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

 To participate patients must:

 1. Be able to communicate meaningfully with the Investigator and be legally competent to
 provide written informed consent.

 2. Female patients must be non-lactating and must either be at least two years
 post-menopausal, or be using adequate contraceptive precautions (i.e. oral
 contraceptives, approved hormonal implant, intrauterine device, diaphragm with
 spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal
 ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy
 are eligible for participation in the study. Female patients (except for those
 patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible
 only if they have a negative pregnancy test throughout the study period.

 3. Age range of 18 to 70 years (inclusive).

 4. Patients must have been on a stable dose of allowed chronic medications for two months
 prior to entering the double-blind treatment period.

 5. All participants must have the following laboratory values:

 -  Hemoglobin ≥ 12 g/dl in males or ≥ 11 g/dl in females

 -  Serum creatinine ≤ 1.5 mg/dl

 -  AST (SGOT) ≤ 2.5 times upper limit of normal

 -  ALT (SGPT) ≤ 2.5 times upper limit of normal

 -  Alkaline phosphatase ≤ 2.5 times upper limit of normal

 Exclusion Criteria:

 Patients will be excluded if any of the following criteria are present:

 1. Individuals with type 1 diabetes or type 2 diabetes and a FPG ≥ 300 mg/dl.

 2. Subjects on sulfonylureas, metformin and/or TZDs unless the dose has been stable for
 at least 2 months prior to study entry.

 3. Patients on any of the following medications: thiazide or furosemide diuretics,
 beta-blockers, or other chronic medications with known adverse effects on glucose
 tolerance levels unless the patient has been on stable doses of such agents for the
 past two months before entry into the study. Patients may be taking stable doses of
 estrogens or other hormonal replacement therapy if the patient has been on these
 agents for the prior two months. Patients taking systemic glucocorticoids will be
 excluded.

 4. Past (within 1 year) or current history of alcohol abuse.

 5. Patients will be excluded if there is a history of clinically significant heart
 disease (New York Heart Classification greater than grade II), peripheral vascular
 disease (history of claudication), or pulmonary disease (dyspnea on exertion of one
 flight or less; abnormal breath sounds on auscultation) or chronic renal failure
 (serum creatinine greater than 1.5 mg/dl).