess post-gastric mechanisms of OBT, which could confound results under these conditions, by determination of intermediary metabolites, gastrointestinal peptides, and basal metabolic rate. METHODS A prospective trial was performed in 25 healthy participants (15 male) at 4559 m (HA) and at 490 m (Zurich). GE was assessed by OBT (428 kcal solid meal) and UGS by visual analogue scales (VAS). Blood sampling of metabolites (glucose, free fatty acids (FFA), triglycerides (TG), beta-hydroxyl butyrate (BHB), L-lactate) and gastrointestinal peptides (insulin, amylin, PYY, etc.) was performed as well as blood gas analysis and spirometry. STATISTICAL ANALYSIS variance analyses, bivariate correlation, and multilinear regression analysis. RESULTS After 24 h under hypoxic conditions at HA, participants developed AMS (p < 0.001). 13 CO2 exhalation kinetics increased (p < 0.05) resulting in reduced estimates of gastric half-emptying times (p < 0.01). However, median resting respiratory quotients and plasma profiles of TG indicated that augmented beta-oxidation was the main predictor of accelerated 13 CO2 -generation under these conditions. CONCLUSION Quantification of 13 C-octanoate oxidation by a breath test is sensitive to variation in metabolic (liver) function under hypoxic conditions. 13 C-breath testing using short-chain fatty acids is not reliable for measurement of gastric function at HA and should be considered critically in other severe hypoxic conditions, like sepsis or chronic lung disease.
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Affiliation(s)
- Patrick-Pascal Strunz
- Division of Rheumatology and Immunology, Department of Medicine II, University Hospital Wurzburg, Germany
| | | | - Mark R Fox
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Digestive Function: Basel, Laboratory and Clinic for Motility Disorders and Functional Digestive Diseases, Klinik Arlesheim, Arlesheim, Switzerland
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Wurzburg, Germany
| | - Marco Maggiorini
- Institute of Intensive Care, University Hospital Zurich, Zurich, Switzerland
| | - Max Gassmann
- Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Heiko Fruehauf
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zentrum für Gastroenterologie und Hepatologie, Zurich, Switzerland
| | - Thomas A Lutz
- Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Oliver Goetze
- Division of Hepatology, Department of Medicine II, University Hospital Wurzburg, Germany
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Abstract
Glucagon like peptide-1 (GLP-1), a peptide hormone from the intestinal tract, plays a central role in the coordination of postprandial glucose homeostasis through actions on insulin secretion, food intake and gut motility. GLP-1 forms the basis for a variety of current drugs for the treatment of type 2 diabetes and obesity, as well as new agents currently being developed. Here, we provide a concise overview of the core physiology of GLP-1 secretion and action, and the role of the peptide in human health, disease and therapeutics.
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Affiliation(s)
- Fiona M Gribble
- Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
| | - Frank Reimann
- Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
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Abildgaard J, Ploug T, Pedersen AT, Eiken P, Pedersen BK, Holst JJ, Hartmann B, Lindegaard B. Preserved postprandial suppression of bone turnover markers, despite increased fasting levels, in postmenopausal women. Bone 2021; 143:115612. [PMID: 32853851 DOI: 10.1016/j.bone.2020.115612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/12/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023]
Abstract
CONTEXT Menopause leads to an increased bone turnover associated with a high risk of fractures. Bone turnover is inhibited by meal intake, to some extent mediated by gut hormones, and interventions based on these endocrine changes may have potential in future prevention of osteoporosis. OBJECTIVE To investigate whether postmenopausal women exhibit postprandial suppression of bone turnover markers to the same extent as premenopausal women, despite higher fasting levels. Furthermore, to assess whether menopausal differences in bone turnover markers are related to postmenopausal changes in plasma gut hormone levels. METHODS A cross-sectional study of 21 premenopausal, 9 perimenopausal, and 24 postmenopausal women between 45 and 60 years of age. Serum/plasma levels of bone turnover markers and gut hormones were investigated during a 120 min oral glucose tolerance test. Bone turnover markers included N-terminal propeptide of type-I procollagen (PINP, bone formation marker) and carboxyterminal collagen I crosslinks (CTX-I, bone resorption marker). Gut hormone secretion was evaluated from responses of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). RESULTS Fasting levels of s-CTX-I were increased in peri- and postmenopausal women compared to premenopausal women (p = 0.001). Despite higher fasting levels, the relative postprandial s-CTX-I suppression was comparable across menopausal status (p = 0.14). Fasting levels of s-PINP were also increased in postmenopausal women compared to premenopausal women (p < 0.001) with comparable and modest s-PINP suppression over menopause (p = 0.13). Postprandial plasma GLP-1 (p = 0.006) and GLP-2 (p = 0.01) were significantly increased in postmenopausal women compared to premenopausal women while GIP responses were slightly increased in the perimenopausal group (p = 0.02) but comparable between pre- and postmenopausal women. None of the postprandial gut hormone increases predicted postprandial bone turnover suppression in these women. CONCLUSIONS Glucose-induced suppression of bone turnover markers is preserved in postmenopausal women, despite significantly higher fasting values, indicating that CTX-I lowering treatments based on these postprandial mechanisms might be a feasible strategy to prevent postmenopausal osteoporosis.
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Affiliation(s)
- Julie Abildgaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark; Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Denmark.
| | - Thorkil Ploug
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Anette Tønnes Pedersen
- Department of Gynaecology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Pia Eiken
- Department of Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark
| | - Bente Klarlund Pedersen
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Birgitte Lindegaard
- Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark; Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, Hillerød, Denmark.
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Aigner L, Becker B, Gerken S, Quast DR, Meier JJ, Nauck MA. Day-to-Day Variations in Fasting Plasma Glucose Do Not Influence Gastric Emptying in Subjects With Type 1 Diabetes. Diabetes Care 2021; 44:479-488. [PMID: 33288653 DOI: 10.2337/dc20-1660] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/17/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Acute experimental variations in glycemia decelerate (hyperglycemia) or accelerate (hypoglycemia) gastric emptying. Whether spontaneous variations in fasting plasma glucose (FPG) have a similar influence on gastric emptying is yet unclear. RESEARCH DESIGN AND METHODS Gastric emptying of a mixed meal was prospectively studied three times in 20 patients with type 1 diabetes and 10 healthy subjects with normal glucose tolerance using a 13C-CO2 octanoate breath test with Wagner-Nelson analysis. The velocity of gastric emptying was related to FPG measured before the test (grouped as low, intermediate, or high). In addition, gastric emptying data from 255 patients with type 1 diabetes studied for clinical indications were compared by tertiles of baseline FPG. RESULTS Despite marked variations in FPG (by 4.8 [95% CI 3.4; 6.2] mmol/L), gastric emptying did not differ among the three prospective examinations in patients with type 1 diabetes (Δ T1/2 between highest and lowest FPG: 1 [95% CI -35; 37] min; P = 0.90). The coefficient of variation for T1/2 determined three times was 21.0%. Similar results at much lower variations in FPG were found in healthy subjects. In the cross-sectional analysis, gastric emptying did not differ between the tertiles of FPG (Δ T1/2 between highest and lowest FPG: 7 [95% CI -10; 23] min; P = 0.66), when FPG varied by 7.2 (6.7; 7.8) mmol/L. However, higher HbA1c was significantly related to slower gastric emptying. CONCLUSIONS Day-to-day variations in FPG not induced by therapeutic measures do not influence gastric emptying significantly. These findings are in contrast with those obtained after rapidly clamping plasma glucose in the hyper- or hypoglycemic concentrations range and challenge the clinical importance of short-term glucose fluctuations for gastric emptying in patients with type 1 diabetes. Rather, chronic hyperglycemia is associated with slowed gastric emptying.
