By Max Bingham, PhD
GDF11 for Treating Type 2 Diabetes: Animal Studies
According to Li et al. (p. ), a key target for achieving restoration or preservation of β-cell function might lie with growth differentiation factor 11 (GDF11). The conclusion comes from a series of experiments involving mice and cells in which the authors systematically investigated the role of GDF11 in diabetes. Previously, the protein was somewhat controversially posited as an anti-aging factor. However, parallel to this, its role in diabetes and specifically islet development was suspected, although never fully established. According to the authors, they first established that circulating levels of GDF11 were likely decreased in mice with chemically induced diabetes fed a high-fat diet. They then established that treating the mice with recombinant GDF11 reduced severe hyperglycemia and HbA1c levels in comparison to controls and that in turn these same mice had higher fasting levels of insulin, glycemic control, and reduced hyperlipidemia, as well as a range of other measures that heavily suggested reversal of diabetes. The same effects could be recapitulated in genetically altered db/db mice that were treated with either the recombinant GDF11 or GDF11 delivered via a viral vector. The use of an anti-GDF11 monoclonal antibody reversed all the effects, resulting in β-cell function loss and severe type 2 diabetes. To then unravel what mechanisms might be involved, the authors go on to report both histological and molecular investigations, also using isolated cells, that they say demonstrate that GDF11 likely attenuates β-cell function loss. Author Guangda Xiang told Diabetes: “The results of our recent work implicate a critical role of GDF11 in the regulation of β-cell function and mass. However, information regarding the role of GDF11 in individuals with type 2 diabetes is scarce. Therefore, the relationship between plasma GDF11 concentration and β-cell function in type 2 diabetes warrants long-term follow-up studies based on representative diabetes cohorts.”
Chronic treatment with GDF11 preserves β-cell mass in diabetic mice. Representative images of pancreatic sections stained for hematoxylin-eosin (H&E) or double-stained for insulin/glucagon (left panel), insulin/Ki67 (middle panel), or insulin/TUNEL (right panel). The nuclei were stained with DAPI (blue). The white arrows indicate proliferating β-cells (middle panel) or apoptotic β-cells (right panel). Scale bar, 20 µm.
Chronic treatment with GDF11 preserves β-cell mass in diabetic mice. Representative images of pancreatic sections stained for hematoxylin-eosin (H&E) or double-stained for insulin/glucagon (left panel), insulin/Ki67 (middle panel), or insulin/TUNEL (right panel). The nuclei were stained with DAPI (blue). The white arrows indicate proliferating β-cells (middle panel) or apoptotic β-cells (right panel). Scale bar, 20 µm.
miR-29 in Skeletal Muscle Linked to Insulin Sensitivity in Type 2 Diabetes: Is Exercise the Key?
The microRNA-29 (miR-29) family appears to regulate glucose metabolism and insulin sensitivity in skeletal muscle according to Massart et al. (p. ), which is likely to have implications for type 2 diabetes because exercise appears to downregulate miR-29 expression and improve insulin sensitivity. The conclusions come from a series of experiments that focused on miR-29 in a bid to uncover the precise role of the microRNA family in human skeletal muscle. The majority of evidence currently points to a broad role for microRNAs in skeletal muscle and to the idea that the miR-29 family might be regulators of glucose homeostasis. However, the underlying gene expression and metabolic steps are reportedly little understood. According to the authors, miR-29a and miR-29c are likely increased in patients with type 2 diabetes, but following exercise training, levels were reduced in both healthy individuals and rats. Subsequent inhibition and overexpression approaches in primary human skeletal cells further suggested that miR-29 likely modulates lipid metabolism and the action of insulin on glucose metabolism. The authors say that at the molecular level miR-29 members likely alter the insulin-signaling cascade and that because it is overexpressed in type 2 diabetes, this contributes to insulin resistance and decreased glucose uptake. They go on to show that exercise resulted in better insulin sensitivity and a concurrent downregulation of miR-29a and miR-29c, suggesting that this might also be related to alterations in lipid utilization. Whether or not exercise or pharmacological approaches are the most appropriate to target miR-29 and thus potentially insulin resistance in type 2 diabetes is unclear for the moment. Nevertheless, the authors say that miR-29 dysregulation is likely linked to insulin resistance and at least their preliminary evidence on exercise suggests downregulation is possible to achieve. Author Anna Krook commented: “miRNAs are able to concurrently tweak the function of several genes, making them attractive targets to modulate metabolism. Reductions in miR29 could be a contributing factor mediating the positive effects of exercise.”
miR-29 expression modulates glucose and lipid metabolism in skeletal muscle. T2DM, type 2 diabetes mellitus.
miR-29 expression modulates glucose and lipid metabolism in skeletal muscle. T2DM, type 2 diabetes mellitus.
