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Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.

ABSTRACT: Pancreatic ? cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of ? cell mass. It's unclear how one begets the other. We have shown that loss of ? cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature ? cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks Hnf4?, Hnf1?, and Pdx1. FoxO-deficient ? cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as an energy source. This results in impaired ATP generation and reduced Ca(2+)-dependent insulin secretion. The present findings demonstrate a secretory defect caused by impaired FoxO activity that antedates dedifferentiation. We propose that defects in both pancreatic ? cell function and mass arise through FoxO-dependent mechanisms during diabetes progression.

SUBMITTER: Kim-Muller JY

PROVIDER: S-EPMC4192072 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.

Kim-Muller Ja Young JY Zhao Shangang S Srivastava Shekhar S Mugabo Yves Y Noh Hye-Lim HL Kim YoungJung R YR Madiraju S R Murthy SR Ferrante Anthony W AW Skolnik Edward Y EY Prentki Marc M Accili Domenico D

Cell metabolism 20140925 4

Pancreatic β cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of β cell mass. It's unclear how one begets the other. We have shown that loss of β cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature β cells results in early-onset, maturity-onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks ...[more]

PMID: 25264246

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Project description:ObjectiveIL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice.MethodsTransgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre+/- mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups.ResultsIL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre+/- mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre+/- controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre+/- controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia.ConclusionsThis study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress.

Dataset Information

Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.

Publications

Metabolic inflexibility impairs insulin secretion and results in MODY-like diabetes in triple FoxO-deficient mice.

Similar Datasets

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