Incretins in Impaired Fasting Glucose

People with high fasting glucose can develop type 2 diabetes with the passage of time. This study is being done to determine the effect of a novel medication in people with this elevated fasting glucose. Sitagliptin is a substance that raises levels of a hormone normally found in the blood. This hormone, called glucagon-like peptide-1 (GLP-1), is normally released by the intestine in response to the presence of food. This hormone acts like a messenger between the intestine and the pancreas to raise insulin levels, and therefore, lower blood sugars. Sitagliptin is effective in people with diabetes, however, this study is being done to determine if Sitagliptin is effective in people with high fasting glucose who do not yet have diabetes.

Impaired fasting glucose (IFG) confers a high risk of progression to diabetes. Its pathogenesis has been an area of active investigation, with defects in insulin and glucagon secretion as well as insulin action likely to play a role. Several studies have suggested that the prediabetic and diabetic state are associated with alterations in circulating incretin concentrations. More recently, a large study of non-diabetic individuals demonstrated decreased GLP-1 concentrations after a glucose challenge in individuals with prediabetes but concluded that defects in GLP-1 secretion were unrelated to insulin secretion. In impaired glucose tolerance (IGT), defects in incretin-induced insulin secretion coexist with defects in glucose induced insulin secretion.

Worsening degrees of glucose tolerance are associated with decreased insulin secretion for the prevailing insulin action. Moreover early glucagon suppression is impaired in IGT. Since GLP-1 is an insulin secretagogue and suppresses glucagon, it is conceivable that defects in GLP-1 secretion could contribute to the pathogenesis of pre-diabetes. Inhibition of Dipeptidyl Peptidase-4 (DPP-4), an enzyme which rapidly degrades the incretin hormones, has been shown to be a useful therapeutic strategy in type 2 diabetes. DPP-4 inhibitors increase (model-calculated) insulin secretion and decrease glucagon concentrations resulting in a lowering of fasting (and postprandial) glucose concentrations in people with type 2 diabetes. Their effects in people with IFG are less certain. However, DPP-4 inhibitors provide an opportunity to directly examine the contribution of abnormal incretin concentrations to the pathogenesis of IFG, by raising concentrations of endogenous incretin hormones.

The current experiments tested this hypothesis by measuring insulin secretion and action and fasting and postprandial glucose turnover before and after 8 weeks of therapy with a DPP-4 inhibitor.

• Drug: Sitagliptin
  100 mg once daily
  Other Name: Januvia
• Other: Placebo
  once daily for duration of the study

• Active Comparator: Sitagliptin
  People with impaired fasting glucose randomized to treatment with sitagliptin 100 mg once daily.
  Intervention: Drug: Sitagliptin
• Placebo Comparator: Placebo
  People with impaired fasting glucose randomized to treatment with placebo once daily.
  Intervention: Other: Placebo

Twenty four participants aged 35 to 70 years with impaired fasting glucose (100mg/dl-125 mg/dl) will be studied.

Inclusion Criteria:

• Males and females between the ages of 35-70.
• Good health as determined by past medical history,physical examination, vital signs, electrocardiogram and laboratory tests at the time of screening.
• Patients on diuretics or thyroid hormone therapy must be on a stable dose (at least 3 months prior to screening) and the maintenance dose may not be adjusted during the study.

Exclusion Criteria:

• Individuals with a body mass index less than 19 or greater than 40 kg/m^2, or a total weight > 130 kg, will be excluded from study.
• Subjects less than 35 years will not be studied in order to minimize the possibility of studying subjects with type 1 diabetes.
• No history of a) significant nephropathy, (i.e., plasma creatinine > 1.4 mg/dl in women and 1.5 mg/dl in men, and/or proteinuria); b) clinically significant atherosclerotic vascular disease (e.g., history of heart attack or angina); c) a known systemic illness.
• Pregnant or lactating females.