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Affiliation(s)
- Lea Aigner
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - Björn Becker
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - Sonja Gerken
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - Daniel R Quast
- Division of Diabetology, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Juris J Meier
- Division of Diabetology, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University, Bochum, Germany
| | - Michael A Nauck
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany .,Division of Diabetology, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University, Bochum, Germany
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Merovci A, Tripathy D, Chen X, Valdez I, Abdul-Ghani M, Solis-Herrera C, Gastaldelli A, DeFronzo RA. Effect of Mild Physiologic Hyperglycemia on Insulin Secretion, Insulin Clearance, and Insulin Sensitivity in Healthy Glucose-Tolerant Subjects. Diabetes 2021; 70:204-213. [PMID: 33033064 PMCID: PMC7881846 DOI: 10.2337/db20-0039] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 10/06/2020] [Indexed: 12/19/2022]
Abstract
The aim of the current study was to evaluate the effect of sustained physiologic increase of ∼50 mg/dL in plasma glucose concentration on insulin secretion in normal glucose-tolerant (NGT) subjects. Twelve NGT subjects without family history of type 2 diabetes mellitus (T2DM; FH-) and 8 NGT with family history of T2DM (FH+) received an oral glucose tolerance test and two-step hyperglycemic clamp (100 and 300 mg/dL) followed by intravenous arginine bolus before and after 72-h glucose infusion. Fasting plasma glucose increased from 94 ± 2 to 142 ± 4 mg/dL for 72 h. First-phase insulin secretion (0-10 min) increased by 70%, while second-phase insulin secretion during the first (10-80 min) and second (90-160 min) hyperglycemic clamp steps increased by 3.8-fold and 1.9-fold, respectively, following 72 h of physiologic hyperglycemia. Insulin sensitivity during hyperglycemic clamp declined by ∼30% and ∼55% (both P < 0.05), respectively, during the first and second hyperglycemic clamp steps. Insulin secretion/insulin resistance (disposition) index declined by 60% (second clamp step) and by 62% following arginine (both P < 0.005) following 72-h glucose infusion. The effect of 72-h glucose infusion on insulin secretion and insulin sensitivity was similar in subjects with and without FH of T2DM. Following 72 h of physiologic hyperglycemia, metabolic clearance rate of insulin was markedly reduced (P < 0.01). These results demonstrate that sustained physiologic hyperglycemia for 72 h 1) increases absolute insulin secretion but impairs β-cell function, 2) causes insulin resistance, and 3) reduces metabolic clearance rate of insulin.
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Affiliation(s)
- Aurora Merovci
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
| | - Devjit Tripathy
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
- Audie L. Murphy VA Hospital, South Texas Veterans Heath Care System, Foundation for Advancing Veterans' Health Research, San Antonio, TX
| | - Xi Chen
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
| | - Ivan Valdez
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
| | - Muhammad Abdul-Ghani
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
| | - Carolina Solis-Herrera
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
| | - Amalia Gastaldelli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
| | - Ralph A DeFronzo
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX
- Audie L. Murphy VA Hospital, South Texas Veterans Heath Care System, Foundation for Advancing Veterans' Health Research, San Antonio, TX
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Jafari-Vayghan H, Varshosaz P, Hajizadeh-Sharafabad F, Razmi HR, Amirpour M, Tavakoli-Rouzbehani OM, Alizadeh M, Maleki V. A comprehensive insight into the effect of glutamine supplementation on metabolic variables in diabetes mellitus: a systematic review. Nutr Metab (Lond) 2020; 17:80. [PMID: 32983244 PMCID: PMC7517657 DOI: 10.1186/s12986-020-00503-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 09/10/2020] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus is one of the most important threats to human health in the twenty-first century.
The use of complementary and alternative medicine to prevent, control, and reduce the complications of diabetes mellitus is increasing at present. Glutamine amino acid is known as a functional food.
The purpose of this systematic review is to determine the potential role of glutamine supplementation on metabolic variables in diabetes mellitus. For this review, PubMed, SCOPUS, Embase, ProQuest, and Google Scholar databases were searched from inception through April 2020. All clinical trial and animal studies assessing the effects of glutamine on diabetes mellitus were eligible for inclusion. 19 studies of 1482 articles met the inclusion criteria. Of the 19 studies, nine studies reported a significant increase in serum GLP-1 levels. Also, eight studies showed reducing in serum levels of fasting blood sugar, four studies reducing in postprandial blood sugar, and triglyceride after glutamine supplementation. Although glutamine resulted in a significant increase in insulin production in seven studies, the findings on Hb-A1c levels were inconclusive. In addition to, despite of the results was promising for the effects of glutamine on weight changes, oxidative stress, and inflammation, more precise clinical trials are needed to obtain more accurate results. In conclusion, glutamine supplementation could improve glycemic control and levels of incretins (such as GLP-1 and GIP) in diabetes mellitus. However, more studies are needed for future studies.
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Affiliation(s)
- Hamed Jafari-Vayghan
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Faculty of Health, Arak University of Medical Sciences, Arak, Iran
| | - Parisa Varshosaz
- Departments of Chemistry and Biochemistry, and Biology and Biomolecular Sciences Program, Laurentian University, Sudbury, ON Canada
| | - Fatemeh Hajizadeh-Sharafabad
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Reza Razmi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Amirpour
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Alizadeh
- Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Maleki
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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Perakakis N, Farr OM, Tuccinardi D, Upadhyay J, Mantzoros CS. Research advances in metabolism 2016. Metabolism 2017; 67:41-53. [PMID: 28081777 PMCID: PMC5871911 DOI: 10.1016/j.metabol.2016.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Revised: 10/30/2016] [Accepted: 11/02/2016] [Indexed: 11/17/2022]
Affiliation(s)
- Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Olivia M Farr
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Dario Tuccinardi
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jagriti Upadhyay
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02130, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02130, USA
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Kampmann K, Ueberberg S, Menge BA, Breuer TGK, Uhl W, Tannapfel A, Meier JJ. Abundance and turnover of GLP-1 producing L-cells in ileal mucosa are not different in patients with and without type 2 diabetes. Metabolism 2016; 65:84-91. [PMID: 26892519 DOI: 10.1016/j.metabol.2015.10.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/01/2015] [Accepted: 10/18/2015] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The gastrointestinal hormone GLP-1 is released from enteroendocrine L-cells and augments postprandial insulin secretion. In patients with type 2 diabetes, the incretin effect is markedly diminished. It is unclear, whether this is due to a reduction in the abundance of L-cells in the intestine. METHODS Ileal tissue samples from 10 patients with and 10 patients without diabetes that underwent surgery for the removal of colon tumors were included. Tissue sections were stained for GLP-1, Ki67, TUNEL and chromogranin A. RESULTS The number of L-cells was not different between patients with and without diabetes in either crypts (1.81±0.21% vs. 1.49±0.24%, respectively; p=0.31) or villi (1.07±0.16% vs. 0.83±0.10%, respectively; p=0.23). L-cell number was higher in crypts than in villi (p<0.0001). L-cell replication was detected rarely and not different between the groups. L-cell apoptosis was similar in patients with and without diabetes in both crypts (7.84±2.77% vs. 8.65±3.77%, p=0.85) and villi (4.48±2.89% vs. 8.62±4.64%, p=0.42). Chromogranin A staining was found in a subset of L-cells only. CONCLUSIONS Intestinal L-cell density is higher in crypts than in villi. Chromogranin A is not a prerequisite for GLP-1 production. L-cell density and turnover are not different between patients with and without diabetes. Thus, alterations in the number of GLP-1 producing cells do not explain the reduced incretin effect in patients with type 2 diabetes.
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Affiliation(s)
- Kirsten Kampmann
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Sandra Ueberberg
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Bjoern A Menge
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Thomas G K Breuer
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Waldemar Uhl
- Department of Surgery, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Ruhr-University Bochum, Bürkle de la Camp-Platz 1, Bochum, 44789, Germany
| | - Juris J Meier
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany.
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Nguyen NQ, Debreceni TL, Burgstad CM, Neo M, Bellon M, Wishart JM, Standfield S, Bartholomeusz D, Rayner CK, Wittert G, Horowitz M. Effects of Fat and Protein Preloads on Pouch Emptying, Intestinal Transit, Glycaemia, Gut Hormones, Glucose Absorption, Blood Pressure and Gastrointestinal Symptoms After Roux-en-Y Gastric Bypass. Obes Surg 2016; 26:77-84. [PMID: 25986427 DOI: 10.1007/s11695-015-1722-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim was to determine the effects of fat and protein preloads on pouch emptying (PE), caecal arrival time (CAT), glucose absorption, blood glucose (BSL), gut hormones, haemodynamics and gastrointestinal (GI) symptoms in subjects who had undergone Roux-en-Y gastric bypass (RYGB) >12 months previously. METHODS Ten RYGB subjects were studied on three occasions, in randomised order, receiving 200-ml preloads of either water, fat (30 ml olive oil) or whey protein (55 g), 30 min before a mixed meal. PE, CAT, BSL, plasma 3-O-methyl-D-glucopyranose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon, blood pressure (BP), heart rate (HR) and GI symptoms were assessed over 270 min. RESULTS Although fat and protein preloads did not alter PE of either solids or liquids, the CAT of solids, but not liquids, was longer than that after the water preload (fat 68 ± 5 min and protein 71 ± 6 min vs. water 46 ± 5 min; P = 0.02). BSL elevated promptly after the meal on all days (P < 0.001), but after protein, the magnitude and integrated increases in the first 75 min were less than fat and water preloads (area under the curve (AUC(0-75 min)), 18.7 ± 18.2 vs. 107.2 ± 30.4 and 76.1 ± 19.3 mmol/L/min; P < 0.05). Compared to water preload, the protein and fat preloads were associated with greater increases in plasma insulin, GLP-1 and glucagon concentrations, a reduction in BP, and greater increases in HR, fullness, bloating and nausea. Plasma 3-OMG levels were lower after the protein than after the water and fat preloads (P < 0.001). CONCLUSIONS Given its effects to attenuate post-prandial glycaemia, reduce intestinal glucose absorption and potentiate the "incretin response", without inducing more adverse post-prandial GI symptom, protein preload may prove clinically useful in RYGB patients and warrant further evaluation, particularly in those with type 2 diabetes (T2DM) and/or dumping syndrome.
