The Role of Fatty Acid Signaling in Islet Beta-Cell Adaptation to Normal Pregnancy

BackgroundMaintenance of a normal fetal nutrient supply requires major adaptations in maternal metabolic physiology, including of the islet beta-cell. The role of lipid signaling processes in the mechanisms of islet beta-cell adaptation to pregnancy has been minimally investigated.ObjectiveTo determine the effects of pregnancy on islet fatty acid (FA) metabolic partitioning and FA augmentation of glucose-stimulated insulin secretion (GSIS).MethodsAge matched virgin, early pregnant (gestational day-11, G11) and late pregnant (G19) Sprague-Dawley rats were studied. Fasted and fed state biochemistry, oral glucose tolerance tests (OGTT), and fasted and post-OGTT liver glycogen, were determined to assess in vivo metabolic characteristics. In isolated islets, FA (BSA-bound palmitate 0.25 mmol/l) augmentation of GSIS, FA partitioning into esterification and oxidation processes using metabolic tracer techniques, lipolysis by glycerol release, triacylglycerols (TG) content, and the expression of key beta-cell genes were determined.ResultsPlasma glucose in pregnancy was lower, including during the OGTT (glucose area under the curve 0-120 min (AUC0-120); 655±24 versus 849±13 mmol.l-1.min; G19 vs virgin; P<0.0001), with plasma insulin concentrations equivalent to those of virgin rats (insulin AUC0-120; 97±7 versus 83±7 ng.ml-1.min; G19 vs virgin; not significant). Liver glycogen was depleted in fasted G19 rats with full recovery after oral glucose. Serum TG increased during pregnancy (4.4±0.4, 6.7±0.5; 17.1±1.5 mmol/l; virgin, G11, G19, P<0.0001), and islet TG content decreased (147±42, 172±27, 73±13 ng/µg protein; virgin, G11, G19; P<0.01). GSIS in isolated islets was increased in G19 compared to virgin rats, and this effect was augmented in the presence of FA. FA esterification into phospholipids, monoacylglycerols and TG were increased, whereas FA oxidation was reduced, in islets of pregnant compared to virgin rats, with variable effects on lipolysis dependent on gestational age. Expression of Ppargc1a, a key regulator of mitochondrial metabolism, was reduced by 51% in G11 and 64% in G19 pregnant rat islets compared to virgin rat islets (P<0.001).ConclusionA lowered set-point for islet and hepatic glucose homeostasis in the pregnant rat has been confirmed. Islet adaptation to pregnancy includes increased FA esterification, reduced FA oxidation, and enhanced FA augmentation of glucose-stimulated insulin secretion.

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Diminished arginine-stimulated insulin secretion in trained men

Journal of Applied Physiology ◽

10.1152/jappl.1990.69.1.261 ◽

1990 ◽

Vol 69 (1) ◽

pp. 261-267 ◽

Cited By ~ 29

Author(s):

F. Dela ◽

K. J. Mikines ◽

B. Tronier ◽

H. Galbo

Keyword(s):

Growth Hormone ◽

Insulin Secretion ◽

Beta Cell ◽

Insulin Response ◽

Cell Secretion ◽

Cell Adaptation ◽

Glucose Stimulated Insulin Secretion ◽

Beta Hydroxybutyrate ◽

Beta Cell Adaptation ◽

Beta Cell Secretion

Glucose-stimulated insulin secretion is depressed by training. To further elucidate the beta-cell adaptation to training, a nonglucose secretagogue was applied. Arginine was infused for 90 min to seven trained and seven untrained young men. Arginine and glucose concentrations increased identically in the groups. The insulin response was biphasic and waned despite increasing arginine concentrations. Both these phases as well as C-peptide responses were reduced in trained subjects, whereas proinsulin responses were similar in the groups. Identical increases were found in glucagon, growth hormone, catecholamines, and production and disappearance of glucose; identical decreases were found in free fatty acids, glycerol, and beta-hydroxybutyrate. In conclusion, in men training diminishes both arginine- and glucose-stimulated insulin secretion, indicating a profound beta-cell adaptation. Being enhanced, the effects of insulin on both production and disposal of glucose are changed in the opposite direction to beta-cell secretion by training. The responses of glucagon- and growth hormone-secreting cells to arginine do not change with training.

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Regulation of insulin secretion by uncoupling protein

Biochemical Society Transactions ◽

10.1042/bst0340802 ◽

2006 ◽

Vol 34 (5) ◽

pp. 802-805 ◽

Cited By ~ 29

Author(s):

C.B. Chan ◽

N. Kashemsant

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Uncoupling Protein ◽

Physiological Role ◽

Atp Production ◽

Ucp2 Expression ◽

Increased Sensitivity ◽

Glucose Stimulated Insulin Secretion

UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet β-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-dependent K+ channels to prevent insulin secretion. It is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. In ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.

