In This Issue of Diabetes

Guénantin et al. (p. 1470) report on a protocol for generating functional human beige adipocytes from human induced pluripotent stem cells (hiPSCs), with the suggestion that the approach can provide unlimited sources of adipocyte cells for metabolic investigations and therapeutic screening. Beige adipocytes have emerged in recent years as potential therapeutic targets for both obesity and diabetes due to their ability when stimulated to burn fat and turn it into heat. As the authors write, “therapies aiming to activate beige adipocytes may offer perspectives to face metabolic diseases.” The approach is based on recapitulating a specific adipogenic developmental pathway that takes hiPSCs through successive steps of mesodermal and adipogenic development. Specifically, the cells are exposed to a variety of protein factors and chemical stimulants and inhibitors to steer the cells through the different stages of cellular differentiation. The process reportedly takes 20 days. According to the authors, the resulting hiPSC-derived adipocytes are insulin sensitive, show specific markers of being of the beige variety, and show specific functional properties, including thermogenic capacities. They go on to show that engraftment of the cells in mice results in the formation of fat pads that positively stain for human antibodies and contain adipocytes that were fully differentiated and vascularized in functional adipose tissue. They suggest that the generation of functionally relevant human beige adipocytes should be useful in a variety of further studies into the role of adipose tissue—the particularly eye-catching one being preclinical therapeutic screening. Commenting more widely on the study, author Corinne Vigouroux told Diabetes: “An important added value of our method relies on the fact that differentiation steps are set up without ectopic expression of adipogenic genes. Although therapeutic developments are obviously long-term perspectives, this protocol is, in the short term, a powerful tool for human disease modeling and pathophysiological studies.”

Guénantin et al. Functional human beige adipocytes from induced pluripotent stem cells. Diabetes 2017;66:1470–1478

Impaired awareness of hypoglycemia might be the result of habituation, according to McNeilly et al. (p. 1696), who suggest it may be a type of adaptive memory response that becomes progressively impaired as a result of repeated exposure to a stimulus. They investigated whether it was possible to restore hypoglycemia awareness through dishabituation, i.e., to acutely restore the habituated response by introducing a novel, strong stimulus. According to the authors, they focused on rats who were repeatedly exposed to episodes of hypoglycemia or not (the controls received saline) over a period of 4 weeks. Following one last exposure to hypoglycemia or control, the rats were then exposed to either no exercise, low-intensity exercise, or a short burst of high-intensity exercise on a treadmill. The result largely shows that following the high-intensity acute exercise bout, readouts of various counterregulatory hormonal responses to hypoglycemia indicate an equivalent response to when the rats were not exposed to hypoglycemia at all. These included key readings for hormones, cytokines, metabolites, and critical items such as glucose, insulin, and glucagon. Subsequent proteomics investigations of brain samples indicated that the levels of a number of proteins potentially linked to intense exercise increased. In particular, they speculate that the brain-derived neurotrophic factor might mediate the dishabituation invoked by the intense exercise and it might achieve this via restoration of glutamatergic activity. Author Rory J. McCrimmon commented: “In my opinion, the most important part of this study was showing that impaired awareness of hypoglycemia may result from a special form of adaptive memory called habituation. If this is correct, it has important implications for clinical practice as well as opening up the possibility of novel treatments designed to restore hypoglycemia awareness and prevent severe hypoglycemia. However, these results need to be replicated in people with type 1 diabetes and show effects on symptoms and hypoglycemia awareness as well as hormone responses.”

McNeilly et al. High-intensity exercise as a dishabituating stimulus restores counterregulatory responses in recurrently hypoglycemic rodents. Diabetes 2017;66:1696–1702

Preclinical research has shown that activation of GPR119, a G-protein–coupled receptor, leads to increased insulin secretion by β-cells. As a result, it has been widely pursued as a potential target for the treatment of diabetes. However, subsequent human clinical trials with GPR119 agonists were disappointing in terms of efficacy in humans, suggesting something is being missed. Panaro et al. (p. 1626) report on a series of experiments in mice designed to reevaluate the role of GPR119 within β-cells and suggest that, in fact, the β-cells might not be a direct target for GPR119 agonists after all. According to the authors, mice with whole-body knockout of Gpr119 had normal body weight and glucose tolerance on a regular diet. However, after a high-fat diet, they had reduced fat mass, improved insulin sensitivity, and better control of blood glucose. When GPR119 was inactivated selectively in β-cells, both the regular and high-fat diets made no difference to glucose tolerance or insulin responses. Further experiments in isolated perfused islets from the various types of mice demonstrated preservation of glucose-stimulated insulin secretion in the absence of GPR119. Additionally, the highly selective GPR119 agonist AR231453 did not directly influence insulin secretion in wild-type mouse islets. Further experiments with AR231453 in both wild-type and β-cell–selective Gpr119 knockout mice revealed rapid reductions in glycemic excursions and increases in insulin following a glucose challenge, irrespective of whether GPR119 was active in β-cells or not. As a result, the authors suggest that β-cell GPR119 is not required for the control of insulin secretion or the pharmacological response to GPR119 agonism. Author Daniel J. Drucker said: “Although GPR119 was originally identified as a 3-cell receptor linked to stimulation of insulin secretion, it appears to function predominantly as a nutrient sensor coupled to incretin secretion in the gut. These findings reemphasize the importance of fully understanding mechanisms of action underlying the development of new drug candidates for the treatment of metabolic disorders.”

Panaro et al. β-Cell inactivation of Gpr119 unmasks incretin dependence of GPR119-mediated glucoregulation. Diabetes 2017;66:1626–1635

Elliott et al. (p. 1713) suggest that DNA methylation is likely not involved in type 2 diabetes etiology but rather that DNA methylation represents a noncausal biomarker of later disease. On the plus side, however, they suggest that it means the patterns of DNA methylation might have utility for disease prediction. The study focused on epigenetic data generated with BeadChip technology from peripheral blood samples of just over 1,000 young individuals, with the authors postulating that type 2 diabetes genetic risk variants exert effects on the disease via perturbation of DNA methylation. Using a type of Mendelian randomization approach, they first focused on identifying any relationships between single nucleotide polymorphisms (SNPs) previously identified as having something to do with type 2 diabetes and DNA methylation. The second stage of the study then tried to identify independent methylation quantitative trait loci and assessed their association with type 2 diabetes. For almost all of the associations identified, they could find no strong evidence that methylation was a key pathway through which the diabetes SNPs might cause type 2 diabetes in later life. Only one locus (KCNQ1) had sufficient evidence to suggest that methylation was likely on a causal pathway for type 2 diabetes later in life. Author Hannah R. Elliott commented: “We know that DNA methylation patterns are altered in patients with type 2 diabetes and even that DNA methylation differences are present several years before the disease is clinically diagnosed. However, whether DNA methylation is causal in type 2 diabetes etiology is unknown. Our study suggests that although there are number of associations between type 2 diabetes SNPs and DNA methylation in the peripheral blood of young individuals, the vast majority do not appear to be on the causal pathway to disease in later life.”

Elliott et al. Role of DNA methylation in type 2 diabetes etiology: using genotype as a causal anchor. Diabetes 2017;66:1713–1722