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Affiliation(s)
- Nam Q Nguyen
- Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.
| | - Tamara L Debreceni
- Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia
| | - Carly M Burgstad
- Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia
| | - Melissa Neo
- Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia
| | - Max Bellon
- Department of Nuclear Medicine, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia
| | - Judith M Wishart
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Scott Standfield
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Dylan Bartholomeusz
- Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia
- Department of Nuclear Medicine, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia
| | - Chris K Rayner
- Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Gary Wittert
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia
| | - Michael Horowitz
- Discipline of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia
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13
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ZEMÁNKOVÁ K, MRÁZKOVÁ J, PIŤHA J, KOVÁŘ J. The Effect of Glucose When Added to a Fat Load on the Response of Glucagon-Like Peptide-1 (GLP-1) and Apolipoprotein B-48 in the Postprandial Phase. Physiol Res 2015; 64:S363-9. [DOI: 10.33549/physiolres.933180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Increased and prolonged postprandial lipemia has been identified as a risk factor of cardiovascular disease. However, there is no consensus on how to test postprandial lipemia, especially with respect to the composition of an experimental meal. To address this question of how glucose, when added to a fat load, affects the selected parameters of postprandial lipemia, we carried out a study in 30 healthy male volunteers. Men consumed an experimental meal containing either 75 g of fat + 25 g of glucose (F+G meal) or 75 g of fat (F meal) in a control experiment. Blood was taken before the meal and at selected time points within the following 8 h. Glucose, when added to a fat load, induced an increase of glycemia and insulinemia and, surprisingly, a 20 % reduction in the response of both total and active glucagon-like peptide-1 (GLP-1) concentration. The addition of glucose did not affect the magnitude of postprandial triglyceridemia and TRL-C and TRL-TG concentrations but stimulated a faster response of chylomicrons to the test meal, evaluated by changes in apolipoprotein B-48 concentrations. The addition of glucose induced the physiological response of insulin and the lower response of GLP-1 to the test meal during the early postprandial phase, but had no effect on changes of TRL-cholesterol and TRL-TG within 8 h after the meal.
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Affiliation(s)
- K. ZEMÁNKOVÁ
- Laboratory for Atherosclerosis Research, Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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14
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Nielsen ST, Janum S, Krogh-Madsen R, Solomon TP, Møller K. The incretin effect in critically ill patients: a case-control study. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2015; 19:402. [PMID: 26567860 PMCID: PMC4645481 DOI: 10.1186/s13054-015-1118-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 10/27/2015] [Indexed: 02/11/2023]
Abstract
Introduction Patients admitted to the intensive care unit often develop hyperglycaemia, but the underlying mechanisms have not been fully described. The incretin effect is reduced in patients with type 2 diabetes. Type 2 diabetes and critical illness have phenotypical similarities, such as hyperglycaemia, insulin resistance and systemic inflammation. Previous studies have shown beneficial effects of exogenous glucagon-like peptide (GLP)-1 on glycaemia in critically ill patients, a phenomenon also seen in patients with type 2 diabetes. In this study, we hypothesised that the incretin effect, which is mediated by the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP), is impaired in critically ill patients. Methods The incretin effect (i.e., the relative difference between the insulin response to oral and intravenous glucose administration) was investigated in a cross-sectional case–control study. Eight critically ill patients without diabetes admitted to a mixed intensive care unit and eight healthy control subjects without diabetes, matched at group level by age, sex and body mass index, were included in the study. All subjects underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the next day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide and plasma levels of GLP-1, GIP, glucagon and proinflammatory cytokines were measured intermittently. The incretin effect was calculated as the increase in insulin secretion during oral versus intravenous glucose administration in six patients. The groups were compared using either Student’s t test or a mixed model of repeated measurements. Results Blood glucose levels were matched between the OGTT and the IVGI in both groups. Compared with control subjects, proinflammatory cytokines, tumour necrosis factor α and interleukin 6, were higher in patients than in control subjects. The endogenous response of GIP and glucagon, but not GLP-1, to the OGTT was greater in patients. The insulin response to the OGTT did not differ between groups, whereas the insulin response to the IVGI was higher in patients. Consequently, the calculated incretin effect was lower in patients (23 vs. 57 %, p = 0.003). Conclusions In critically ill patients, the incretin effect was reduced. This resembles previous findings in patients with type 2 diabetes. Trial registration ClinicalTrials.gov identifier: NCT01347801. Registered on 2 May 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13054-015-1118-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Signe Tellerup Nielsen
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Susanne Janum
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Department of Anaesthesiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
| | - Rikke Krogh-Madsen
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
| | - Thomas P Solomon
- School of Sport, Exercise, and Rehabilitation Sciences, Centre for Endocrinology, Diabetes, and Metabolism, University of Birmingham, Birmingham, UK.
| | - Kirsten Møller
- Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. .,Neurointensive Care Unit, Department of Neuroanaesthesiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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15
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Wang F, Yoder SM, Yang Q, Kohan AB, Kindel TL, Wang J, Tso P. Chronic high-fat feeding increases GIP and GLP-1 secretion without altering body weight. Am J Physiol Gastrointest Liver Physiol 2015; 309:G807-15. [PMID: 26336929 PMCID: PMC4652142 DOI: 10.1152/ajpgi.00351.2013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 08/20/2015] [Indexed: 01/31/2023]
Abstract
The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), enhance postprandial insulin secretion, promote adipogenesis, and regulate gastrointestinal motility and food intake. To date, a consensus on how the incretin response is altered in obesity is lacking. We investigated the effects of chronic high-fat (HF) feeding on incretin secretion in the lymph fistula rat model. Male Sprague-Dawley rats (8 wk) were provided a semipurified AIN93M HF or low-fat (LF) diet ad libitum for 3 or 13 wk; a HF pair-fed (HF-PF) group was included as a control during the 3-wk feeding trial. Energy intake, body weight, and body composition were regularly monitored. At the culmination of the feeding period, an intestinal lymphatic duct cannula and duodenal infusion tube were installed. All animals were challenged with a 3-ml Ensure bolus (3.125 kcal/animal) to measure lymphatic incretin secretion. Despite a significantly higher energy intake, both the 3-wk and 13-wk HF-fed animals did not have an increase in body weight and only a slight increase in body fat compared with LF-fed rats. Following the duodenal Ensure challenge, the 3-wk and 13-wk HF-fed rats had significantly greater lymphatic GIP and GLP-1 secretion than the LF-fed animals. Additionally, the HF-PF group displayed a secretion profile similar to the HF-fed animals for GIP but a similar pattern to the LF-fed animals for GLP-1. The HF-PF data suggest that the increased GIP secretion is driven by the greater percentage of fat intake, whereas the increased GLP-1 secretion is driven by the excess caloric intake.
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Affiliation(s)
| | | | | | | | | | | | - Patrick Tso
- Department of Pathology and Laboratory, University of Cincinnati, Cincinnati, Ohio
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16
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Hashimoto KI, Horikawa Y, Takeda J. Complementary glucagonostatic and insulinotropic effects of DPP-4 inhibitors in the glucose-lowering action in Japanese patients with type 2 diabetes. Diabetol Int 2015; 7:133-140. [PMID: 30603256 DOI: 10.1007/s13340-015-0219-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 06/21/2015] [Indexed: 10/23/2022]
Abstract
The dipeptidyl peptidase-4 (DPP-4) inhibitors have a low risk of causing hypoglycemia as monotherapy. However, insulin administration is frequently required, particularly in patients with type 2 diabetes and with reduced insulin secretory capacity. The effects of adding DPP-4 inhibitors were evaluated using continuous glucose monitoring (CGM) in Japanese patients with type 2 diabetes who were insufficiently controlled by basal insulin with biguanide. The effects of adding DPP-4 inhibitors on blood glucose and plasma insulin and glucagon levels were evaluated. Δ glucagon showed a significant association with post-prandial glucose increase in the group with diminished insulin secretory capacity, C-peptide index (CPI) <0.8 (p = 0.016), while Δ C-peptide reached significant association in the group with relatively intact insulin secretory capacity, CPI ≥0.8 (p = 0.017). The mean plasma glucose levels and M values were similarly improved in patients treated with the three DPP-4 inhibitors. Hypoglycemia did not occur in any of the DPP-4 inhibitor groups. In conclusion, complementary glucagonostatic and insulinotropic effects of adding DPP-4 inhibitors are involved in the glucose-lowering action of Japanese patients with type 2 diabetes according to their insulin secretory capacity. Such combination therapy may well be a superior therapeutic option for the treatment of diabetes in Japanese patients who often exhibit reduced insulin secretory capacity.
