scholarly journals β-Cell Glucagon-Like Peptide-1 Receptor Contributes to Improved Glucose Tolerance After Vertical Sleeve Gastrectomy

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3405-3409 ◽  
Author(s):  
Darline Garibay ◽  
Anne K. McGavigan ◽  
Seon A. Lee ◽  
James V. Ficorilli ◽  
Amy L. Cox ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
High Fat Diet ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Vertical Sleeve Gastrectomy ◽  
High Fat ◽  
Β Cell ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible for this remain incompletely defined. Glucagon-like peptide-1 (GLP-1) is a gut hormone that contributes to the maintenance of glucose homeostasis and is elevated after VSG. VSG-induced increases in postprandial GLP-1 secretion have been proposed to contribute to the glucoregulatory benefits of VSG; however, previous work has been equivocal. In order to test the contribution of enhanced β-cell GLP-1 receptor (GLP-1R) signaling we used a β-cell-specific tamoxifen-inducible GLP-1R knockout mouse model. Male β-cell-specific Glp-1rβ-cell+/+ wild type (WT) and Glp-1rβ-cell−/− knockout (KO) littermates were placed on a high-fat diet for 6 weeks and then switched to high-fat diet supplemented with tamoxifen for the rest of the study. Mice underwent sham or VSG surgery after 2 weeks of tamoxifen diet and were fed ad libitum postoperatively. Mice underwent oral glucose tolerance testing at 3 weeks and were euthanized at 6 weeks after surgery. VSG reduced body weight and food intake independent of genotype. However, glucose tolerance was only improved in VSG WT compared with sham WT, whereas VSG KO had impaired glucose tolerance relative to VSG WT. Augmentation of glucose-stimulated insulin secretion during the oral glucose tolerance test was blunted in VSG KO compared with VSG WT. Therefore, our data suggest that enhanced β-cell GLP-1R signaling contributes to improved glucose regulation after VSG by promoting increased glucose-stimulated insulin secretion.

scholarly journals β-cell knockout of SENP1 reduces responses to incretins and worsens oral glucose tolerance in high fat diet-fed mice

2021 ◽  
Author(s):  
Haopeng Lin ◽  
Nancy Smith ◽  
Aliya F Spigelman ◽  
Kunimasa Suzuki ◽  
Mourad Ferdaoussi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Glucagon Secretion ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
High Fat ◽  
Β Cell ◽  
Islet Mass

SUMOylation reduces oxidative stress and preserves islet mass at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme <u>sen</u>trin-specific <u>p</u>rotease <u>1</u> (SENP1) following metabolic stress, we put pancreas/gut-specific SENP1 knockout mice (pSENP1-KO) on a high fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls, but only in response to oral glucose. A similar phenotype was observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 1 (GLP-1) responses were identical in pSENP1-KO and -WT littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and β-cell exocytotic responses to the GLP-1 receptor agonist Exendin-4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we generated β-cell-specific SENP1 knockout mice (βSENP1-KO). These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired β-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca<sup>2+</sup> levels. Thus, β-cell SENP1 limits oral glucose intolerance following HFD by ensuring robust insulin secretion at a point downstream of incretin signaling.

scholarly journals β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High Fat Diet-Fed Mice

Diabetes ◽  
2021 ◽  
pp. db201235
Author(s):  
Haopeng Lin ◽  
Nancy Smith ◽  
Aliya F Spigelman ◽  
Kunimasa Suzuki ◽  
Mourad Ferdaoussi ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
High Fat Diet ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
High Fat ◽  
Β Cell

scholarly journals β-cell knockout of SENP1 reduces responses to incretins and worsens oral glucose tolerance in high fat diet-fed mice

2021 ◽  
Author(s):  
Haopeng Lin ◽  
Nancy Smith ◽  
Aliya F Spigelman ◽  
Kunimasa Suzuki ◽  
Mourad Ferdaoussi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Glucagon Secretion ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
High Fat ◽  
Β Cell ◽  
Islet Mass

SUMOylation reduces oxidative stress and preserves islet mass at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme <u>sen</u>trin-specific <u>p</u>rotease <u>1</u> (SENP1) following metabolic stress, we put pancreas/gut-specific SENP1 knockout mice (pSENP1-KO) on a high fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls, but only in response to oral glucose. A similar phenotype was observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 1 (GLP-1) responses were identical in pSENP1-KO and -WT littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and β-cell exocytotic responses to the GLP-1 receptor agonist Exendin-4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we generated β-cell-specific SENP1 knockout mice (βSENP1-KO). These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired β-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca<sup>2+</sup> levels. Thus, β-cell SENP1 limits oral glucose intolerance following HFD by ensuring robust insulin secretion at a point downstream of incretin signaling.

Effects of a Seven Day High-Fat Diet on Oral Glucose Tolerance and Endothelial Function in Young Males

2015 ◽  
Vol 47 ◽  
pp. 289-290
Author(s):  
Cody G. Durrer ◽  
Zhongxiao Wan ◽  
Nia Lewis ◽  
Philip N. Ainslie ◽  
Nathan T. Jenkins ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Endothelial Function ◽  
High Fat Diet ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
High Fat ◽  
Young Males
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