In This Issue of Diabetes

Support for the repurposing of the decades-old antihypertension drug verapamil for type 1 diabetes (T1D) treatment continues to grow, with Xu et al. (p. 1460) now reporting that it prevents the decline of IGF-I and promotes its signaling in β-cells. Previous studies have suggested that the drug protects against β-cell death in various models of diabetes, and trial data point to the promotion or preservation of β-cell function in adults and children with T1D, among many other lines of evidence. The authors found that in individuals with T1D, levels of IGF-I declined during disease progression, and the decline was blunted by verapamil. In human islets, they found that the drug reduced β-cell expression of IGF-binding protein 3 (IGFBP3), while islets exposed to T1D-associated cytokines had increased expression of the very same protein. According to the authors, IGFBP3 binds to IGF-I, which blocks signaling and results in β-cell apoptosis and impaired glucose metabolism. They also show that verapamil increases β-cell IGF-I signaling and activates the IGF-I receptor, which point to beneficial effects in T1D. The authors also found that verapamil could downregulate thioredoxin-interacting protein (TXNIP) expression, which is considered detrimental to human islets. Indeed, they confirmed that TXNIP promotes IGFBP3 expression and inhibited the activation of IGF-I receptor, adding yet another potential mechanism associated with the drug in T1D. Commenting further, author Guanlan Xu said, “Together with our previous work on TXNIP signaling and verapamil treatment of diabetes in mice and humans, we believe that revealing these additional effects on IGF-I signaling will result in a better understanding and acceptance of this therapeutic approach and the repurposing of verapamil for diabetes treatment. We also hope that, combined, our findings will lead to the establishment of much-needed better therapeutic biomarkers in T1D.”

The phosphorylation of a protein called eukaryotic translation initiation factor 2a, or eIF2α, appears to be central to the control of whole-body energy metabolism, according to Kim et al. (p. 1384). They suggest that eIF2α phosphorylation regulates hypothalamic neurons that produce agouti-related peptide (AgRP) and, via several mechanistic steps, influences energy metabolism and feeding behavior. A considerable amount of work has been completed in this area. It is known, for example, that eIF2α phosphorylation is closely correlated with obesity progression. However, the specific physiological processes involved were unknown, prompting the study. Based mainly on a mouse model with impaired eIF2α phosphorylation in AgRP neurons, the authors investigated the role of the protein in short-term energy deficit conditions to understand the underlying intracellular mechanisms involved. In a series of experiments, they found that energy deficit specifically promoted eIF2α phosphorylation in AgRP neurons and that it affected feeding behavior and the expression of unfolded protein response and autophagy genes. They also found that a deficiency in eIF2α phosphorylation in AgRP neurons induced molecular changes that affect leptin sensitivity and thus food intake. Crucially, the authors found that mice with the specific impairment in eIF2α phosphorylation had (compared with controls) reduced body weight, food intake, and fat tissue weight. The mice also had increased energy expenditure, activity levels, body temperature, and uncoupling protein 1 in brown adipose tissue (i.e., an indication of thermogenesis). According to the authors, the overall findings suggest that eIF2α phosphorylation in AgRP neurons plays a critical role in regulating the unfolded protein response and autophagy activation and induction during energy deficit and whole-body energy metabolism. Additionally, they propose that eIF2α phosphorylation acts as a cellular indicator of energy levels in hunger-promoting AgRP neurons and thus appears to control feeding behavior, suggesting that it is a route toward managing obesity.

Glucagon secretion from α-cells appears to be controlled by an interaction between fatty acid oxidation and glucose metabolism, according to Armour et al. (p. 1446). The inhibitory mechanism, which has been a matter of debate, appears to rely on changes in enzymic activity that lower mitochondrial fatty acid oxidation, which results in reduced intracellular ATP, membrane repolarization, and inhibition of glucagon secretion. Under normal conditions, if glucose levels are low, glucagon secretion is increased to stimulate hepatic glucose production. However, glucagon levels are often elevated in obesity and diabetes and are thought to contribute to hyperglycemia. Therapeutic intervention to lower glucagon levels has been difficult, with the underlying mechanisms only subject to hypothetical scenarios. The authors hypothesized that the effects of glucose on glucagon secretion from α-cells depend on the presence of nonesterified fatty acids. Using isolated islets from mouse and human donors, they describe a series of experiments using live-cell imaging and electrophysiology to investigate the relationship. The findings suggest that α-cells do require nonesterified fatty acids to maintain inhibitory effects of glucose on glucagon secretion and that increases in glucose lead to lower intracellular ATP through reduced fatty acid oxidation. The effects appear to depend in part on changes in the activity of pyruvate dehydrogenase and carnitine palmitoyl transferase 1A. The authors further demonstrate that the increase in glucose leads to repolarization of plasma membranes, which underlies the glucose-induced inhibition of electrical activity and glucagon secretion. “This study furthers our understanding of α-cell metabolism and could perhaps provide a unifying framework for how glucose regulates glucagon secretion,” said author Jakob G. Knudsen. “The findings we present here really underline a growing body of literature suggesting that α-cells are not only glucose sensors but also play a central role in relaying information about changes in substrate utilization in the periphery to the liver.”

A genetic predisposition for abdominal obesity increases waist circumference regain after intentional weight loss, according to Christiansen et al. (p. 1424). Conversely, a genetic predisposition toward higher BMI does not predict overall weight regain after weight loss. According to the authors, the results suggest that the influence of genetics is greater in abdominal obesity compared with that of general obesity during weight gain. The findings come from further analysis of the Look AHEAD (Action for Health in Diabetes) trial and specifically included participants who achieved ≥3% initial weigh loss following 1 year on a weight loss program. The ∼1,400 participants were followed over the first year for changes in weight and waist circumference and then were monitored for changes between years 1, 2, and 4. All participants were also genotyped to construct genetic risk scores for BMI and adjusted waist-to-hip ratio. The authors found that participants who received intensive lifestyle intervention lost more weight than those on relatively standard care, but there were no differences in the genetic risk scores between the groups for either BMI or waist-to-hip ratio. BMI score was not associated with waist circumference in either the first or subsequent years. However, higher waist-to-hip ratio scores were associated with smaller 1-year waist circumference reduction and greater increases in waist circumference in subsequent years. On that basis, the authors propose there are distinct biological mechanisms behind both abdominal obesity and general obesity, so further studies are needed to determine appropriate polygenic scores. “Our findings indicate that genetic makeup can significantly influence the loss and regain of abdominal fat during a lifestyle intervention,” said author Tuomas O. Kilpeläinen. “We hope our findings will encourage further investigation into the biological mechanisms behind abdominal fat loss and regain and pave the way for the development of more personalized and effective weight loss interventions.”