Although genome-wide association studies have been very successful in identifying novel single nucleotide polymorphisms (SNPs) associated with many common diseases, including type 2 diabetes (T2D), a limitation of many of these studies has been the inability to unequivocally identify the true functional variant that is marked by the associated SNP and the gene or pathway in which the functional variant falls. Moreover, even if the relevant gene or pathway is known, the associated variant often only modestly perturbs gene function so that the total impact of the gene on disease susceptibility cannot be determined. A recent study by Bonnefond et al. builds on previous findings of robust but modest associations between common variants in MTNR1B, the gene encoding melatonin receptor 1B, and T2D. In this report, exon resequencing in 7,632 Europeans revealed 36 very rare, nonsynonymous variants that were strongly associated with T2D. Of these, four were characterized by a complete loss of melatonin binding and signaling capabilities. Among the very rare variants, only those associated with partial or total loss of function were associated with diabetes. The magnitude of this association was large (odds ratio [OR] 5.67 [95% CI 2.17–14.82]) and much stronger than associations observed for common variants (∼1.10–1.15). The authors then genotyped the four complete loss-of-function variants in an unrelated sample of nearly 12,000 individuals and confirmed the association with T2D, again with a relatively large magnitude of effect (OR 3.88 [95% CI 1.49–6.18]). This report establishes a firm link between MTNR1B and T2D risk and highlights the potential importance of disrupted circadian rhythms in glucose regulation. — Helaine E. Resnick, PhD, MPH

Bonnefond et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet 2012;44:297–301

Although the benefits of exercise on metabolic and other disorders are well described, the cellular mechanisms underlying these effects are poorly understood. A new report by He et al. highlights the role of autophagy in the ability of exercise to ameliorate metabolic characteristics that are perturbed in diabetes. Under stressful conditions, autophagy facilitates cellular adaptation through protein catabolism. In animal models, autophagy also protects against a number of conditions including insulin resistance. In a compelling series of experiments, He et al. first demonstrate that exercise induces autophagy in skeletal and cardiac muscle of fed mice and then show that mice, which are deficient in exercise-induced autophagy resulting from knock-in mutations in BCL2 phosphorylation sites, have lower exercise capacity and impaired exercise-induced insulin sensitivity. Interestingly, although four weeks of a high-fat diet resulted in similar levels of glucose intolerance in both mutant and wild-type mice, mutant mice showed less improvement in glucose tolerance in response to exercise relative to their wild-type counterparts. These findings not only demonstrate the relationship between exercise and autophagy but also show that glucose metabolism is more favorable in mice that can induce autophagy relative to those that cannot. A mutation in BCL2 blocks these beneficial effects, thereby highlighting its potential role in exercise-induced autophagy and glucose regulation. The authors propose that manipulation of the autophagy pathway and/or the BCL2 protein may offer new opportunities to mimic the beneficial effects of exercise and ultimately prevent or treat impaired glucose homeostasis that characterizes diet-induced obesity. — H.E.R.

He et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 2012;481:511–515

New studies investigating actions of the insulin-targeted transcription factor FoxO1 may provide new insights for underlying mechanisms of advanced diabetic cardiomyopathy. The FoxO1 protein is a downstream target of insulin signaling and is involved in cellular growth and metabolism. While FoxO1 activity is influenced by insulin, this transcription factor also serves in a feedback control capacity to regulate the insulin signaling cascade. A new series of experiments reported by Battiprolu et al. has implicated FoxO1-dependent signaling in diabetic cardiomyopathy. The authors’ experimental model utilized knockout mice with selective loss of FoxO1 in cardiac myocytes. Their data suggest that under conditions of diabetes induced by long-term high-fat feeding, activation of FoxO1 in cardiac myocytes is correlated with increased lipid uptake, decreased insulin responsiveness, and alterations in cellular metabolism that are associated with cardiomyopathy. Greater than 4 months on high-fat feeding in mice leads to insulin resistance, diabetes, and heart failure. Interestingly, heart failure was prevented in hearts that were deficient for the transcription factor FoxO1. Further, in contrast to the myocytes of wild-type mice on a high-fat diet, lipid accumulation and alterations in cellular metabolism were not detected in the hearts of FoxO1 knockout mice. Additional studies focused on the insulin signaling cascade in cardiac myocytes and showed that FoxO1 activation led to downregulation of IRS1, which the authors suggest is a key molecular defect in this diabetic model. These studies not only highlight the complexity of insulin signaling and its involvement in the pathology of diabetic cardiomyopathy but also provide compelling data suggesting that FoxO1 may be a promising new therapeutic target in advanced diabetic cardiomyopathy. — Eileen M. Resnick, PhD

Battiprolu et al. Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 2012;122:1109–1118

A fundamental but elusive therapeutic target in type 1 diabetes is identification of novel approaches to replacing functioning β-cells in affected individuals. Although pancreatic and gut Neurog3+ cells both represent endocrine precursor cell populations, they have divergent characteristics and potential. In contrast to their pancreatic counterparts that are only formed during embryonic development and give rise to insulin-producing β-cells, enteroendocrine progenitors are formed continually in the gut, thereby contributing to ongoing cellular repopulation, but do not generate insulin-producing populations. In an interesting series of experiments, Talchai et al. demonstrated that in mice, deletion of Foxo1 from Neurog3+ enteroendocrine precursor cells resulted in a 10-fold increase in these cells. The investigators also observed insulin immunoreactive (Ins+) cells in the gut of both newborn and adult mice resulting from Foxo1 deletion from precursor cells. Additional experiments showed that these Ins+ cells secreted bioactive insulin and C-peptide in response to glucose and sulfonylureas. Finally, experiments involving streptozotocin administration to both wild-type and knockout mice showed that glucose levels in knockout mice began to spontaneously decrease on day 9 in a manner consistent with restoration of insulin production. Upon withdrawal of insulin, 75% of knockout mice survived until the end of the experiments, but all wild-type mice died. These experiments suggest that gut epithelium may be a promising avenue of investigation for β-cell replacement in type 1 diabetes. — H.E.R.

Talchai et al. Generation of functional insulin-producing cells in the gut by Foxo1 ablation. Nat Genet 2012;44:406–412

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