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The optimal insulin therapy in T2DM is controversial and its impact on nonalcoholic fatty liver disease (or NAFLD, a common condition in T2DM; Cusi K, Current Diabetes Reports 2009) has not been systematically studied before, and in particular, never when using the new insulin formulations detemir (Levemir®) or aspart (Novolog®). This study was to determine the effect on hepatic steatosis and insulin secretion/action of lowering the fasting plasma glucose (FPG) to target with once daily basal insulin detemir alone or combining insulin detemir with premeal insulin aspart in patients with uncontrolled type 2 diabetes mellitus (T2DM).
In the first 3 months the investigators will optimize metabolic control in all patients with intensive basal (bedtime) detemir insulin aiming at a normal fasting plasma glucose. After this treatment period, patients will be randomized in the second 3 months in a 2:1 ratio to insulin detemir or detemir plus aspart. The investigators propose that insulin will improve day-long glycemic control and A1c, reduce hepatic steatosis (NAFLD) (primary endpoint) and insulin secretion/sensitivity being well tolerated while causing minimal weight gain and hypoglycemia (secondary endpoints). The study will allow to assess if there is an additional benefit of adding pre-meal rapid-acting insulin aspart to basal insulin to these endpoints.
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.
Allocation: Randomized, Control: Active Control, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Type 2 Diabetes
Long-acting bedtime insulin detemir (Levemir), Insulin detemir and pre-meal insulin aspart.
The University of Texas H.S.C. at San Antonio and the San Antonio Audie L. Murphy VA Hospital
The University of Texas Health Science Center at San Antonio
Published on BioPortfolio: 2014-08-27T03:18:33-0400
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A recombinant long-acting insulin and HYPOGLYCEMIC AGENT in which a MYRISTIC ACID is conjugated to a LYSINE at position B29. It is used to manage BLOOD GLUCOSE levels in patients with DIABETES MELLITUS.
An insulin preparation that is designed to provide immediate and long term glycemic control in a single dosage. Biphasic insulin typically contains a mixture of REGULAR INSULIN or SHORT-ACTING INSULIN combined with a LONG-ACTING INSULIN.
Insulin formulation containing substance which delays or retards time period of the absorption of insulin.
A recombinant LONG ACTING INSULIN and HYPOGLYCEMIC AGENT that is used to manage BLOOD GLUCOSE in patients with DIABETES MELLITUS.
A syndrome with excessively high INSULIN levels in the BLOOD. It may cause HYPOGLYCEMIA. Etiology of hyperinsulinism varies, including hypersecretion of a beta cell tumor (INSULINOMA); autoantibodies against insulin (INSULIN ANTIBODIES); defective insulin receptor (INSULIN RESISTANCE); or overuse of exogenous insulin or HYPOGLYCEMIC AGENTS.
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