This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The primary objective of this study is to determine the effect of a single dose of LAF237 on the rate of appearance of endogenous glucose (RaE) during the overnight post-absorptive period in type 2 diabetics. Secondary objectives will determine: (1) the rate of disappearance of glucose during the overnight post-absorptive period; (2) the effect on fasting plasma glucose concentration; (3) effects on insulin secretion rates, glucagon levels, and rate of glucose entry from the GI tract; (4) if alterations in insulin and glucagon secretion affect plasma free fatty acid levels; and (5) the acute effects of LAF237 on the proinsulin/insulin ratio. RESEARCH PLAN/METHODS: This is a randomized, cross-over comparison study of the effect of LAF237 and placebo on endogenous glucose production. LAF237 is an investigational agent that blocks the enzyme dipeptidyl-peptidase-IV. This enzyme, DPP-4, is responsible for rapidly degrading glucagons-like peptide-1 (GLP-1) upon its release in the intestine after a meal. GLP-1 suppresses glucagons release, suppressing hepatic glucose output. Thus, if is expected that LAF237 should lead to increased GLP-1 levels, decreased glucagons production, and lower blood sugars. This translates into an improved glucose homeostasis for diabetics. Investigators will study adults ages 18-75 with type 2 diabetes, otherwise in good health, HbA1c at 7-11%, fasting blood sugar 160-280, diet- or oral hypoglycemic agent-controlled diabetes, and BMS 22 to 45. Subjects will be seen on the GCRC four times. During the second and third visits, patients will receive a meal-tolerance test consisting of a boiled egg, parmesan cheese, and orange-flavored water with C14-labeled glucose. In addition, they will receive an infusion of H3-labeled glucose, and serial blood samples for glucose pharmacokinetics (total samples up to 882 ml). The goal is to determine the pharmacokinetics of both the C14-labeled and H3-labeled glucose. CLINICAL RELEVANCE: LAF is a new oral antidiabetic agent that works by inhibiting DDP-IV, leading to inhibition of glucagon secretion and stimulation of insulin secretion. It can be used as monotherapy or in combination with currently approved antidiabetic agents.