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Affiliation(s)
- Ken-Ichi Hashimoto
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194 Japan
| | - Yukio Horikawa
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194 Japan
| | - Jun Takeda
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194 Japan
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17
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Oh TJ, Park KS, Cho YM. Correlation of the incretin effect with first- and second-phase insulin secretions in Koreans with various glucose tolerance statuses. Clin Endocrinol (Oxf) 2015; 83:59-66. [PMID: 25267549 DOI: 10.1111/cen.12623] [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] [Received: 06/26/2014] [Revised: 07/22/2014] [Accepted: 09/23/2014] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To examine the relationship between beta-cell function and the incretin effect. DESIGN We performed a 180-min hyperglycaemic clamp study with oral glucose administration at 60 min in Korean subjects with normal glucose tolerance (NGT, n = 9), impaired fasting glucose (IFG, n = 6) and type 2 diabetes mellitus (T2DM, n = 6). MEASUREMENTS First- and second-phase insulin secretions were measured during the first 60 min. The insulin response to intravenous glucose during the 60- to 120-min interval (Insiv) was calculated using a prediction method. The insulin response to oral glucose (Ins(oral)) was calculated by subtracting the Insiv from the overall insulin response during the 60- to 120-min interval (Ins(overall)). The incretin effect under the hyperglycaemic clamp condition (IE(clamp)) was calculated by the equation: 100 × [(Ins(overall) - Insiv)/Ins(overall)]. RESULTS The IE(clamp) was comparable among the three groups (46.3 ± 6.4%, 35.7 ± 8.8% and 51.4 ± 7.4% for the NGT, IFG and T2DM group, respectively, P = 0.327) and was not correlated with the first- and second-phase insulin secretions. However, the Ins(oral) (mU/l 60 min) was significantly different between the NGT, IFG and T2DM groups (5199 ± 1185, 2164 ± 956 and 1034 ± 355, respectively; P = 0.010) and was well correlated with the first- and second-phase insulin secretions. CONCLUSIONS The incretin effect measured by the hyperglycaemic clamp with oral glucose loading was neither correlated with beta-cell function nor different between NGT, IFG and T2DM groups in Koreans.
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Affiliation(s)
- Tae Jung Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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18
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Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal. J Neurol 2015; 262:1946-53. [DOI: 10.1007/s00415-015-7799-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/23/2015] [Accepted: 05/25/2015] [Indexed: 02/07/2023]
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19
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Boronikolos GC, Menge BA, Schenker N, Breuer TGK, Otte JM, Heckermann S, Schliess F, Meier JJ. Upper gastrointestinal motility and symptoms in individuals with diabetes, prediabetes and normal glucose tolerance. Diabetologia 2015; 58:1175-82. [PMID: 25725624 DOI: 10.1007/s00125-015-3538-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 02/02/2015] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS Type 2 diabetes has been associated with upper gastrointestinal motility dysfunction, but the relationship with diabetes duration and glucose control is less well understood. Gastric emptying, oesophageal motility and gastrointestinal symptoms were examined in volunteers with diabetes, prediabetes (impaired fasting glucose [IFG] or impaired glucose tolerance [IGT]) and normal glucose tolerance (NGT). METHODS The study included 41 patients with type 2 diabetes, 17 individuals with IFG/IGT and 31 individuals with NGT. A gastric emptying breath test and high-resolution oesophageal manometry were performed. Gastrointestinal symptoms were assessed using questionnaires. RESULTS Gastric emptying was delayed in individuals with IFG/IGT (p < 0.05) but was normal in the diabetic group. Amongst the diabetic patients, gastric emptying rate was fastest in those with longer diabetes duration and the highest HbA1c levels (p < 0.001). Oesophageal motility variables were similar between the groups. However, the lower oesophagus resting pressure was reduced in patients with longer diabetes duration (p = 0.01). Abdominal pain/discomfort was more frequent amongst patients with diabetes (p = 0.04) but was unrelated to gastric emptying. Significant associations between various oesophageal motility variables and gastrointestinal symptoms were observed. CONCLUSIONS/INTERPRETATION Gastric emptying and oesophageal motility are not generally altered in patients with type 2 diabetes. In more advanced disease stages, however, gastric emptying and oesophageal motility may be disturbed, probably as a consequence of autonomic neuropathy. Delayed gastric emptying in IFG/IGT individuals might be secondary to acute hyperglycaemia. Determination of gastric emptying and oesophageal manometry should be considered for the diagnostic workup of patients with diabetes and gastrointestinal symptoms.
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Affiliation(s)
- Georgios C Boronikolos
- Diabetes Division, Department of Medicine I, St Josef Hospital, Ruhr University Bochum, Gudrunstr. 56, 44791, Bochum, Germany
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20
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Cho YM. Incretin physiology and pathophysiology from an Asian perspective. J Diabetes Investig 2014; 6:495-507. [PMID: 26417406 PMCID: PMC4578486 DOI: 10.1111/jdi.12305] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 10/21/2014] [Indexed: 12/25/2022] Open
Abstract
Incretin hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted on oral nutrient ingestion and regulate postprandial glucose homeostasis by conveying the signal of intestinal glucose flux. In East Asians, the secretion of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 is not reduced in type 2 diabetes relative to normal glucose tolerance. Although the incretin effect is blunted in European patients with type 2 diabetes, a few East Asian studies showed no difference in the incretin effect between type 2 diabetes and normal glucose tolerance. Interestingly, the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 receptor agonists was reported to be greater in Asians than in non-Asians. The difference in the treatment responses could be ascribed to a different pathophysiology of type 2 diabetes (lower insulin secretory function and less insulin resistance), lower body mass index, different genetic makeups, preserved incretin effect and different food compositions in East Asians compared with other ethnic groups. Based on the currently available data, incretin-based therapies appear to be safe and well tolerated in East Asians. Nevertheless, continuous pharmacovigilance is required. The characteristics of incretin biology and treatment responses to incretin-based therapies should be considered in developing ethnicity-specific treatment guidelines and making patient-centered decisions for patients with type 2 diabetes.
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Affiliation(s)
- Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine Seoul, Korea
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21
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Fernández-García JC, Murri M, Coin-Aragüez L, Alcaide J, El Bekay R, Tinahones FJ. GLP-1 and peptide YY secretory response after fat load is impaired by insulin resistance, impaired fasting glucose and type 2 diabetes in morbidly obese subjects. Clin Endocrinol (Oxf) 2014; 80:671-6. [PMID: 23573808 DOI: 10.1111/cen.12221] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Revised: 02/20/2013] [Accepted: 04/06/2013] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Both glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are gut hormones involved in energy homoeostasis. Obesity, insulin resistance and hyperglycaemia are significant confounders when GLP-1 and PYY secretion is assessed. Thus, we evaluated GLP-1 and PYY response after fat load in morbidly obese patients with different degrees of insulin resistance and glycemic status. DESIGN We studied 40 morbidly obese subjects (mean age, 40·6 ± 1·3 years; mean BMI, 53·1 ± 1·2 kg/m(2) ) divided into groups according to their glycemic status: normal fasting glucose (NFG) group, impaired fasting glucose (IFG) group and type 2 diabetes mellitus (T2D) group. NFG patients were additionally subclassified, according to the homoeostasis model assessment of insulin resistance (HOMAIR ), into a low insulin-resistance (LIR) group (HOMAIR <3·9) or a high insulin-resistance (HIR) group (HOMAIR ≥3·9). MEASUREMENTS Lipid emulsion was administered orally and measurements made at baseline and 180 min postprandially of levels of GLP-1, PYY, insulin, glucose, free fatty acids, triglycerides and leptin. RESULTS At the 180-minute postprandial reading, GLP-1 and PYY had increased in LIR-NFG subjects (41·84%, P = 0·01; 35·7%, P = 0·05; respectively), whereas no changes were observed in HIR-NFG, IFG or T2D subjects. CONCLUSIONS These results suggest that in morbidly obese subjects, both insulin resistance and abnormal glucose metabolism (IFG or T2D) impair the GLP-1 and PYY response to fat load. The implications of this attenuated enteroendocrine response should be elucidated by further studies.