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2082-P: A Negative Regulatory Role of Insulinoma Beta Cell–Derived Exosomes in Glucose-Stimulated Insulin Secretion of Beta-Cells by Upregulating Exosomal MicroRNAs-Associated Signals

Diabetes ◽

10.2337/db20-2082-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2082-P

Author(s):

SHING-HWA LIU ◽

CHENG-TIEN WU ◽

CHIA-CHING YU

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cells ◽

Regulatory Role ◽

Glucose Stimulated Insulin Secretion ◽

Negative Regulatory Role

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Free Fatty Acid Induced Reduction in Glucose-Stimulated Insulin Secretion: Evidence for a Role of Oxidative Stress In Vitro and In Vivo

Diabetes ◽

10.2337/db07-0075 ◽

2007 ◽

Vol 56 (12) ◽

pp. 2927-2937 ◽

Cited By ~ 127

Author(s):

A. I. Oprescu ◽

G. Bikopoulos ◽

A. Naassan ◽

E. M. Allister ◽

C. Tang ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Secretion ◽

Fatty Acid ◽

Free Fatty Acid ◽

Glucose Stimulated Insulin Secretion

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2072-P: Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) in the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Function In Vitro and Strongly Impairs Glucose-Stimulated Insulin Secretion In Vivo

Diabetes ◽

10.2337/db20-2072-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2072-P

Author(s):

ELENI GEORGIADOU ◽

PAULINE L. CHABOSSEAU ◽

ALEJANDRA TOMAS ◽

ISABELLE LECLERC ◽

GUY A. RUTTER

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Pancreatic Beta Cell ◽

Structure And Function ◽

Insulin Secretion In Vivo ◽

Mitochondrial Structure ◽

Glucose Stimulated Insulin Secretion ◽

And Function

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What Is the Metabolic Amplification of Insulin Secretion and Is It (Still) Relevant?

Metabolites ◽

10.3390/metabo11060355 ◽

2021 ◽

Vol 11 (6) ◽

pp. 355

Author(s):

Ingo Rustenbeck ◽

Torben Schulze ◽

Mai Morsi ◽

Mohammed Alshafei ◽

Uwe Panten

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Adenine Nucleotides ◽

Pancreatic Beta Cell ◽

Secretory Response ◽

Mitochondrial Activity ◽

Insulin Synthesis ◽

Sequence Of Events ◽

Insulin Granules

The pancreatic beta-cell transduces the availability of nutrients into the secretion of insulin. While this process is extensively modified by hormones and neurotransmitters, it is the availability of nutrients, above all glucose, which sets the process of insulin synthesis and secretion in motion. The central role of the mitochondria in this process was identified decades ago, but how changes in mitochondrial activity are coupled to the exocytosis of insulin granules is still incompletely understood. The identification of ATP-sensitive K+-channels provided the link between the level of adenine nucleotides and the electrical activity of the beta cell, but the depolarization-induced Ca2+-influx into the beta cells, although necessary for stimulated secretion, is not sufficient to generate the secretion pattern as produced by glucose and other nutrient secretagogues. The metabolic amplification of insulin secretion is thus the sequence of events that enables the secretory response to a nutrient secretagogue to exceed the secretory response to a purely depolarizing stimulus and is thus of prime importance. Since the cataplerotic export of mitochondrial metabolites is involved in this signaling, an orienting overview on the topic of nutrient secretagogues beyond glucose is included. Their judicious use may help to define better the nature of the signals and their mechanism of action.

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mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells

Journal of Endocrinology ◽

10.1530/joe-12-0351 ◽

2012 ◽

Vol 216 (1) ◽

pp. 21-29 ◽

Cited By ~ 21

Author(s):

Olivier Le Bacquer ◽

Gurvan Queniat ◽

Valery Gmyr ◽

Julie Kerr-Conte ◽

Bruno Lefebvre ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Function ◽

Antagonistic Effect ◽

Dominant Negative ◽

Insulin Content ◽

Insulin Biosynthesis ◽

Direct Role ◽

Β Cell Function ◽

Glucose Stimulated Insulin Secretion

Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively. Recent studies demonstrated the role of rictor in the development and function of β-cells. mTORC1 has long been known to impact β-cell function and development. However, most of the studies evaluating its role used either drug treatment (i.e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear. In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2. Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content. Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA. Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling. Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis.

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