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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Tadalafil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>A single dose of placebo is administered 30 min before a mixed meal. | Drug: Tadalafil<br>* This is an acute study. Tadalafil 20 mg administered prior to a meal<br>* Other names: Cialis;|
| Active Comparator: Tadalafil<br>A single dose of tadalafil 20 mg is administered 30 min before a mixed meal. | Drug: Tadalafil<br>* This is an acute study. Tadalafil 20 mg administered prior to a meal<br>* Other names: Cialis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Capillary recruitment, muscle glucose uptake and circulating glucose levels following a meal | 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. | Five hours after a mixed meal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vascular function and circulating biomarkers. | Arterial stiffness as measured by pulse wave velocity and circulating concentrations of metabolic variables | Five hours after a mixed meal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin resistance, Phosphodiesterase-5 inhibition, Microdialysis, Type 2 diabetes, Endothelial dysfunction, Oral hypoglycaemic agents