Microbial influencers: treating diabetes through the gut.

A recently published study by Bell et al. shows altered immunotolerance in people with type 1 diabetes by dietary supplementation of modified resistant starch fibre.

Dipeptidyl peptidase-4 inhibitors and cardiovascular and renal disease in type 2 diabetes: What have we learned from the CARMELINA trial?

Dipeptidyl peptidase-4 inhibitors are a relatively new class of oral anti-hyperglycaemic drugs to treat type 2 diabetes through prevention of degradation of incretins by the dipeptidyl peptidase-4 enzyme. The large trials evaluating the dipeptidyl peptidase-4 inhibitors sitagliptin, alogliptin and saxagliptin demonstrated safety for cardiovascular disease. Post hoc analyses on renal endpoints yielded similar findings. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor evaluated in the CARMELINA trial. CARMELINA included individuals with type 2 diabetes and high cardiovascular and renal risk. Even in this setting, linagliptin displayed cardiovascular safety. CARMELINA also removed initial concerns for heart failure as a class-specific side-effect of dipeptidyl peptidase-4 inhibitors, as no signal for heart failure was found. Although numerically low, CARMELINA did confirm increased rates of pancreatitis in the linagliptin group, suggesting that pancreatitis is a class-specific side-effect of dipeptidyl peptidase-4 inhibitors. Linagliptin reduced progression of albuminuria, but had no effect on other hard renal endpoints. Overall, dipeptidyl peptidase-4 inhibitors are safe but do not confer significant reductions in complications observed for some of the other new glucose-lowering drugs. However, linagliptin is a safe alternative in renal impairment, without dose adjustment. Furthermore, dipeptidyl peptidase-4 inhibitors may hold value as alternatives to sulfonyl-urea derivatives or as an add-on therapy to delay insulin prescription given their favourable safety profile.

Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes.

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.