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

Clinical studies suggest that 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 (i.e, long-acting insulins detemir
or glargine, alone or combined with pre-meal short-acting insulins). Most studies have
focused on glycemic control without a careful examination to the underlying mechanisms, with
some studies reporting on improved hepatic and muscle insulin sensitivity. We have found in
our 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 (see attached articles). 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 (as
suggested by a growing body of literature, see Cusi K, Current Diabetes Reports 2009) we
speculate that if reversed by a strategy of basal long-acting insulin (i.e., insulin
detemir) alone, or combined with a rapid-acting analog (i.e., pre-meal insulin aspart) may
be a good strategy for the treatment of T2DM. However, the effects of intensive insulin
therapy on NAFLD in T2DM (measured by the gold-standard magnetic resonance and spectroscopy
or MRS) or on insulin action and insulin secretion using gold-standard metabolic techniques.