Contraction Mediated Glucose Uptake as a Therapeutic Target in Type 2 Diabetes

Aim 1: To determine whether acute infusion of sodium nitroprusside, an NO donor, increases leg glucose uptake at rest in patients with type 2 diabetes.

Twenty male type 2 diabetic patients aged between 30 and 60 years will be recruited from our clinic and through advertisement. The inclusion criteria:

• non-smokers
• free of overt coronary disease (stress ECG)
• body mass index < 35 kg.m-2
• fasting plasma glucose > 7 mmol.L-1 and / or post 75 gm oral glucose load plasma glucose levels of > 11.1 mmol.L-1
• unmedicated (diet controlled)

The leg blood flow (thermodilution) and glucose uptake responses (arterial-venous differences) to three cumulative doses of sodium nitroprusside (0.1, 0.3 and 0.6 ug.kg-1.min-1, 10 mins per dose) infused into the femoral artery using techniques established in our laboratory will be assessed. Doses are based on our extensive unpublished observations and have been calculated to lie on the linear part of the dose-response curve and to induce local and not systemic hemodynamic effects. As a control we will also assess responses to the nitrate independent vasodilator, Verapamil (Isoptin) (1, 3 and 6 ug.kg-1.min-1 Doses). Verapamil is a calcium channel antagonist which causes vasodilatation by direct actions on the smooth muscle. Doses will be titrated to give similar blood flow responses and the two drugs will be administered in randomized order with a 60 min wash-out period. Verapamil doses will be determined in pilot experiments. Vastus lateralis biopsies will be performed at baseline and after the highest dose of each drug and cGMP and GLUT-4 translocation measured.

A single Vastus lateralis biopsy will be performed as a comparison against type 2 diabetics.