scholarly journals Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Joseph P. Tiano ◽  
Chandra R. Tate ◽  
Bin S. Yang ◽  
Richard DiMarchi ◽  
Franck Mauvais-Jarvis
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3–42) and GLP-1(9–36)amide, on insulin secretion and glucose homeostasis in ob/ob mice

2006 ◽  
Vol 191 (1) ◽  
pp. 93-100 ◽  
Author(s):  
J C Parker ◽  
K S Lavery ◽  
N Irwin ◽  
B D Green ◽  
B Greer ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Plasma Glucose ◽  
Glucose Control ◽  
Chronic Exposure ◽  
Blood Glucose Control ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3–42) and GLP-1(9–36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9–36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3–42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3–42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.

scholarly journals Synaptotagmin-7 phosphorylation mediates GLP-1–dependent potentiation of insulin secretion from β-cells

2015 ◽  
Vol 112 (32) ◽  
pp. 9996-10001 ◽  
Author(s):  
Bingbing Wu ◽  
Shunhui Wei ◽  
Natalia Petersen ◽  
Yusuf Ali ◽  
Xiaorui Wang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Drug Target ◽  
Β Cells ◽  
Receptor Agonists ◽  
Intracellular Ca ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Kinase A

Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca2+. Ca2+ then binds to synaptotagmin-7 as a major Ca2+ sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment is ameliorated by glucagon-like peptide-1 (GLP-1) or by GLP-1 receptor agonists, which improve glucose homeostasis. However, the mechanism by which GLP-1 receptor agonists boost insulin secretion remains unclear. Here, we report that GLP-1 stimulates protein kinase A (PKA)-dependent phosphorylation of synaptotagmin-7 at serine-103, which enhances glucose- and Ca2+-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca2+-triggered exocytosis, whereas a phospho-inactive synaptotagmin-7 mutant disrupts GLP-1 potentiation of insulin secretion. Our findings thus suggest that synaptotagmin-7 is directly activated by GLP-1 signaling and may serve as a drug target for boosting insulin secretion. Moreover, our data reveal, to our knowledge, the first physiological modulation of Ca2+-triggered exocytosis by direct phosphorylation of a synaptotagmin.

scholarly journals Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice

1999 ◽  
Vol 277 (6) ◽  
pp. E996-E1004 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Elimination Rate ◽  
Glucose Disposal ◽  
Sensitivity Index ◽  
Maximal Effect ◽  
Glucose Effectiveness ◽  
Plasma Insulin Levels ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

We examined the dose-related net effects of glucagon-like peptide 1 (GLP-1) on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance in anesthetized mice. GLP-1 dose dependently potentiated insulin secretion after glucose administration, with the half-maximal effect at 1 nmol/kg. GLP-1 also dose dependently reduced the area under the glucose curve (AUCglucose) and increased the glucose elimination rate (KG) but did not affect the glucose effectiveness (SG). Furthermore, the insulin sensitivity index (SI) was reduced after administration of GLP-1. Because insulin secretion was stimulated to a larger degree than SI was reduced, the peptide increased the global disposition index (GDI = AUCinsulin × SI). Matching plasma insulin levels after GLP-1 by exogenous insulin reproduced the influences of GLP-1 on AUCglucose, KG, SI, and GDI. Finally, the GLP-1 receptor antagonist exendin-3-(9—39) inhibited the actions of GLP-1. We conclude that GLP-1 increases glucose tolerance in the mouse mainly by potently stimulating insulin secretion.

Glucagon-like peptide-1 accelerates the onset of insulin action on glucose disappearance in mice

2007 ◽  
Vol 292 (6) ◽  
pp. E1808-E1814 ◽  
Author(s):  
K. Thomaseth ◽  
A. Pavan ◽  
G. Pacini ◽  
B. Ahrén
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Minimal Model ◽  
Insulin Action ◽  
Intravenous Glucose Tolerance Test ◽  
Model Parameters ◽  
Intravenous Glucose ◽  
Glucose Disappearance ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) plays a significant role in glucose homeostasis through its incretin effect on insulin secretion. However, GLP-1 also exhibits extrapancreatic actions, and in particular its possible influences on insulin sensitivity are controversial. To study the dynamic action of GLP-1 on insulin sensitivity, we applied advanced statistical modeling methods to study glucose disappearance in mice that underwent intravenous glucose tolerance test with administration of GLP-1 at various dose levels. In particular, the minimal model of glucose disappearance was exploited within a population estimation framework for accurate detection of relationships between glucose disappearance parameters and GLP-1. Minimal model parameters were estimated from glucose and insulin data collected in 209 anesthetized normal mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03–100 nmol/kg). Insulin secretion markedly increased, as expected, with increasing GLP-1 dose. However, minimal model-derived indexes, i.e., insulin sensitivity and glucose effectiveness, did not significantly change with GLP-1 dose. Instead, fractional turnover rate of insulin action [P2 = 0.0207 ± 24.3% (min) at zero GLP-1 dose] increased steadily with administered GLP-1 dose, with significant differences at 10.4 nmol/kg (P2 = 0.040 ± 15.5%, P = 0.0046) and 31.2 nmol/kg (P2 = 0.050 ± 29.2%, P = 0.01). These results show that GLP-1 influences the dynamics of insulin action by accelerating insulin action following glucose challenge. This is a novel mechanism contributing to the glucose-lowering action of GLP-1.

scholarly journals Minireview: Finding the Sweet Spot: Peripheral Versus Central Glucagon-Like Peptide 1 Action in Feeding and Glucose Homeostasis

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 2997-3001 ◽  
Author(s):  
Diana L. Williams
Keyword(s):  
Body Weight ◽  
Insulin Secretion ◽  
Food Intake ◽  
Glucose Homeostasis ◽  
Sweet Spot ◽  
Food Intake Regulation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Intake Regulation ◽  
The Brain

Glucagon-like peptide 1 (GLP-1) is both a gut-derived hormone and a neurotransmitter synthesized in the brain. Early reports suggested that GLP-1 acts in the periphery to promote insulin secretion and affect glucose homeostasis, whereas central GLP-1 reduces food intake and body weight. However, current research indicates that in fact, GLP-1 in each location plays a role in these functions. This review summarizes the evidence for involvement of peripheral and brain GLP-1 in food intake regulation and glucose homeostasis and proposes a model for the coordinated actions of GLP-1 at multiple sites.

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