Deletion of CDKAL1 Affects High-Fat Diet–Induced Fat Accumulation and Glucose-Stimulated Insulin Secretion in Mice, Indicating Relevance to Diabetes

Abstract

Background/ObjectiveThe 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.MethodsIn 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 FindingsOn 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.

RNAi Screening in Primary Human Hepatocytes of Genes Implicated in Genome-Wide Association Studies for Roles in Type 2 Diabetes Identifies Roles for CAMK1D and CDKAL1, among Others, in Hepatic Glucose Regulation

“…Demonstrating this role in primary human hepatocytes would be valuable and should be done when protocols for transducing primary hepatocytes without affecting their properties can be developed. The contribution of CDKAL1 and CDK5RAP1 to secretory function and signal transduction continue to emerge as recent studies extend the functions of these proteins [44], [46], [47], [68], [69], but available evidence suggests that these functions are not mutually exclusive.…”

An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery

“…Some studies suggested potential roles of these genes in pancreatic beta cell function or survival. For example, knockdown of Cdkal1 enhanced endoplasmic reticulum (ER) stress in insulinoma cells (Brambillasca et al, 2012), while Cdkal1 −/− mice show reduced first phase insulin exocytosis (Ohara-Imaizumi et al, 2010) and are hypersensitive to high fat diet-induced ER stress (Wei et al, 2011) and defects in glucose-stimulated insulin secretion (Okamura et al, 2012). …”

Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type

“…The protein encoded by CDKAL1 (CDK5 regulatory subunit associated protein 1-like 1) is a member of the methylthiotransferase family. Inactivation in the mouse is associated with abnormalities in insulin secretion but not with abnormal limbs 23 . SOX4 (sex determining region on Y-box 4) is expressed in the developing limb buds and a key player in cartilage and bone development 24 25.…”