High-Intensity Exercise Risks Hypoglycemia in Patients With Type 1 Diabetes: The Key Is Awareness
High-intensity interval training is likely to suppress normal awareness of hypoglycemia in patients with type 1 diabetes, according to Rooijackers et al. (p. ), who now caution that the exercise approach may increase the risk of subsequent hypoglycemia episodes. They report the outcomes of a randomized crossover study that compared the effects of the intense exercise approach in patients with type 1 diabetes with either normal or reduced awareness of hypoglycemia or healthy patients. Awareness of hypoglycemia was then tested following either exercise or rest during a hyperinsulinemic-hypoglycemic clamp. According to the authors, during the hypoglycemia phase of the clamp, patients with normal awareness of hypoglycemia reported reduced symptoms following high-intensity training in comparison to the equivalent phase of the test following rest. In patients with already reduced awareness of hypoglycemia and healthy patients, high-intensity training made no difference to symptoms during the induced hypoglycemia phase. It is on this basis that the authors caution about the subsequent risk for hypoglycemia—if intense exercise blunts awareness of symptoms, patients need to take care that they avoid a potentially dangerous later drop in blood glucose levels. In terms of mechanisms (some of which could be revealed from the biochemical analyses performed), the authors speculate that exercise-induced increases in lactate levels may explain the suppressive effects on symptom awareness. They say that lactate can be used by the brain as a fuel and that this might help explain why cognitive dysfunction was reduced following the exercise regime. Author Hanne M. Rooijackers said: "The results of our study imply that patients with type 1 diabetes should carefully monitor their blood glucose levels after high-intensity interval exercise. Reduced awareness of subsequent hypoglycemia may increase the risk of hypoglycemia and should lead to restraint when correcting exercise-induced short-term increments in glucose values. Future research should also address the long-term effects of high-intensity interval training on awareness of hypoglycemia.”
Empagliflozin Reduces the Threshold for Urinary Excretion of Glucose: Type 2 Diabetes Implications
Empagliflozin can reduce blood glucose in type 2 diabetes, but quite how it achieves this, other than acting as a sodium–glucose cotransporter 2 (SGLT2) inhibitor, has remained a mystery. According to Al-Jobori et al. (p. ), it seems likely that the drug can reduce the threshold at which glucose passes into urine, explaining why patients with type 2 diabetes who use the drug typically go on to experience reductions in mean plasma glucose concentrations (A1C). The study, which focused on patients with type 2 diabetes and healthy individuals (15 in each group), used a stepped hyperglycemia clamp approach to try to figure out how empagliflozin affects plasma glucose levels. They reportedly found that at baseline, the patients with type 2 diabetes had greater maximal renal glucose transport rates than the healthy individuals and that empagliflozin reduced the rates after 48 h and even further after 14 days. Following further analysis, they report that the threshold for glucose spillage into urine was reduced to less than 40 mg/dL. Author Ralph A. DeFronzo commented on some of the wider implications of the study: “Our study demonstrates that empagliflozin reduces the threshold for glucose spillage into the urine to a level well below the fasting plasma glucose concentration in subjects without diabetes and explains why virtually all patients with diabetes with normal/near-normal GFR [glomerular filtration rate] have a significant glucosuric effect and respond with a reduction in mean plasma glucose concentration.” He also said that “there is a time-related effect that requires up to 2 weeks for empagliflozin to exert its maximum effect to inhibit renal glucose reabsorption”—a point that is probably worth highlighting when it comes to the clinical use of the drug. However, DeFronzo stressed that “the glucosuric effect of empagliflozin and other SGLT2 inhibitors is offset by ∼30% by SGLT1 reabsorption of glucose. These results provide credence for the use of combined SGLT2/SGLT1 inhibitor therapy to maximize the effect of SGLT inhibition on glucosuria and reduction in A1C."
