can exenatide prevent increase in egp in response to dapagliflozin-induced increase in glucosuria

Conditions: Diabetes Mellitus, Type 2

Summary: research design/plan: after screening, each subject will receive 1 measurements of endogenous glucose production \[egp\] with prime-continuous infusion of 3-3h-glucose. after completing the egp measurement each subject will receive a double tracer oral glucose tolerance test \[ogtt\]. methods: visit 1: screening. medical history will be obtained, physical exam performed, and pregnancy test performed. visit 2: endogenous glucose production measurement: the rate of egp will be measured with 3-3h-glucose. visit 3: double tracer ogtt

eligible subjects will receive a measurement of endogenous glucose production (egp) with a prime-continuous infusion of 3-3h-glucose. the egp measurement will be performed in the morning after a 10-12 hour overnight fast and will last 8 hours (from 6 am to 2 pm). after a 3-hour tracer equilibration period, subjects (20 per group) will receive one of the following medications: (i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg plus exenatide 5 ug. following the test medication at 9 am, blood samples will be drawn every 15 minutes for an additional 5 hours and plasma glucose, insulin, c-peptide, glucagon, cortisol, growth hormone, and catecholamine concentrations and glucose specific activity will be measured. visit 1: screening. medical history \& physical exam will be performed. blood will be drawn for fasting plasma glucose \[fpg\], routine blood chemistries, complete blood count \[cbc\], lipid profile, hba1c, and thyroid function \[tsh\], urinalysis, electrocardiogram \[ekg\], albumin/creatinine ratio and pregnancy test will be performed. visit 2: egp measurement: the rate of endogenous glucose production will be measured with 3-3h-glucose infusion. \[3-3h\]-glucose infusion will be started at 6 in the morning \[am\] and continued until 2:30 afternoon \[pm\](5 hours after drug administration). at 6 am a catheter will be placed into an anticubital vein and a prime (40 uci x fpg/100)- continuous (0.4 uci) infusion of \[3-3h\]- glucose will be started and continued until 2:30 pm. (5 hours after drug administration). participant's hand will be placed in a box heated to 50-60°c (122-140°f). baseline blood samples will be obtained at-210, -60, -50, -45, -40, -35, -30, -20, -10, and 0 . after 3.5 hours of tracer equilibration blood samples will be obtained every 10-20 minutes from 9 am to 2 pm. plasma glucose, insulin, c-peptide, glucagon, cortisol, growth hormone, and catecholamine concentrations, and \[3-3h\]-glucose specific activity will be measured. urine will be collected from 6 to 9 am and from 9 am to 2 pm. urinary volume and glucose concentration will be measured and urinary glucose excretion rate calculated. the study will end at 2:30 pm. visit 3: double tracer oral glucose tolerance test \[ogtt\]: within the week after the measurement of egp, all subjects will have a 5-hour ogtt with measurement of plasma glucose, insulin (i), c-peptide (cp), and glucagon concentrations at -180, -6-, -5-, -45, -40, -35, -30, -20, -10, 0 and every 15-30 minutes thereafter to obtain a measure of overall glucose tolerance, insulin secretion (cp0-120/g0-120), insulin sensitivity (\[matsuda index=mi\]), beta cell function, (cp0-120/g0-120 x mi), and suppression of plasma glucagon concentration (64). at 7 am a catheter will be placed into an antecubital vein and a prime (25 uci x fpg/100)- continuous (0.25 uci) infusion of \[3-3h\]- glucose will be started and continued until 3 pm. urinary volume and glucose concentration will be measured and urinary glucose excretion rate calculated. hba1c will be measured 2x, 1 on the day of the ogtt \& 1 on the day of the egp measurement.

Eligibility criteria:
inclusion criteria: * health status: type 2 diabetes mellitus according to ada criteria (subjects must be in good general health as determined by physical exam, medical history, blood chemistry-cbc, tsh, t4, ekg and urinalysis) * bmi: 21-45kg/m * hba1c\>7.0% and \<10.5% * medication: drug naïve and/or on a stable dose of metformin and/or sulfonylurea (more than 3 months) exclusion criteria: * health status: type 1 diabetics * proliferative diabetic retinopathy * plasma creatinine greater than 1.4mg/dl in females or greater than 1.5mg/dl in males, or 24 hour urine albumin excretion greater than 300mg/dl * medication: subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea)