Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) on Insulin Secretion and Action in Type 2 Diabetes

The control of hyperglycemia in T2DM ameliorates the metabolic abnormalities of T2DM but whether this improves hepatic steatosis has not been examined carefully with the use of improved insulin formulations (long-acting insulins detemir or glargine, alone or combined with pre-meal short-acting insulins). Most research studies have focused on glycemic control without a careful examination to the underlying mechanisms, with some of these studies reporting on improved hepatic and muscle insulin sensitivity. The investigators have found in the laboratory that intensified insulin therapy in T2DM is associated with enhanced glycogen synthase fractional velocity and non-oxidative glucose disposal, but with no improvement at the level of insulin-stimulated insulin receptor tyrosine phosphorylation, hexokinase II mRNA or enzyme function, phosphatidylinositol 3-kinase (PI 3-kinase) associated with IRS-1, or Akt phosphorylation. Our work did not examine hepatic steatosis or insulin secretion/action, nor was designed to distinguish between the relative contribution of reduced glucotoxicity on insulin sensitivity vs. beta-cell function from pre-meal regular vs. NPH insulin. It is possible that the beneficial effects of insulin therapy of reduced plasma glucose and FFA concentrations may be offset by excessive hyperinsulinemia and weight gain from the use of insulins with suboptimal pharmacokinetics compared to the newer insulin formulations.

Insulin detemir is an insulin analogue approved in 2005 by the FDA. It is a long-acting insulin analogue that has shown to be more predictable in achieving therapeutic plasma insulin levels compared to NPH insulin. This is associated with several clinical benefits, such as better glycemic control, less hypoglycemia, modest weight gain and better quality of life for patients with type 2 diabetes. If gluco-lipotoxicity likely play an important role in the development of hepatic steatosis (NAFLD) in T2DM the investigators speculate that if reversed by a strategy of basal long-acting insulin (insulin detemir) alone, or combined with a rapid-acting analog (pre-meal insulin aspart) may be a good strategy for the treatment of T2DM.