Metabolic Signaling in Fuel-Induced Insulin Secretion

Prentki, Marc; Matschinsky, Franz M.

doi:10.1016/j.cmet.2013.05.018

Cited by 483 publications

(685 citation statements)

References 233 publications

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“…The resulting depolarisation of the plasma membrane triggers Ca 2+ influx through voltagedependent Ca 2+ channels, leading to an increased cytosolic Ca 2+ concentration which is required for insulin granule exocytosis. However, GSIS also occurs via metabolic coupling factors other than ATP [3]. In addition, insulin secretion can be mediated by various hormones, including leptin, growth hormone and glucagon-like peptide 1 (GLP-1) [2].…”

Section: Introductionmentioning

confidence: 99%

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RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Zhai

Yang

et al. 2016

Diabetologia

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Aims/hypothesis CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain-and loss-of-function experiments and to further decipher the underlying molecular mechanisms. Methods A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3′ untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.Results CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose-and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3′ UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose-and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. Conclusions/interpretation We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

“…Glucose-stimulated insulin secretion (GSIS) occurs via glucose metabolism in beta cells [3]. Glucose metabolism leads to an increased cytosolic ATP/ ADP ratio and the closure of ATP-sensitive K + channels in the plasma membrane.…”

Section: Introductionmentioning

confidence: 99%

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Zhai

Yang

et al. 2016

Diabetologia

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“…ChREBP is also expressed in beta cells where it regulates expression of glycolytic and lipogenic genes and contributes to glucose-stimulated beta cell proliferation [5][6][7]. A major function of pancreatic beta cells is to secrete insulin in response to a rise in circulating glucose concentrations, and the signalling pathway involved depends on glucose metabolism [8]. In pancreatic alpha cells, an as yet incompletely defined mechanism, which probably also involves glucose metabolism, links hypoglycaemia to the release of glucagon [9].…”

Section: Introductionmentioning

confidence: 99%

GLUT2, glucose sensing and glucose homeostasis

2014

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The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.

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“…Esterification and oxidative metabolism of LCFA has been shown to mediate the effects of LCFA on glucose and energy homeostasis (2)(3)(4)(5), and the actions of glucose in the brain mainly involve changes in the AMP/ATP ratio (6). In peripheral tissues, glucose regulates the partitioning of LCFA-CoA between oxidation and esterification, a process fundamental to glucose regulation of insulin release by the pancreatic beta cell (7). Despite this knowledge, it is not known if glucose and LCFA metabolism is coupled in the hypothalamus nor which cell types and intracellular signaling pathways are involved.…”

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confidence: 99%

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

Taïb

Bouyakdan

Hryhorczuk

et al. 2013

Journal of Biological Chemistry

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Background: Hypothalamic long-chain fatty acids (LCFA) and glucose are critical for energy balance, but it is not known if their metabolism is coupled. Results: Glucose regulates hypothalamic metabolism of palmitate via AMP-activated kinase. Conclusion: Glucose and LCFA metabolism is coupled in a cell-type and LCFA-dependent manner. Significance: This is the first evidence for glucose regulation of LCFA metabolic fate in the hypothalamus.

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Metabolic Signaling in Fuel-Induced Insulin Secretion

Cited by 483 publications

References 233 publications

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

GLUT2, glucose sensing and glucose homeostasis

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

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