Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) on Insulin Secretion and Action in Type 2 Diabetes
The optimal insulin therapy in T2DM is controversial and its impact on nonalcoholic fatty liver disease (NAFLD) has not been systematically studied before, and in particular, never when using the new insulin formulations detemir (Levemir®) or aspart (Novolog®). This study is 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.
|Type 2 Diabetes||Drug: Long-acting bedtime insulin detemir (Levemir) Drug: Insulin detemir and pre-meal insulin aspart.||Phase 4|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) to Improve Insulin Secretion and Action in Subjects With Type 2 Diabetes|
- Hepatic Steatosis [ Time Frame: 3 and 6 months ]Hepatic steatosis measured by proton magnetic resonance spectroscopy (1H-MRS).
- Metabolic Control as Measured by the A1c [ Time Frame: 3 and 6 months ]
- Change in Insulin Secretion [ Time Frame: 3 and 6 months. ]Derived from the hyperglycemic clamp (Plasma C-peptide change vs. pretreatment in first and second phase).
- Intramyocellular (IMCL) by Magnetic Resonance Imaging and Spectroscopy (MRS). [ Time Frame: 3 and 6 months. ]Percent intramyocellular (IMCL) by magnetic resonance imaging and spectroscopy (MRS).
- Plasma Lipid Concentration. [ Time Frame: 3 and 6 months. ]Fasting plasma lipid concentration on day of admission at 3 and 6 months.
- Change in Anthropometric Measure (Body Weight). [ Time Frame: 3 and 6 months. ]Change in anthropometric measure (body weight) done on day of admission at 3 and 6 months.
- Number of Hypoglycemic Events [ Time Frame: 3 and 6 months ]Defined as hypoglycemia <40 mg/dl and/or requiring medical assistance during the trial.
- Metabolic Control as Measured by the Fasting Plasma Glucose Concentration [ Time Frame: 3 and 6 months ]
- Metabolic Control as Measured by the Postprandial Plasma Glucose During the Day-long Plasma Glucose Profile. [ Time Frame: 3 and 6 months ]
- Advanced Lipid Testing [ Time Frame: 3 and 6 months ]Change in lipoprotein particle number was determined using NMR.
- Change in Anthropometric Measure (Body Mass Index [BMI]). [ Time Frame: 3 and 6 months. ]Change in anthropometric measure (body mass index [BMI]) done on day of admission at 3 and 6 months.
- Percent Change From Baseline in Vascular Inflammatory Markers [ Time Frame: 3 and 6 months ]Inflammatory Markers include: Adiponectin, MMP-9, E-selectin, sICAM, and sVCAM
|Study Start Date:||June 2007|
|Study Completion Date:||February 2010|
|Primary Completion Date:||February 2010 (Final data collection date for primary outcome measure)|
Active Comparator: Insulin detemir only
Patients with uncontrolled T2DM are treated with insulin detemir for 6 months. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl. This group will receive Long-acting bedtime insulin detemir (Levemir).
Drug: Long-acting bedtime insulin detemir (Levemir)
This group will receive Insulin detemir. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.
Other Name: Levemir insulin (trademark insulin by Novo Nordisk)
Experimental: Insulin detemir plus aspart
After baseline evaluations, insulin detemir will be given at bedtime and titrated to achieve a fasting plasma glucose between 80-100 mg/dl. After 3 months patients will be admitted to assess the metabolic effects of intervention. After this, insulin aspart (insulin detemir plus aspart) will be added before breakfast, lunch and dinner titrated to normalize the postprandial plasma glucose. After another 3 months patients are readmitted and all study procedures repeated. This group will receive Insulin detemir and pre-meal insulin aspart.
Drug: Insulin detemir and pre-meal insulin aspart.
This group will receive Insulin detemir plus aspart. The group will start with Insulin detemir at bedtime. Then in three months they will Insulin aspart before breakfast, lunch and dinner.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00998335
|United States, Texas|
|The University of Texas H.S.C. at San Antonio and the San Antonio Audie L. Murphy VA Hospital|
|San Antonio, Texas, United States, 78229-3900|
|Principal Investigator:||Kenneth Cusi, M.D.||University of Flordia|