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Olfactomedin 4 Deletion Improves Male Mouse Glucose Intolerance and Insulin Resistance Induced by a High-Fat Diet.

ABSTRACT: Glucose-stimulated insulin secretion (GSIS) is essential for blood glucose homeostasis and is impaired in type 2 diabetes mellitus. Understanding the regulatory components of GSIS has clinical implications for diabetes treatment. In this study, we found that olfactomedin 4 (OLFM4) is endogenously expressed in pancreatic islet ? cells and further investigated its potential roles in glucose homeostasis and the pathogenesis of type 2 diabetes using mouse models. Olfm4-deficient mice showed significantly improved glucose tolerance and significantly increased insulin levels after glucose challenge compared with wild-type (WT) mice. GSIS, mitochondrial ATP production, and mitochondrial respiration were all significantly increased in islets isolated from Olfm4-deficient mice compared with those isolated from WT mice. In a high-fat diet (HFD)-induced diabetic mouse model, the increase in insulin levels after glucose challenge was significantly higher in Olfm4-deficient mice compared with WT mice. The impaired glucose tolerance and insulin resistance in HFD-fed mice were improved by loss of Olfm4. Olfm4 was found to be mainly localized in the mitochondria and interacts with GRIM-19 (a gene associated with retinoid-interferon mortality) in Min6 pancreatic ? cells. Collectively, these studies suggest that Olfm4 negatively regulates GSIS. OLFM4 may represent a potential therapeutic target for impaired glucose tolerance and patients with type 2 diabetes.

SUBMITTER: Liu W

PROVIDER: S-EPMC6098226 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Olfactomedin 4 Deletion Improves Male Mouse Glucose Intolerance and Insulin Resistance Induced by a High-Fat Diet.

Liu Wenli W Aerbajinai Wulin W Li Hongzhen H Liu Yueqin Y Gavrilova Oksana O Jain Shalini S Rodgers Griffin P GP

Endocrinology 20180901 9

Glucose-stimulated insulin secretion (GSIS) is essential for blood glucose homeostasis and is impaired in type 2 diabetes mellitus. Understanding the regulatory components of GSIS has clinical implications for diabetes treatment. In this study, we found that olfactomedin 4 (OLFM4) is endogenously expressed in pancreatic islet β cells and further investigated its potential roles in glucose homeostasis and the pathogenesis of type 2 diabetes using mouse models. Olfm4-deficient mice showed signific ...[more]

PMID: 30052841

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Project description:BACKGROUND/OBJECTIVE:The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects. METHODS:In Cdkal1-deficient (Cdkal1?/?) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese. PRINCIPAL FINDINGS:On a standard diet, Cdkal1?/? mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1?/? mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P?=?0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1?/? mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1?/? mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1?/? mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI. CONCLUSIONS:Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.

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Olfactomedin 4 Deletion Improves Male Mouse Glucose Intolerance and Insulin Resistance Induced by a High-Fat Diet.

Publications

Olfactomedin 4 Deletion Improves Male Mouse Glucose Intolerance and Insulin Resistance Induced by a High-Fat Diet.

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