Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) on Insulin Secretion and Action in Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Long-acting bedtime insulin detemir (Levemir); Insulin detemir and pre-meal insulin aspart.
Intervention type(s): Drug; Drug
Intervention description(s): This group will receive Insulin detemir. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.; 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.
Other intervention name(s): Levemir insulin (trademark insulin by Novo Nordisk); Insulin detemir = Levemir (Novo Nordisk); Insulin aspart = Novolog (Novo Nordisk)
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin, Long-Acting; Insulin degludec, insulin aspart drug combination; Insulin Detemir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Type 2 diabetes mellitus; Insulin therapy; Detemir (Levemir); Aspart (Novolog); Hepatic steatosis