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Affiliation(s)
- José C Fernández-García
- Department of Endocrinology, Virgen de la Victoria University Hospital, Málaga, Spain; Research laboratory, Virgen de la Victoria University Hospital, Málaga, Spain; Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBERObn CB06/003), Instituto de Salud Carlos III, Madrid, Spain
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Gerich J. Pathogenesis and management of postprandial hyperglycemia: role of incretin-based therapies. Int J Gen Med 2013; 6:877-95. [PMID: 24403842 PMCID: PMC3884108 DOI: 10.2147/ijgm.s51665] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Postprandial plasma glucose concentrations are an important contributor to glycemic control. There is evidence suggesting that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that predominantly reduce postprandial plasma glucose levels. DPP-4 inhibitors are associated with fewer gastrointestinal side effects than GLP-1 receptor agonists and are administered orally, unlike GLP-1 analogs, which are administered as subcutaneous injections. GLP-1 receptor agonists are somewhat more effective than DPP-4 inhibitors in reducing postprandial plasma glucose and are usually associated with significant weight loss. For these reasons, GLP-1 receptor agonists are generally preferred over DPP-4 inhibitors as part of combination treatment regimens in patients with glycated hemoglobin levels above 8.0%. This article reviews the pathogenesis of postprandial hyperglycemia, the mechanisms by which GLP-1 receptor agonists and DPP-4 inhibitors reduce postprandial plasma glucose concentrations, and the results of recent clinical trials (ie, published 2008 to October 2012) that evaluated the effects of these agents on postprandial plasma glucose levels when evaluated as monotherapy compared with placebo or as add-on therapy to metformin, a sulfonylurea, or insulin. Findings from recent clinical studies suggest that both GLP-1 receptor agonists and DPP-4 inhibitors could become valuable treatment options for optimizing glycemic control in patients unable to achieve glycated hemoglobin goals on basal insulin, with the added benefits of weight loss and a low risk of hypoglycemia.
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Affiliation(s)
- John Gerich
- Department of Medicine, Endocrine/Metabolism Division, University of Rochester School of Medicine, Rochester, NY, USA
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Opinto G, Natalicchio A, Marchetti P. Physiology of incretins and loss of incretin effect in type 2 diabetes and obesity. Arch Physiol Biochem 2013; 119:170-8. [PMID: 23859800 DOI: 10.3109/13813455.2013.812664] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
An important role in the regulation of glucose homeostasis is played by incretins, which are gut-derived hormones released in response to nutrient ingestion. In humans, the major incretin hormones are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), and together they fully account for the incretin effect (that is, higher insulin release in response to an oral glucose challenge compared to an equal intravenous glucose load). Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, and the loss of incretin effect is likely to contribute importantly to the postprandial hyperglycaemia in type 2 diabetes. However, the specific cause-effect relationship between disease and incretins is still unclear. This review focuses on several key studies elucidating the association of defective incretin action with obesity and T2DM and the effects of metformin and other anti-diabetic agents on the incretin system.
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Affiliation(s)
- Giuseppina Opinto
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari School of Medicine , Bari , Italy and
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Bonde L, Vilsbøll T, Nielsen T, Bagger JI, Svare JA, Holst JJ, Larsen S, Knop FK. Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus. Diabetes Obes Metab 2013; 15:713-20. [PMID: 23406269 DOI: 10.1111/dom.12082] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 10/24/2012] [Accepted: 01/20/2013] [Indexed: 01/23/2023]
Abstract
AIM We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established. METHODS Eleven women with GDM [plasma glucose (PG) concentration at 120 min after a 75-g oral glucose tolerance test (OGTT): 10.0 ± 0.9 mM (mean ± SD); age: 31 ± 6 years; body mass index (BMI): 31.6 ± 6.4 kg/m(2) ; haemoglobin A1c (HbA1c): 5.6 ± 0.5%] and eight pregnant women with NGT (PG(120 min), OGTT : 5.7 ± 0.7 mM; age: 28 ± 3 years; BMI: 29.7 ± 5.4 kg/m(2) ; HbA1c: 5.4 ± 0.3%) were investigated with a 4-h liquid meal test during third trimester (TT) and 3-4 months postpartum (PP). All patients with GDM re-established NGT following delivery. RESULTS Pregnancy was associated with low postprandial GLP-1 responses. Patients with GDM exhibited reduced postprandial GLP-1 responses compared to their PP levels [area under curve (AUC): 5.5 ± 1.3 vs. 8.4 ± 3.2 nM × min, p=0.005], but the difference among NGT women (7.3 ± 2.8 vs. 8.8 ± 2.0 nM × min, p=0.066) was not statistically significant. Pregnancy did not influence postprandial responses of the other incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in any of the groups, but GDM patients were characterized by greater postprandial GIP responses during both TT and PP compared to NGT subjects. CONCLUSIONS Pregnancy is associated with reduced postprandial GLP-1 responses (most pronounced in patients with GDM) that normalize after delivery. In contrast, postprandial GIP responses seem unaffected by pregnancy but is increased in GDM patients.
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Affiliation(s)
- L Bonde
- Department of Internal Medicine, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
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25
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Solomon TPJ, Knudsen SH, Karstoft K, Winding K, Holst JJ, Pedersen BK. Examining the effects of hyperglycemia on pancreatic endocrine function in humans: evidence for in vivo glucotoxicity. J Clin Endocrinol Metab 2012; 97:4682-91. [PMID: 23043193 DOI: 10.1210/jc.2012-2097] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Investigating the impact of hyperglycemia on pancreatic endocrine function promotes our understanding of the pathophysiology of hyperglycemia-related disease. OBJECTIVE The objective of the study was to test the hypothesis that experimental hyperglycemia impairs insulin and glucagon secretion. DESIGN A randomized, crossover in healthy controls, compared with type 2 diabetic patients. SETTING The study was conducted at a university hospital. PARTICIPANTS Normal glucose-tolerant subjects (n = 10) and patients with type 2 diabetes (n = 10), individually matched by age, sex, and body mass index. INTERVENTIONS Normal glucose-tolerant subjects underwent 24 h of experimental hyperglycemia (+5.4 mm above basal). Subjects with type 2 diabetes did not undergo an intervention. MAIN OUTCOME MEASURES Insulin secretion, glucagon secretion, insulin sensitivity, disposition index, and endogenous glucose production (via [6,6-(2)H(2)]glucose infusion) were measured during hyperglycemic clamps combined with infusion of glucagon-like peptide (GLP)-1(7-36) (0.5 pmol/kg · min) and injection of arginine (5 g). RESULTS Insulin secretion was correlated with glucagon suppression in subjects with normal glucose tolerance only. Individuals with type 2 diabetes had lower insulin sensitivity (-33 ± 11%) and insulin secretory responses to glucose, GLP-1, and arginine (-40 ± 11, -58 ± 7, and -36 ± 13%, respectively) and higher plasma glucagon and endogenous glucose production compared with normal glucose-tolerant subjects (all P < 0.05). After 24 h of experimental hyperglycemia, insulin sensitivity (-29 ± 10%), disposition index (-24 ± 16%), and GLP-1- (-19 ± 7%) and arginine-stimulated (-15 ± 10%) insulin secretion were decreased in normal glucose-tolerant subjects (all P < 0.05). However, plasma glucagon responses were not affected. Furthermore, experimental hyperglycemia abolished the correlation between insulin secretion and glucagon suppression. CONCLUSIONS Experimental hyperglycemia impaired pancreatic β-cell function but did not acutely impair α-cell glucagon secretion in normal glucose-tolerant subjects.
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Affiliation(s)
- Thomas P J Solomon
- The Centre of Inflammation and Metabolism, Department of Infectious Diseases, Rigshospitalet, Copenhagen 2100, Denmark.
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Salehi M, Aulinger B, D'Alessio DA. Effect of glycemia on plasma incretins and the incretin effect during oral glucose tolerance test. Diabetes 2012; 61:2728-33. [PMID: 22733799 PMCID: PMC3478560 DOI: 10.2337/db11-1825] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The incretin effect, reflecting the enhancement of postprandial insulin secretion by factors including the intestinal hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, increases in proportion to meal size. However, it is unknown whether the incretin effect is dependent on ambient glucose. The goal of this study was to determine the effect of plasma glycemia on the incretin effect. Thirteen healthy subjects consumed 50 g oral glucose solution mixed with d-xylose during fixed hyperglycemia at 8 and 10.5 mmol/L, on 3 separate days, twice at lower glycemia (LOW) and once at higher values (HIGH). The relative increase in insulin release after glucose ingestion at fixed hyperglycemia, a surrogate for the incretin effect, was similar among all three studies. The GLP-1 response to oral glucose was significantly lower at higher plasma glycemia, as was the appearance of d-xylose after the meal. Between the two LOW studies, the reproducibility of insulin release in response to intravenous glucose alone and intravenous plus ingested glucose was similar. These findings indicate that the incretin contribution to postprandial insulin release is independent of glycemia in healthy individuals, despite differences in GLP-1 secretion. The incretin effect is a reproducible trait among humans with normal glucose tolerance.
