GLP-1 response to sequential mixed meals: influence of insulin resistance

2017 ◽  
Vol 131 (24) ◽  
pp. 2901-2910 ◽  
Author(s):  
Eleni Rebelos ◽  
Brenno Astiarraga ◽  
Roberto Bizzotto ◽  
Andrea Mari ◽  
Maria Laura Manca ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Release ◽  
Cell Function ◽  
Fasting Glucose ◽  
Insulin Resistant ◽  
Esterified Fatty Acids ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.

scholarly journals miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1621 ◽  
Author(s):  
Alessandro Matarese ◽  
Jessica Gambardella ◽  
Angela Lombardi ◽  
Xujun Wang ◽  
Gaetano Santulli
Keyword(s):  
Insulin Release ◽  
Cell Function ◽  
Specific Interaction ◽  
Β Cells ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
First Time

Glucagon-like peptide-1 (GLP-1) has been shown to potentiate glucose-stimulated insulin secretion binding GLP-1 receptor on pancreatic β cells. β-arrestin 1 (βARR1) is known to regulate the desensitization of GLP-1 receptor. Mounting evidence indicates that microRNAs (miRNAs, miRs) are fundamental in the regulation of β cell function and insulin release. However, the regulation of GLP-1/βARR1 pathways by miRs has never been explored. Our hypothesis is that specific miRs can modulate the GLP-1/βARR1 axis in β cells. To test this hypothesis, we applied a bioinformatic approach to detect miRs that could target βARR1; we identified hsa-miR-7-5p (miR-7) and we validated the specific interaction of this miR with βARR1. Then, we verified that GLP-1 was indeed able to regulate the transcription of miR-7 and βARR1, and that miR-7 significantly regulated GLP-1-induced insulin release and cyclic AMP (cAMP) production in β cells. Taken together, our findings indicate, for the first time, that miR-7 plays a functional role in the regulation of GLP-1-mediated insulin release by targeting βARR1. These results have a decisive clinical impact given the importance of drugs modulating GLP-1 signaling in the treatment of patients with type 2 diabetes mellitus.

Determinants of glucose metabolism and the role of NPY in the progression of insulin resistance in chronic migraine

Cephalalgia ◽  
2017 ◽  
Vol 38 (11) ◽  
pp. 1773-1781 ◽  
Author(s):  
Zeynep Oşar Siva ◽  
Derya Uluduz ◽  
Fatma Ela Keskin ◽  
Feyza Erenler ◽  
Huriye Balcı ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Neuropeptide Y ◽  
Chronic Migraine ◽  
Cell Function ◽  
Episodic Migraine ◽  
Oral Glucose ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance. Methods In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions. Results Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls ( p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07). Discussion Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance by specific alterations in energy intake and activation of the sympathoadrenal system.

scholarly journals GPR142 prompts glucagon-like Peptide-1 release from islets to improve β cell function

2018 ◽  
Vol 11 ◽  
pp. 205-211 ◽  
Author(s):  
Hua V. Lin ◽  
Jingru Wang ◽  
Jie Wang ◽  
Weiji Li ◽  
Xuesong Wang ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Herring Milt and Herring Milt Protein Hydrolysate Are Equally Effective in Improving Insulin Sensitivity and Pancreatic Beta-Cell Function in Diet-Induced Obese- and Insulin-Resistant Mice

Marine Drugs ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. 635
Author(s):  
Yanwen Wang ◽  
Sandhya Nair ◽  
Jacques Gagnon
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Cell Function ◽  
Protein Hydrolysate ◽  
High Fat ◽  
Β Cell ◽  
Insulin Resistant ◽  
Β Cell Function ◽  
Casein Protein ◽  
Dietary Casein

Although genetic predisposition influences the onset and progression of insulin resistance and diabetes, dietary nutrients are critical. In general, protein is beneficial relative to carbohydrate and fat but dependent on protein source. Our recent study demonstrated that 70% replacement of dietary casein protein with the equivalent quantity of protein derived from herring milt protein hydrolysate (HMPH; herring milt with proteins being enzymatically hydrolyzed) significantly improved insulin resistance and glucose homeostasis in high-fat diet-induced obese mice. As production of protein hydrolysate increases the cost of the product, it is important to determine whether a simply dried and ground herring milt product possesses similar benefits. Therefore, the current study was conducted to investigate the effect of herring milt dry powder (HMDP) on glucose control and the associated metabolic phenotypes and further to compare its efficacy with HMPH. Male C57BL/6J mice on a high-fat diet for 7 weeks were randomized based on body weight and blood glucose into three groups. One group continued on the high-fat diet and was used as the insulin-resistant/diabetic control and the other two groups were given the high-fat diet modified to have 70% of casein protein being replaced with the same amount of protein from HMDP or HMPH. A group of mice on a low-fat diet all the time was used as the normal control. The results demonstrated that mice on the high-fat diet increased weight gain and showed higher blood concentrations of glucose, insulin, and leptin, as well as impaired glucose tolerance and pancreatic β-cell function relative to those on the normal control diet. In comparison with the high-fat diet, the replacement of 70% dietary casein protein with the same amount of HMDP or HMPH protein decreased weight gain and significantly improved the aforementioned biomarkers, insulin sensitivity or resistance, and β-cell function. The HMDP and HMPH showed similar effects on every parameter except blood lipids where HMDP decreased total cholesterol and non-HDL-cholesterol levels while the effect of HMPH was not significant. The results demonstrate that substituting 70% of dietary casein protein with the equivalent amount of HMDP or HMPH protein protects against obesity and diabetes, and HMDP is also beneficial to cholesterol homeostasis.

