Central Mechanisms That Regulate Glucose Metabolism in Humans

Therapuetic Areas:Endocrinology
Age Range:21 - 60
Start Date:May 2011
End Date:December 2022
Contact:Tiffany S Cheng, B.S.

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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.

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.

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
We found this trial at
Bronx, New York 10467
Principal Investigator: Meredith Hawkins, MD
Bronx, NY
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