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Affiliation(s)
- Marzieh Salehi
- Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
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27
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Moore MC, Coate KC, Winnick JJ, An Z, Cherrington AD. Regulation of hepatic glucose uptake and storage in vivo. Adv Nutr 2012; 3:286-94. [PMID: 22585902 PMCID: PMC3649460 DOI: 10.3945/an.112.002089] [Citation(s) in RCA: 246] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
In the postprandial state, the liver takes up and stores glucose to minimize the fluctuation of glycemia. Elevated insulin concentrations, an increase in the load of glucose reaching the liver, and the oral/enteral/portal vein route of glucose delivery (compared with the peripheral intravenous route) are factors that increase the rate of net hepatic glucose uptake (NHGU). The entry of glucose into the portal vein stimulates a portal glucose signal that not only enhances NHGU but concomitantly reduces muscle glucose uptake to ensure appropriate partitioning of a glucose load. This coordinated regulation of glucose uptake is likely neurally mediated, at least in part, because it is not observed after total hepatic denervation. Moreover, there is evidence that both the sympathetic and the nitrergic innervation of the liver exert a tonic repression of NHGU that is relieved under feeding conditions. Further, the energy sensor 5'AMP-activated protein kinase appears to be involved in regulation of NHGU and glycogen storage. Consumption of a high-fat and high-fructose diet impairs NHGU and glycogen storage in association with a reduction in glucokinase protein and activity. An understanding of the impact of nutrients themselves and the route of nutrient delivery on liver carbohydrate metabolism is fundamental to the development of therapies for impaired postprandial glucoregulation.
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Affiliation(s)
- Mary Courtney Moore
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Katie C. Coate
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN,current address: Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX
| | - Jason J. Winnick
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Zhibo An
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN,current address: Department of Medicine, Division of Endocrinology, University of Cincinnati Medical Center, Cincinnati, OH
| | - Alan D. Cherrington
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN
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Carrel G, Egli L, Tran C, Schneiter P, Giusti V, D'Alessio D, Tappy L. Contributions of fat and protein to the incretin effect of a mixed meal. Am J Clin Nutr 2011; 94:997-1003. [PMID: 21849595 PMCID: PMC3742299 DOI: 10.3945/ajcn.111.017574] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The relative contributions of fat and protein to the incretin effect are still largely unknown. OBJECTIVE This study assessed the incretin effects elicited by a mixed meal, and by its fat and protein components alone, with the use of a hyperglycemic clamp combined with oral nutrients. DESIGN Eight healthy volunteers were studied over 6 h after ingestion of a sandwich containing 1) dried meat, butter, and white bread; 2) dried meat alone; 3) butter alone; or 4) no meal (fasting control). Meals were ingested during a hyperglycemic clamp, and the incretin effect was calculated as the increment in plasma insulin after food intake relative to the concentrations observed during the control study. RESULTS A significant augmentation of postprandial insulin secretion, independent of plasma glycemia, occurred after ingestion of the mixed nutrients and the lipid component of the mixed meal (203 ± 20.7% and 167.4 ± 22.9% of control, respectively; both P < 0.05), whereas the protein component did not induce a significant incretin effect (129.0 ± 7.9% of control; P = 0.6) CONCLUSIONS Fat ingestion, in an amount typical of a standard meal, increases insulin secretion during physiologic hyperglycemia and thus contributes to the incretin effect. In contrast, ingestion of protein typical of normal meals does not contribute to the augmentation of postprandial insulin secretion. This trial was registered at clinicaltrials.gov as NCT00869453.
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Affiliation(s)
- Guillaume Carrel
- Department of Physiology, University of Lausanne, Lausanne, Switzerland
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29
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Samocha-Bonet D, Wong O, Synnott EL, Piyaratna N, Douglas A, Gribble FM, Holst JJ, Chisholm DJ, Greenfield JR. Glutamine reduces postprandial glycemia and augments the glucagon-like peptide-1 response in type 2 diabetes patients. J Nutr 2011; 141:1233-8. [PMID: 21593352 PMCID: PMC7212026 DOI: 10.3945/jn.111.139824] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Impaired glucagon-like peptide (GLP-1) secretion or response may contribute to ineffective insulin release in type 2 diabetes. The conditionally essential amino acid glutamine stimulates GLP-1 secretion in vitro and in vivo. In a randomized, crossover study, we evaluated the effect of oral glutamine, with or without sitagliptin (SIT), on postprandial glycemia and GLP-1 concentration in 15 type 2 diabetes patients (glycated hemoglobin 6.5 ± 0.6%). Participants ingested a low-fat meal (5% fat) after receiving either water (control), 30 g l-glutamine (Gln-30), 15 g L-glutamine (Gln-15), 100 mg SIT, or 100 mg SIT and 15 g L-glutamine (SIT+Gln-15). Studies were conducted 1-2 wk apart. Blood was collected at baseline and postprandially for 180 min for measurement of circulating glucose, insulin, C-peptide, glucagon, and total and active GLP-1. Gln-30 and SIT+Gln-15 reduced the early (t = 0-60 min) postprandial glycemic response compared with control. All Gln treatments enhanced the postprandial insulin response from t = 60-180 min but had no effect on the C-peptide response compared with control. The postprandial glucagon concentration was increased by Gln-30 and Gln-15 compared with control, but the insulin:glucagon ratio was not affected by any treatment. In contrast to Gln-30, which tended to increase the total GLP-1 AUC, SIT tended to decrease the total GLP-1 AUC relative to control (both P = 0.03). Gln-30 and SIT increased the active GLP-1 AUC compared with control (P = 0.008 and P = 0.01, respectively). In summary, Gln-30 decreased the early postprandial glucose response, enhanced late postprandial insulinemia, and augmented postprandial active GLP-1 responses compared with control. These findings suggest that glutamine may be a novel agent for stimulating GLP-1 concentration and limiting postprandial glycemia in type 2 diabetes.
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Affiliation(s)
- Dorit Samocha-Bonet
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
| | - Olivia Wong
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
| | - Emma-Leigh Synnott
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
| | - Naomi Piyaratna
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
| | - Ashley Douglas
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
| | - Fiona M Gribble
- The Cambridge Institute of Medical Research and Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom
| | - Jens J. Holst
- Department of Medical Physiology, University of Copenhagen, the Panum Institute, Copenhagen, Denmark
| | - Donald J. Chisholm
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
- Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Jerry R Greenfield
- Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
- Faculty of Medicine, University of New South Wales, Sydney, Australia
- Department of Endocrinology and Diabetes Center, St. Vincent’s Hospital, Sydney, Australia
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Holst JJ, Knop FK, Vilsbøll T, Krarup T, Madsbad S. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 2011; 34 Suppl 2:S251-7. [PMID: 21525464 PMCID: PMC3632188 DOI: 10.2337/dc11-s227] [Citation(s) in RCA: 207] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Jens J Holst
- Department of Biomedical Sciences, Panum Institute, Copenhagen, Denmark.
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31
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Lee SH, Kim JH, Shin JA, Kim ES, Cho JH, Ko SH, Yoon KH, Ahn YB. Incretin secretion is not restored by short-term strict glycaemic control in Korean hyperglycaemic patients with type 2 diabetes. Diabetes Res Clin Pract 2011; 92:74-81. [PMID: 21292338 DOI: 10.1016/j.diabres.2011.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 01/05/2011] [Accepted: 01/10/2011] [Indexed: 10/18/2022]
Abstract
AIMS To determine whether short-term strict glycaemic control could restore incretin secretion in type 2 diabetic patients. The factors associated with incretin levels were also investigated. METHODS A meal tolerance test (MTT) was performed in eighteen poorly controlled (pDM) and fifteen well controlled (wDM) diabetic patients. Fourteen patients in the pDM group underwent follow-up MTT after strict glycaemic control. The secretions of intact glucagon-like peptide-1 (iGLP-1) and total glucose-dependent insulinotropic polypeptide (tGIP) during MTT were calculated by total and incremental area under the curve (TAUC and IAUC) values. RESULTS Posttreatment HbA1c level was significantly improved in the pDM group (11.2±0.9 to 7.9±0.9%). However, the secretion of incretin hormones was not increased in the posttreatment pDM group (TAUCiGLP-1, 3612±587 to 2916±405 pmol/L min; TAUCtGIP, 9417±1099 to 8338±903 pmol/L min). IAUCiGLP-1 was negatively correlated (r=-0.446, P=0.011) and independently associated (β=-137.2, P=0.027) with insulin resistance assessed by homeostasis model assessment. CONCLUSIONS Incretin secretion is not restored by short-term strict glycaemic control. Decreased incretin secretion seems to develop early in the course of type 2 diabetes with increasing insulin resistance, but not to be influenced by glycaemic status.