scholarly journals Basal Receptor Activation by Locally Produced Glucagon-Like Peptide-1 Contributes to Maintaining β-Cell Function

2005 ◽  
Vol 19 (5) ◽  
pp. 1373-1382 ◽  
Author(s):  
Kai Masur ◽  
Elmi C. Tibaduiza ◽  
Ci Chen ◽  
Brooke Ligon ◽  
Martin Beinborn
Keyword(s):  
Cell Function ◽  
Receptor Activation ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Insulin Regulates Glucagon-Like Peptide-1 Secretion from the Enteroendocrine L Cell

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 580-591 ◽  
Author(s):  
Gareth E. Lim ◽  
Guan J. Huang ◽  
Nina Flora ◽  
Derek LeRoith ◽  
Christopher J. Rhodes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Oral Glucose ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Resistant ◽  
L Cell ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Phosphatidylinositol 3

Insulin resistance and type 2 diabetes mellitus are associated with impaired postprandial secretion of glucagon-like peptide-1 (GLP-1), a potent insulinotropic hormone. The direct effects of insulin and insulin resistance on the L cell are unknown. We therefore hypothesized that the L cell is responsive to insulin and that insulin resistance impairs GLP-1 secretion. The effects of insulin and insulin resistance were examined in well-characterized L cell models: murine GLUTag, human NCI-H716, and fetal rat intestinal cells. MKR mice, a model of chronic hyperinsulinemia, were used to assess the function of the L cell in vivo. In all cells, insulin activated the phosphatidylinositol 3 kinase-Akt and MAPK kinase (MEK)-ERK1/2 pathways and stimulated GLP-1 secretion by up to 275 ± 58%. Insulin resistance was induced by 24 h pretreatment with 10−7m insulin, causing a marked reduction in activation of Akt and ERK1/2. Furthermore, both insulin-induced GLP-1 release and secretion in response to glucose-dependent insulinotropic peptide and phorbol-12-myristate-13-acetate were significantly attenuated. Whereas inhibition of phosphatidylinositol 3 kinase with LY294002 potentiated insulin-induced GLP-1 release, secretion was abrogated by inhibiting the MEK-ERK1/2 pathway with PD98059 or by overexpression of a kinase-dead MEK1-ERK2 fusion protein. Compared with controls, MKR mice were insulin resistant and displayed significantly higher fasting plasma insulin levels. Furthermore, they had significantly higher basal GLP-1 levels but displayed impaired GLP-1 secretion after an oral glucose challenge. These findings indicate that the intestinal L cell is responsive to insulin and that insulin resistance in vitro and in vivo is associated with impaired GLP-1 secretion. Insulin is a novel secretagogue of the incretin hormone, glucagon-like peptide-1 (GLP-1), and L cell insulin resistance impairs heterologous secretagogue-induced GLP-1 secretion in vitro and in vivo.

scholarly journals Upregulated insulin secretion in insulin-resistant mice: evidence of increased islet GLP1 receptor levels and GPR119-activated GLP1 secretion

2013 ◽  
Vol 2 (2) ◽  
pp. 69-78 ◽  
Author(s):  
L Ahlkvist ◽  
K Brown ◽  
B Ahrén
Keyword(s):  
Cell Function ◽  
Hormone Secretion ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Insulin Resistant ◽  
Protein Levels ◽  
Islet Hormone ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Insulin Responses

We previously demonstrated that the overall incretin effect and the β-cell responsiveness to glucagon-like peptide-1 (GLP1) are increased in insulin-resistant mice and may contribute to the upregulated β-cell function. Now we examined whether this could, first, be explained by increased islet GLP1 receptor (GLP1R) protein levels and, secondly, be leveraged by G-protein-coupled receptor 119 (GPR119) activation, which stimulates GLP1 secretion. Female C57BL/6J mice, fed a control (CD, 10% fat) or high-fat (HFD, 60% fat) diet for 8 weeks, were anesthetized and orally given a GPR119 receptor agonist (GSK706A; 10 mg/kg) or vehicle, followed after 10 min with gavage with a liquid mixed meal (0.285 kcal). Blood was sampled for determination of glucose, insulin, intact GLP1, and glucagon, and islets were isolated for studies on insulin and glucagon secretion and GLP1R protein levels. In HFD vs CD mice, GPR119 activation augmented the meal-induced increase in the release of both GLP1 (AUCGLP1 81±9.6 vs 37±6.9 pM×min, P=0.002) and insulin (AUCINS 253±29 vs 112±19 nM×min, P<0.001). GPR119 activation also significantly increased glucagon levels in both groups (P<0.01) with, however, no difference between the groups. By contrast, GPR119 activation did not affect islet hormone secretion from isolated islets. Glucose elimination after meal ingestion was significantly increased by GPR119 activation in HFD mice (0.57±0.04 vs 0.43±0.03% per min, P=0.014) but not in control mice. Islet GLP1R protein levels was higher in HFD vs CD mice (0.8±0.1 vs 0.5±0.1, P=0.035). In conclusion, insulin-resistant mice display increased islet GLP1R protein levels and augmented meal-induced GLP1 and insulin responses to GPR119 activation, which results in increased glucose elimination. We suggest that the increased islet GLP1R protein levels together with the increased GLP1 release may contribute to the upregulated β-cell function in insulin resistance.

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