scholarly journals Apolipoprotein A-I Increases Insulin Secretion and Production From Pancreatic β-Cells via a G-Protein-cAMP-PKA-FoxO1–Dependent Mechanism

2014 ◽  
Vol 34 (10) ◽  
pp. 2261-2267 ◽  
Author(s):  
Blake J. Cochran ◽  
Radjesh J. Bisoendial ◽  
Liming Hou ◽  
Elias N. Glaros ◽  
Jérémie Rossy ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
G Protein ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Apolipoprotein A ◽  
Dependent Mechanism

scholarly journals Apolipoprotein A-V Modulates Insulin Secretion in Pancreatic β-cells Through its Interaction with Midkine

2009 ◽  
Vol 24 (5-6) ◽  
pp. 451-460 ◽  
Author(s):  
Audrey Helleboid-Chapman ◽  
Maxime Nowak ◽  
Stéphane Helleboid ◽  
Emmanuelle Moitrot ◽  
Corinne Rommens ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Apolipoprotein A

scholarly journals Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein–coupled receptor BAI3

2018 ◽  
Vol 293 (47) ◽  
pp. 18086-18098 ◽  
Author(s):  
Rajesh Gupta ◽  
Dan C. Nguyen ◽  
Michael D. Schaid ◽  
Xia Lei ◽  
Appakalai N. Balamurugan ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Insulin Secretion ◽  
G Protein ◽  
Human Islets ◽  
Whole Body ◽  
Inhibitory Effects ◽  
G Protein Coupled Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
G Protein Coupled

Secreted proteins are important metabolic regulators in both healthy and disease states. Here, we sought to investigate the mechanism by which the secreted protein complement 1q-like-3 (C1ql3) regulates insulin secretion from pancreatic β-cells, a key process affecting whole-body glucose metabolism. We found that C1ql3 predominantly inhibits exendin-4– and cAMP-stimulated insulin secretion from mouse and human islets. However, to a lesser extent, C1ql3 also reduced insulin secretion in response to KCl, the potassium channel blocker tolbutamide, and high glucose. Strikingly, C1ql3 did not affect insulin secretion stimulated by fatty acids, amino acids, or mitochondrial metabolites, either at low or submaximal glucose concentrations. Additionally, C1ql3 inhibited glucose-stimulated cAMP levels, and insulin secretion stimulated by exchange protein directly activated by cAMP-2 and protein kinase A. These results suggest that C1ql3 inhibits insulin secretion primarily by regulating cAMP signaling. The cell adhesion G protein–coupled receptor, brain angiogenesis inhibitor-3 (BAI3), is a C1ql3 receptor and is expressed in β-cells and in mouse and human islets, but its function in β-cells remained unknown. We found that siRNA-mediated Bai3 knockdown in INS1(832/13) cells increased glucose-stimulated insulin secretion. Furthermore, incubating the soluble C1ql3-binding fragment of the BAI3 protein completely blocked the inhibitory effects of C1ql3 on insulin secretion in response to cAMP. This suggests that BAI3 mediates the inhibitory effects of C1ql3 on insulin secretion from pancreatic β-cells. These findings demonstrate a novel regulatory mechanism by which C1ql3/BAI3 signaling causes an impairment of insulin secretion from β-cells, possibly contributing to the progression of type 2 diabetes in obesity.

Abstract 34: Apolipoprotein A-I Increases Insulin Secretion from β-cells via a Protein Kinase A Dependent Mechanism

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Blake J Cochran ◽  
Kerry-Anne Rye
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Adenyl Cyclase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Kinase A ◽  
Dependent Mechanism

Introduction: The progression to hyperglycaemia in type 2 diabetes is marked by β-cell insulin secretory dysfunction and cell loss. We have previously demonstrated that apolipoprotein (apo) A-I, the major protein constituent of high density lipoproteins (HDL) increases insulin expression and secretion from β-cells. Clinical data also suggests that pharmacological elevation of HDL levels is associated with improved glycemic control in patients with type 2 diabetes. With the current interest in HDL raising therapeutics, defining the mechanism by which apoA-I acts on insulin secretion is of importance. Objective: To elucidate the cell signalling events responsible for increasing insulin secretion from pancreatic β-cells treated with lipid-free apoA-I. Methods: Ins-1E (rat insulinoma) cells were pre-treated for 30 min with the Protein kinase A (PKA) specific inhibitor H89 (20 μM), soluble and transmembrane adenyl cyclase specific inhibitors (KH7, 30 μM and 2’5’ dideoxyadenosine, 50 μM, respectively) or vehicle control, then incubated for 1 h with lipid-free apoA-I (final concentration 1 mg/mL) under both basal (2.8 mM) and high (25 mM) glucose conditions. The insulin concentration in the culture supernatants was determined by radioimmunoassay and the cells were either lysed for protein analysis by western blotting or treated with 0.1 M HCl for determining cAMP by enzyme immunoassay. Results: Incubation of Ins-1E cells with apoA-I increased insulin secretion up to 3-fold. This increase was no longer apparent when the cells were pre-treated with H89. Incubation with apoA-I increased cAMP accumulation in Ins-1E cells 2.5-fold. This increase was totally inhibited when the cells were pre-incubated with 2’5’ dideoxyadenosine but not by KH7, indicating that transmembrane adenyl cyclase(s) are responsible for this response. ApoA-I also activated the small GTPase Cdc42, which may link cell surface apoA-I receptors with transmembrane adenyl cyclases. Conclusion: ApoA-I increases insulin secretion from pancreatic β-cells via a PKA-dependent mechanism involving transmembrane, but not soluble, adenyl cyclases and possibly Cdc42. This provides a possible explanation of the clinical observations that increased HDL may be beneficial in type 2 diabetes.

Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

2020 ◽  
Vol 33 (5) ◽  
pp. 671-674
Author(s):  
Tashunka Taylor-Miller ◽  
Jayne Houghton ◽  
Paul Munyard ◽  
Yadlapalli Kumar ◽  
Clinda Puvirajasinghe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Newborn Period ◽  
Case Presentation ◽  
Male Baby ◽  
Common Causes ◽  
Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

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