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Affiliation(s)
- Seung-Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, The Catholic University of Korea, St. Vincent's Hospital, 93-6, Ji-dong, Paldal-gu, Suwon 442-723, Republic of Korea
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Abstract
Novel therapeutic options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were introduced in 2005. Incretin-based therapies consist of two classes: (1) the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor and (2) dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) as oral medications raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In type 2 diabetes therapy, incretin-based therapies are attractive and more commonly used due to their action and safety profile. Stimulation of insulin secretion and inhibition of glucagon secretion by the above-mentioned agents occur in a glucose-dependent manner. Therefore, incretin-based therapies have no intrinsic risk for hypoglycemias. GLP-1 receptor agonists allow weight loss; DPP-4 inhibitors are weight neutral. This review gives an overview on the mechanism of action and the substances and clinical data available.
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Affiliation(s)
- Baptist Gallwitz
- Medizinische Klinik IV, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.
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33
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Solomon TP, Haus JM, Kelly KR, Cook MD, Filion J, Rocco M, Kashyap SR, Watanabe RM, Barkoukis H, Kirwan JP. A low-glycemic index diet combined with exercise reduces insulin resistance, postprandial hyperinsulinemia, and glucose-dependent insulinotropic polypeptide responses in obese, prediabetic humans. Am J Clin Nutr 2010; 92:1359-68. [PMID: 20980494 PMCID: PMC2980961 DOI: 10.3945/ajcn.2010.29771] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Accepted: 09/19/2010] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The optimal lifestyle intervention that reverses diabetes risk factors is not known. OBJECTIVE We examined the effect of a low-glycemic index (GI) diet and exercise intervention on glucose metabolism and insulin secretion in obese, prediabetic individuals. DESIGN Twenty-two participants [mean ± SEM age: 66 ± 1 y; body mass index (in kg/m(2)): 34.4 ± 0.8] underwent a 12-wk exercise-training intervention (1 h/d for 5 d/wk at ≈ 85% of maximum heart rate) while randomly assigned to receive either a low-GI diet (LoGIX; 40 ± 0.3 units) or a high-GI diet (HiGIX; 80 ± 0.6 units). Body composition (measured by using dual-energy X-ray absorptiometry and computed tomography), insulin sensitivity (measured with a hyperinsulinemic euglycemic clamp with [6,6-(2)H(2)]-glucose), and oral glucose-induced insulin and incretin hormone secretion were examined. RESULTS Both groups lost equal amounts of body weight (-8.8 ± 0.9%) and adiposity and showed similar improvements in peripheral tissue (+76.2 ± 14.9%) and hepatic insulin sensitivity (+27.1 ± 7.1%) (all P < 0.05). However, oral glucose-induced insulin secretion was reduced only in the LoGIX group (6.59 ± 0.86 nmol in the prestudy compared with 4.70 ± 0.67 nmol in the poststudy, P < 0.05), which was a change related to the suppressed postprandial response of glucose-dependent insulinotropic polypeptide. When corrected for changes in β cell glucose exposure, changes in insulin secretion were attenuated in the LoGIX group but became significantly elevated in the HiGIX group. CONCLUSIONS Although lifestyle-induced weight loss improves insulin resistance in prediabetic individuals, postprandial hyperinsulinemia is reduced only when a low-GI diet is consumed. In contrast, a high-GI diet impairs pancreatic β cell and intestinal K cell function despite significant weight loss. These findings highlight the important role of the gut in mediating the effects of a low-GI diet on type 2 diabetes risk reduction.
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Affiliation(s)
- Thomas Pj Solomon
- Department of Pathobiology, Lerner Research Institute and Nutrition, Case Western Reserve University, Cleveland, OH, USA.
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Kuo P, Wishart JM, Bellon M, Smout AJ, Holloway RH, Fraser RJL, Horowitz M, Jones KL, Rayner CK. Effects of physiological hyperglycemia on duodenal motility and flow events, glucose absorption, and incretin secretion in healthy humans. J Clin Endocrinol Metab 2010; 95:3893-3900. [PMID: 20501683 DOI: 10.1210/jc.2009-2514] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
CONTEXT Acute hyperglycemia slows gastric emptying, but its effects on small intestinal motor activity and glucose absorption are unknown. In type 2 diabetes, the postprandial secretion of glucose-dependent insulinotropic polypeptide (GIP) is preserved, but that of glucagon-like peptide-1 (GLP-1) is possibly reduced; whether the latter is secondary to hyperglycemia or diabetes per se is unknown. AIM The aim was to investigate the effects of acute hyperglycemia on duodenal motility and flow events, glucose absorption, and incretin hormone secretion. METHODS Nine healthy volunteers were studied on two occasions. A combined manometry/impedance catheter was positioned in the duodenum. Blood glucose was clamped at either 9 mmol/liter (hyperglycemia) or 5 mmol/liter (euglycemia) throughout the study. Manometry and impedance recordings continued between T=-10 min and T=180 min. Between T=0 and 60 min, an intraduodenal glucose infusion was given (approximately 3 kcal/min), together with 14C-labeled 3-O-methylglucose (3-OMG) to evaluate glucose absorption. RESULTS Hyperglycemia had no effect on duodenal pressure waves or flow events during the 60 min of intraduodenal glucose infusion, when compared to euglycemia. During hyperglycemia, there was an increase in plasma GIP (P<0.05) and 14C-3-OMG (P<0.05) but no effect on GLP-1 concentrations in response to the intraduodenal infusion, compared to euglycemia. CONCLUSION Acute hyperglycemia in the physiological range has no effect on duodenal pressure waves and flow events but is associated with increased GIP secretion and rate of glucose absorption in response to intraduodenal glucose.
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Affiliation(s)
- Paul Kuo
- Discipline of Medicine, University of Adelaide, Level 6, Eleanor Harrald Building, Royal Adelaide Hospital, Adelaide, Australia
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Gallwitz B. The evolving place of incretin-based therapies in type 2 diabetes. Pediatr Nephrol 2010; 25:1207-17. [PMID: 20130920 PMCID: PMC2874027 DOI: 10.1007/s00467-009-1435-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2009] [Revised: 11/09/2009] [Accepted: 11/25/2009] [Indexed: 12/25/2022]
Abstract
Treatment options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were first introduced in 2005. These comprise the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor on the one hand and orally active dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In adult medicine, both treatment options are attractive and more commonly used because of their action and safety profile. The incretin-based therapies stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner and carry no intrinsic risk of hypoglycaemia. GLP-1 receptor agonists allow weight loss, whereas DPP-4 inhibitors are weight neutral. This review gives an overview of the mechanism of action and the substances and clinical data available.
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Affiliation(s)
- Baptist Gallwitz
- Medizinische Klinik IV, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.
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36
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Radulescu A, Gannon MC, Nuttall FQ. The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato. J Clin Endocrinol Metab 2010; 95:3385-91. [PMID: 20444922 PMCID: PMC3213865 DOI: 10.1210/jc.2009-2559] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
INTRODUCTION We are interested in the metabolic response to ingested macronutrients and the interaction between macronutrients in meals. Recently, we have determined the insulin and glucose response to ingestion of lard, olive oil, or safflower oil, fat sources varying in fatty acid composition and carbohydrate (CHO), in the form of potato. OBJECTIVE Our aim was to determine the effect of these dietary fats ingested alone or with potato on glucagon, glucagon-like peptide-1 (GLP-1) (7-37 and 7-36 amide), and total and acyl-ghrelin concentrations. METHODS Healthy subjects ingested 25 g fat (lard, olive oil, or safflower oil), 50 g CHO (potato), 25 g fat with 50 g CHO, or water only. Glucagon, GLP-1 (7-37 and 7-36 amide), and total and acyl-ghrelin responses were determined over 4 h. RESULTS All fats when ingested alone increased glucagon. Glucagon increases were dramatically attenuated when fats were ingested with the potato. GLP-1 increased after all meals, but was greatest when fats were ingested alone. The fat-stimulated increase was completely negated when fats were ingested with potato. Both acyl and total ghrelin decreased when only fats were ingested, as expected. When potato was ingested with any of the fats, the fat-induced decrease in acyl-ghrelin response also was essentially negated. Paradoxically, ghrelin increased when potato alone was ingested. CONCLUSIONS The current data indicate that the glucagon, GLP-1 and ghrelin responses to ingested fats, varying in fatty acid composition, are significantly affected by co-ingestion of CHO. Overall, the interaction between ingested foods in general is likely to be complex.
