Effects of PDE-5 Inhibition on Postprandial Hyperglycemia in Type 2 Diabetes

The Effect of Selective PDE-5 Inhibition on Capillary Recruitment, Glucose Uptake and Endothelial Function Following a Mixed Meal in Patients With Type 2 Diabetes Patients.

An increase of blood flow and capillary permeability decrease the impact of an endothelial barrier for glucose and insulin allowing them to reach their target cells in peripheral insulin sensitive organ in the human body. It is well known that insulin-resistant type 2 diabetes patients have an impaired blood flow in skeletal muscle and it is therefore important to elucidate means to reverse this metabolic defect. The investigators have in a recently published study in type 2 diabetes patients used a drug against erectile dysfunction, the PDE-5 inhibitor tadalafil, with known effects on several vascular territories, to increase muscle blood flow in type 2 diabetes patients who were studied after fasting overnight. The aim of this study is to test the hypothesis that tadalafil, compared to placebo, increases muscle glucose uptake and lowers blood glucose following a mixed meal served to type 2 diabetes patients.

An increase of blood flow and capillary permeability decrease the impact of an endothelial barrier for glucose and insulin allowing them to reach their target cells in peripheral insulin sensitive organ in the human body. It is well known that insulin-resistant type 2 diabetes patients have an impaired blood flow in skeletal muscle and it is therefore important to elucidate means to reverse this metabolic defect. The investigators have in a recently published study in type 2 diabetes patients used a drug against erectile dysfunction, the PDE-5 inhibitor tadalafil, with known effects on several vascular territories, to increase muscle blood flow in type 2 diabetes patients who were studied after fasting overnight. In fact, the investigators observed that tadalafil compared to placebo increased glucose uptake in muscle in parallel with an augmented capillary recruitment in muscle. This was the first publication to show that the pharmacological principle to inhibit the enzyme phosphodiesterase-5 (PDE-5) may mediate an increased muscle glucose uptake and, hence, may be a novel strategy to lower blood glucose in type 2 diabetes patients. The aim of this study is to test the hypothesis that tadalafil, compared to placebo, increases muscle glucose uptake and lowers blood glucose following a mixed meal served to type 2 diabetes patients.

Insulin resistance, Phosphodiesterase-5 inhibition, Microdialysis, Type 2 diabetes, Endothelial dysfunction, Oral hypoglycaemic agents

Capillary recruitment and glucose uptake in forearm muscle as well as circulating glucose levels following acute administration of tadalafil or placebo in type 2 diabetes patients.

Arterial stiffness as measured by pulse wave velocity and circulating concentrations of metabolic variables

Inclusion Criteria: Postmenopausal state, defines as natural amenorrhea for at least 12 months. Age; females 52-65 years, males: 40-65 years. Type 2 diabetes based on fasting plasma glucose or 2-hr glucose after an OGTT. Diabetes duration less than 5 years. Exclusion Criteria: Patients with concurrent use of nitrates or NO donors, history of heart or cerebrovascular disease, cardiac failure (stages NYHA II-IV), uncontrolled hypertension (> 160/100 mm Hg), significant diabetic complications, and inadequate glycemic control (HbA1c > 7%, ref value 3.5-5.3%) Patients on glitazones, insulin, beta-blockers, ACE-inhibitors and corticosteroids

Region of Västra Götaland, Sahlgrenska University Hospital/Sahlgrenska University at University of Göteborg, Dept of Molecular and Clinical Medicine, SE 413 45 Göteborg, Sweden

The Wallenberg Laboratory, Dept of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Bruna stråket 16,

Jansson PA, Murdolo G, Sjogren L, Nystrom B, Sjostrand M, Strindberg L, Lonnroth P. Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes. Diabetologia. 2010 Oct;53(10):2205-8. doi: 10.1007/s00125-010-1819-4. Epub 2010 Jun 10.