Central Mechanisms That Regulate Glucose Metabolism in Humans
Increased endogenous glucose production (EGP) is the major cause of postabsorptive hyperglycemia in type 2 diabetes mellitus (T2DM). While EGP is inhibited by both glucose and insulin in non-diabetic animals and humans, T2DM is associated with increased EGP despite elevated plasma glucose and insulin concentrations. In fact, we and others have reported direct inhibitory effects of hyperglycemia itself on EGP in nondiabetic subjects, independent of other hormonal or metabolic signals, which are markedly blunted in subjects with T2DM. The medial hypothalamus mediates hormonal signals which affect glucose metabolism. ATP-sensitive potassium (KATP) channels are expressed in the hypothalamus and can be activated by insulin. Activation of these channels appears to be an important common mechanism whereby both systemic glucose and insulin suppress EGP, and may account for almost 50% of EGP suppression by both agents. Diazoxide has been shown to inhibit EGP in rodents via the activation of these KATP channels in the hypothalamus, while the KATP channel inhibitor glyburide blocks these effects. There is evidence to suggest that central activation of KATP channels is still able to suppress EGP in animal models that are otherwise resistant to the effects of systemic glucose and insulin.
- Type 2 Diabetes
- Eligible Ages
- Between 21 Years and 60 Years
- Eligible Genders
- Accepts Healthy Volunteers
- BP < 130/90 (+-2 meds)
- BMI 23-27
- No family history of diabetes
- Noth other medical problems with exception: HTN (on < or = 2 meds), hypercholesterolemia, and stable retinopathy
- BMI 27-32
- A1C >8
- BP>130/90 (+- medications)
- BMI > 27
- Abnormal EKG
- History of CAD or exertional chest pain
- First degree relative with early CAD or MI
- Medications for medical or psychiatric conditions including: dofetilide, fosphenytoin/phenytoin trichlormethiazide (any thiazide), chlorpromazine and warfarin
- < 4 week history of participation in another drug trial
- Phase 2
- Study Type
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Single (Participant)
Vagal Nerve Stimulator
- NCT ID
- Albert Einstein College of Medicine, Inc.
Study ContactTiffany S Cheng, B.S.
The current proposal will address the potential impact of diazoxide on inhibiting EGP, and ultimately to investigate its use as a potential treatment for diabetes mellitus. Additionally, to determine the importance of central signaling to the effects of hyperglycemia and hyperinsulinemia on EGP in humans, we will administer glyburide prior to raising glucose or insulin levels under controlled clamp conditions.