By Max Bingham, PhD

Chronic bilateral stimulation of the vagus nerve can restore whole-body glucose metabolism and insulin sensitivity in obese miniature Yucatan pigs. Moreover, such effects appear to work via both peripheral and central mechanisms. According to Malbert et al. (p. 848), the experiments focused on 15 adult miniature pigs in which stimulating electrodes were placed around the dorsal and ventral vagus nerves and connected to an electrical stimulator device. After that, five of the animals received a high-fat diet (to stimulate obesity) and vagal stimulation, five received a high-fat diet but no stimulation, and five received a low-fat diet and no stimulation. At 12 weeks, the pigs underwent a variety of analyses to assess glucose metabolism and insulin sensitivity. As expected, the pigs on the high-fat diet increased body weight over the study period while the pigs on the low-fat diet maintained a low body weight. The obese pigs that did not receive any vagal stimulation had reduced (by 34%) whole-body insulin sensitivity and reduced hepatic and muscle glucose uptake. However, no such effect was observed in the obese pigs that received vagal stimulation, as their insulin sensitivity values were almost identical to the lean animals. In addition, the authors report an analysis of PET data to further understand the origins of the improvements in glucose metabolism in brain, liver, and muscle components. Commenting more widely on the study, author Charles-Henri Malbert told Diabetes: “To date, chronic vagal stimulation has not been investigated in obese insulin-resistant patients since acute vagal stimulation increases insulin secretion, which is assumed to be deleterious. Our study demonstrates that chronic vagal stimulation does not behave in the same way as an acute stimulation and that this procedure might represent an interesting therapy for obesity-related insulin resistance.”

Malbert et al. Obesity-associated alterations in glucose metabolism are reversed by chronic bilateral stimulation of the abdominal vagus nerve. Diabetes 2017;66:848–857

Tridimensional projection of the brain areas for which statistical differences in glucose metabolism between the obese-nonstimulated and the obese-stimulated groups were evident.

Tridimensional projection of the brain areas for which statistical differences in glucose metabolism between the obese-nonstimulated and the obese-stimulated groups were evident.

Using cold exposure as an experimental paradigm, Morton et al. (p. 823) report that the sympathetic nervous system (SNS) likely elicits coordinated adjustments of both insulin secretion and insulin sensitivity to preserve glucose homeostasis while also supporting increased thermogenesis. Their experiments focused on rats exposed to cold conditions or room temperature followed by assessments of blood glucose levels and insulin. The rats were also exposed to the intravenous α-adrenergic receptor blocker phentolamine or not to test the involvement of the SNS. Accordingly, cold exposure resulted in increased insulin sensitivity, which was perfectly offset by a decline in glucose-induced insulin secretion. Consequently, glucose tolerance was unchanged. On top of this, the administration of phentolamine reversed the effects of cold exposure on insulin and glucose dynamics, directly implicating the SNS in metabolic adaptations that preserve glucose homeostasis during cold exposure. The authors also report that the relationship between insulin secretion and insulin sensitivity in rats is hyperbolic, as it is in humans. Accordingly, this means conditions associated with reduced insulin sensitivity are compensated for by a proportionate increase of insulin secretion, and vice versa. As type 2 diabetes results when insulin secretion fails to increase to compensate for insulin resistance, gaining insight into mechanisms underlying this coupling process is a high priority. Author Michael W. Schwartz said: “Our results support the emerging view that the brain, in partnership with pancreatic islets, helps to establish the defended level of glycemia and that this occurs in part by ensuring that insulin secretion and insulin sensitivity are properly coupled to one another. By extension, the possibility that defects in this central control system contribute to the defense of elevated blood glucose levels in patients with type 2 diabetes can also be considered. If so, therapeutic interventions targeting the brain may have untapped potential to correct the underlying problem and thereby normalize blood glucose levels in affected individuals.”

Morton et al. Evidence that the sympathetic nervous system elicits rapid, coordinated, and reciprocal adjustments of insulin secretion and insulin sensitivity during cold exposure. Diabetes 2017;66:823–834

Model for central nervous system regulation of insulin secretion and insulin sensitivity via the SNS during cold exposure.