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Affiliation(s)
- Angela Radulescu
- Endocrine, Metabolism, and Nutrition Section (111G), Veterans Affairs Medical Center, Minneapolis, MN 55417, USA
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Diab DL, D'Alessio DA. The contribution of enteroinsular hormones to the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep 2010; 10:192-8. [PMID: 20425582 DOI: 10.1007/s11892-010-0114-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gastrointestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), termed incretins, are essential regulators of normal glucose homeostasis. Research indicates that the incretin effect is impaired in type 2 diabetes, and this seems to be a consequence rather than a cause of type 2 diabetes. This review describes the defects in the incretin system seen in diabetic patients and discusses the potential roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes. In addition, new information on clinical applications that exploit the enteroinsular axis to control blood glucose is discussed.
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Affiliation(s)
- Dima L Diab
- Division of Endocrinology/Metabolism, Cincinnati VA Medical Center, University of Cincinnati, ML 0547, Vontz Center, Cincinnati, OH 45220-0547, USA
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Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function? Diabetes 2010; 59:1117-25. [PMID: 20427697 PMCID: PMC2857890 DOI: 10.2337/db09-1899] [Citation(s) in RCA: 148] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Juris J Meier
- Department of Medicine I, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
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Maffeis C, Surano MG, Cordioli S, Gasperotti S, Corradi M, Pinelli L. A high-fat vs. a moderate-fat meal in obese boys: nutrient balance, appetite, and gastrointestinal hormone changes. Obesity (Silver Spring) 2010; 18:449-55. [PMID: 19713952 DOI: 10.1038/oby.2009.271] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Meal composition is a contributing factor to fat gain. In this study, we investigated the relationship between postprandial nutrient balance, satiety, and hormone changes induced by a high-fat meal vs. a moderate-fat meal. Ten prepubertal obese boys (BMI z-score range: 1.3-3.0) were recruited. Two meals (energy: 590 kcal) were compared: (i) high-fat (HF) meal: 12% protein, 52% fat, 36% carbohydrates; (ii) moderate-fat (MF) meal: 12% protein, 27% fat, 61% carbohydrates. Pre- and postprandial (5 h) substrate oxidation (indirect calorimetry), appetite (visual analogue scale), biochemical parameters and gastrointestinal hormone concentrations were measured. Carbohydrate balance was significantly (P < 0.001) lower (31.3 (5.7) g/5 h vs. 66.9 (5.9) g/5 h) and fat balance was significantly (P < 0.001) higher (11.5 (3.3) g/5 h vs. -0.7 (2.9) g/5 h) after HF than MF meal. Appetite (area under the curve (AUC)) was significantly reduced after an MF than an HF meal (494 (55) cm.300 min vs. 595 (57) cm.300 min, P < 0.05). Postprandial triglyceride concentration (AUC) was significantly (P < 0.05) higher after an HF than an MF meal: 141.1 (30.3) mmol.300 min/l vs. 79.3 (23.8) mmol.300 min/l, respectively. Peptide YY (PYY), cholecystokinin (CCK), and ghrelin concentrations (AUC) were not significantly different after an HF and MF meal. Glucagon-like peptide-1 (GLP-1) was significantly (P < 0.05) higher after an HF than after an MF meal (72.3 (9.8) ng/ml vs. 22.7 (7.6) ng/ml, respectively), but it did not affect subjective appetite. In conclusion, an MF meal induced a better postprandial metabolic nutrient balance, triglyceride levels, and appetite suppression than an HF meal. Gastrointestinal hormones were not related to clinically assessed hunger suppression after both meals.
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Affiliation(s)
- Claudio Maffeis
- Regional Center for Juvenile Diabetes, Department of Mother and Child, Biology-Genetics, Section of Pediatrics, University of Verona, Verona, Italy.
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Carr RD, Larsen MO, Jelic K, Lindgren O, Vikman J, Holst JJ, Deacon CF, Ahrén B. Secretion and dipeptidyl peptidase-4-mediated metabolism of incretin hormones after a mixed meal or glucose ingestion in obese compared to lean, nondiabetic men. J Clin Endocrinol Metab 2010; 95:872-8. [PMID: 20008019 DOI: 10.1210/jc.2009-2054] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are cleaved by dipeptidyl peptidase-4 (DPP-4); plasma activity of DPP-4 may be increased in obesity. The impact of this increase on incretin hormone secretion and metabolism is not known. OBJECTIVE The aim of the study was to assess incretin hormone secretion and degradation in lean and obese nondiabetic subjects. DESIGN, SETTINGS, AND PARTICIPANTS We studied the ingestion of a mixed meal (560 kcal) or oral glucose (2 g/kg) in healthy lean (n = 12; body mass index, 20-25 kg/m(2)) or obese (n = 13; body mass index, 30-35 kg/m(2)) males at a University Clinical Research Unit. MAIN OUTCOME MEASURES We measured the area under the curve of plasma intact (i) and total (t) GIP and GLP-1 after meal ingestion and oral glucose. RESULTS Plasma DPP-4 activity was higher in the obese subjects (38.5 +/- 3.0 vs. 26.7 +/- 1.6 mmol/min . microl; P = 0.002). Although GIP secretion (AUC(tGIP)) was not reduced in obese subjects after meal ingestion or oral glucose, AUC(iGIP) was lower in obese subjects (8.5 +/- 0.6 vs. 12.7 +/- 0.9 nmol/liter x 300 min; P < 0.001) after meal ingestion. GLP-1 secretion (AUC(tGLP-1)) was reduced in obese subjects after both meal ingestion (7.3 +/- 0.9 vs. 10.0 +/- 0.6 nmol/liter x 300 min; P = 0.022) and oral glucose (6.6 +/- 0.8 vs. 9.6 +/- 1.1 nmol/liter x 180 min; P = 0.035). iGLP-1 was reduced in parallel to tGLP-1. CONCLUSIONS 1) Release and degradation of the two incretin hormones show dissociated changes in obesity: GLP-1 but not GIP secretion is lower after meal ingestion and oral glucose, whereas GIP but not GLP-1 metabolism is increased after meal ingestion. 2) Increased plasma DPP-4 activity in obesity is not associated with a generalized augmented incretin hormone metabolism.
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Affiliation(s)
- Richard D Carr
- Department of Clinical Sciences Lund, B11 BMC, SE-2221 84 Lund, Sweden
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Parker HE, Reimann F, Gribble FM. Molecular mechanisms underlying nutrient-stimulated incretin secretion. Expert Rev Mol Med 2010; 12:e1. [PMID: 20047700 DOI: 10.1017/s146239940900132x] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in the intestinal epithelium in response to nutrient ingestion. The actions of GLP-1 and GIP - not only on local gut physiology but also on glucose homeostasis, appetite control and fat metabolism - have made these hormones an attractive area for drug discovery programmes. The potential range of strategies to target the secretion of these hormones therapeutically has been limited by an incomplete understanding of the mechanisms underlying their release. The use of organ and whole-animal perfusion techniques, cell line models and primary L- and K-cells has led to the identification of a variety of pathways involved in the sensing of carbohydrate, fat and protein in the gut lumen. This review focuses on our current understanding of these signalling mechanisms that might underlie nutrient responsiveness of L- and K-cells.
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Affiliation(s)
- Helen E Parker
- Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK
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Totani N, Morita A, Nishinaka M, Tateishi S, Kida H. A novel body weight-loss promoting oil prepared with vegetable protein. J Oleo Sci 2010; 59:41-8. [PMID: 20032598 DOI: 10.5650/jos.59.41] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
It has been reported that oil thermally processed with wheat gluten (gluten oil) exhibited safe weight-loss promoting effects in animal experiments. However, as the oil has a high color index, and its chemical properties and smell differ from those of fresh oil, it is uncertain if the oil will find market acceptance. In order to resolve the issue, frying oil was heated with soybean protein under reduced pressure (soybean protein oil), resulting in a product with an appearance, chemical properties and smell comparable to those of fresh oil. This improved oil was mixed (7 wt%) with powdered AIN93G no fat, defined standard diet and fed to 10-week-old Wistar rats ad libitum. The experimental rats grew normally, ingesting the same amount as that of the control rats; however, there was a negative correlation between body weight increases and fecal weight increases. After the 12-week feeding period, all the rats were sacrificed to obtain blood and organs. In the experimental group, liver weight, retroperitoneal fat tissue weight and serum triacylglycerol (TG) levels decreased significantly. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and histological analysis supported the safety of the improved oil. In conclusion, it was found that soybean protein oil inhibited body weight increases without any adverse effects in animal experiments. The oil holds promise as a novel dieting oil that steadily decreases body weight at an appropriate rate.
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Affiliation(s)
- Nagao Totani
- Department of Nutritional Physiology, Faculty of Nutrition, Kobe-Gakuin University, Kobe, 651-2180, Japan.
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