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

Inclusion Criteria


- 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

- Non-smoker


- BMI 27-32

- A1C >8

Exclusion Criteria

  • 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

Study Design

Phase 2
Study Type
Intervention Model
Parallel Assignment
Primary Purpose
Single (Participant)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
administered orally
  • Drug: Diazoxide
    4mg-6mg/kg orally once before study
    Other names:
    • Proglycem
Active Comparator
administered orally
  • Drug: Glyburide
    Administered orally at beginning of study
Active Comparator
Vagal Nerve Stimulator
VNS device
  • Device: Vagal Nerve Stimulator
    Device approved for the purpose of decreasing seizure frequency in patients with poorly-controlled epilepsy

More Details

Active, not recruiting
Albert Einstein College of Medicine

Study Contact

Detailed Description

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.