Model for central nervous system regulation of insulin secretion and insulin sensitivity via the SNS during cold exposure.

According to Onogi et al. (p. 1008), platelet-derived growth factor (PDGF) and the corresponding signaling network may play a key role in the expansion of white adipose tissue and, in turn, this may have an impact on glucose metabolism. Initially focusing on normal mice, the authors report that on a normal diet, blood vessels in white adipose tissue were tightly wrapped in pericytes. However, when the same type of mice were fed a high-fat diet to induce obesity, these pericytes detached, letting the endothelial cells proliferate further into the white adipose tissue. Subsequent analyses revealed that PDGF-B was likely involved in the detachment of the pericytes and that M1-macrophages were a major source of PDGF-B in obese tissue. Turning to mice with a systemic deletion of the gene for PDGF receptor β (PDGFRβ), they found that pericyte detachment did not take place, that adipocytes were much smaller, and that there was much less chronic inflammation detectable in comparison to controls. Obesity in the knockout mice was considerably less, and there was no deterioration in glucose metabolism. As a result, they suggest PDGF-related signaling appears to represent a fundamental target for the prevention of obesity and type 2 diabetes. Author Toshiyasu Sasaoka said: “The relationship between PDGF and insulin resistance has been a topic of discussion for a long time. In this study, we propose a new fundamental mechanism for PDGF-induced insulin resistance by focusing on obesity-associated neoangiogenesis, which is connected to adipose tissue expansion. Pericytes are known to inhibit proliferation of endothelial cells, and we found that the detachment of pericytes from vessels gives a command to initiate angiogenesis in the obese adipose tissue. PDGF-B–PDGFRβ signaling is a key to exactly control this detachment. The regulation of angiogenesis by pericytes could be an attractive interventional target for obesity.”

Onogi et al. PDGFRβ regulates adipose tissue expansion and glucose metabolism via vascular remodeling in diet-induced obesity. Diabetes 2017;66:1008–1021

A conceptual model of vascular remodeling and adipose tissue expansion in adult obesity.

A conceptual model of vascular remodeling and adipose tissue expansion in adult obesity.

A comprehensive survey of DNA methylation in human pancreatic islet cells has revealed considerable variation in differentially methylated regions as a result of type 2 diabetes, and this includes some loci that are known to influence islet function. The study by Volkov et al. (p. 1074) focused on islet cells from patients with diabetes and control subjects without diabetes and used whole-genome bisulfite sequencing, a method that can reportedly identify DNA methylation at a single nucleotide resolution. According to the authors, they managed to identify nearly 26,000 differentially methylated regions in six sets of islets from the patients with type 2 diabetes. Of these, a considerable number covered loci with known islet function. Examples included PDX1, a transcription factor involved in pancreatic development and β-cell maturation, and TCF7L2, which is a genetic marker associated with type 2 diabetes risk. Numerous other differentially methylated regions were found in binding sites for islet-specific transcription factors or genetic enhancer regions. Identifying such regions via sequencing can only reveal candidate genes but cannot prove their involvement. And so, the authors turned to cultured β-cells where candidate genes were either overexpressed or silenced. In short, this resulted in impaired insulin secretion, effectively linking DNA methylation back to impaired islet function. Author Charlotte Ling commented: “For many years, it has been one of my dreams to perform whole-genome bisulfite sequencing and analyze DNA methylation of 2.4 × 107 CpG sites in pancreatic islets from donors with type 2 diabetes and control subjects without diabetes. We were very thrilled to identify altered DNA methylation of seven regions annotated to PDX1 in islets from donors with type 2 diabetes. Also, the increased DNA methylation and decreased expression of SLC2A2, which encodes GLUT2, was a very exciting result, as well as the identification of numerous new candidates. Overall, our study supports the hypothesis that epigenetic modifications contribute to the disease. We are currently following up these results to try to develop novel therapies that improve insulin secretion.”

Volkov et al. Whole-genome bisulfite sequencing of human pancreatic islets reveals novel differentially methylated regions in type 2 diabetes pathogenesis. Diabetes 2017;66:1074–1085

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