Islet hormonal hypersecretion and metformin’s effect on islet hormonal secretion studied in vitro and in vivo

Sammanfattning: Childhood obesity has surged globally. Elevated levels of free fatty acids contribute to hyperinsulinemia, hyperproinsulinemia, and hyperglucagonemia connected with both obesity and type 2 diabetes mellitus (T2DM). Metformin has beneficial effects on islets by influencing metabolism and reducing stress-induced cell death. The aim of the study was to define underlying mechanisms of free fatty acids induced islet hormone hypersecretion, especially in insulin, proinsulin and glucagon and how metformin influenced hormone levels in vitro and in vivo.Glucose stimulated insulin secretion (GSIS) from isolated human islets increased after culture in palmitate for up to 1 day, but declined with continued palmitate exposure. Whereas addition of metformin increased GSIS from islets exposed to palmitate for 1 day, metformin reduced GSIS from islets exposed to palmitate for 0.5 day. In some children with obesity insulin levels were accentuated after metformin treatment for at least 6 months, whereas insulin levels were attenuated in other children. The reduction of insulin levels was accompanied by lowering in 2-h glucose and triglycerides levels.In islets, palmitate treatment also increased proinsulin secretion, which was connected with decreasing prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE). Metformin normalized expression of PC1/3 and CPE, and proinsulin and insulin secretion. In children with obesity, metformin treatment reduced the proinsulin to insulin ratio (PI:I) in subjects with T2DM as well as in subjects with prediabetes, coupled with reduced 2-hour glucose and HbA1c.To address the role of palmitate on glucagon secretion we cultured αTC1 cells with palmitate. Palmitate exposure increased glucagon secretion, which was accompanied by increased ATP production, maximal respiratory capacity and protein levels of fission protein DRP-1. Knockdown or inhibition of DRP-1 decreased ATP production and glucagon secretion. Long-term palmitate treatment also changed transcripts levels of genes related to glycolysis and TCA cycle metabolism.In conclusion, metformin has beneficial effects on hyperinsulinemia and insulin processing, if introduced when insulin secretory levels are high and stable and not declining. Additionally, palmitate-induced glucagon hypersecretion was connected with increased mitochondrial fission protein DRP-1 and metabolism. Thereby, the thesis could contribute to understanding T2DM development and delineate ways to prevent its development.