Targeting the Brain to Cure Type 2 Diabetes.

Abstract

Present pharmacological treatments of type 2 diabetes aim mainly at increasing insulin secretion by pancreatic β-cells, at improving insulin action on liver, fat, or muscle, and, more recently, at favoring renal glucose elimination. Although efficacious, these treatments do not have the rapid and long-term efficacy of bariatric surgery on correcting diabetic hyperglycemia, suggesting that alternate therapeutic targets can still be identified. Neuronal circuits in the brain, in particular in the hypothalamus and brain stem, can exert strong control on glucose homeostasis. The activity of these circuits is controlled by a variety of cell types—neurons, glial cells, tanycytes—that are sensitive to interoceptive signals such as glucose and various hormones, including insulin, leptin, or ghrelin. When activated, these neuronal circuits can regulate, by controlling autonomic nervous system activity, the secretion of insulin and glucagon by pancreatic endocrine cells as well as glucose metabolic pathways in liver, fat, and muscle. Targeting these neuronal circuits could lead to innovative therapies for diabetes. In the report by Scarlett et al. (1) in this issue of Diabetes and in a previous publication (2), the Schwartz group demonstrated that a single intracerebroventricular (i.c.v.) injection of fibroblast growth factor 1 (FGF1) in diabetic mice and rats leads to a long-term (up to 18 weeks) correction of diabetic hyperglycemia. FGF1 belongs to the fibroblast growth factor (FGF) family, which contains 18 members (3). Most of the FGFs act as paracrine regulators because they bind to heparan sulfate proteoglycans present in the extracellular space, preventing their diffusion beyond the local environment where they are secreted. The exceptions to this rule are FGF15 (or the human ortholog FGF19) and FGF21, which lack the heparan sulfate proteoglycan binding site and, thus, act as classic endocrine hormones. FGF1 binds to all FGF receptors (FGFRs) (FGFR1 to FGFR4) and their splice variants; high-affinity binding …