The aim is to continue our program on PDE5 inhibition by evaluating effects on insulin resistance, including glucose metabolism and subclinical inflammation, after a 6-week administration of tadalafil in T2D patients. The primary objective is to study the effect of tadalafil compared with placebo on insulin sensitivity during a euglycemic hyperinsulinemic clamp.

This is a double-blind, placebo-controlled crossover study with one study site. Twenty-five T2D patients will be recruited and randomized to per oral intake of tadalafil 20 mg o.d. for six weeks and after a wash-out period of eight weeks intake of placebo for another six weeks, or vice versa. At the end of each 6 week treatment period a glucose clamp, subcutaneous needle biopsies as well as muscle and subcutaneous microdialysis will be performed. Endothelial function tests and arginin stimulation of insulin secretion tests will be performed after 3 weeks in each treatment arm.

Inclusion Criteria:

1. T2D patient, previously diagnosed by fasting or 2-hr OGTT plasma glucose levels
2. Age females: 55-70 yrs (post-menopausal state defined as natural amenorrhea for at least 12 months); Age males: 40-70 yrs
3. BMI: 27-40 kg/m2
4. HbA1c < 60 mmol/mol
5. Type 2 diabetes duration > 3 months and < 10 yrs
6. Understand and speak Swedish

Exclusion Criteria:

1. Diabetes treatment with glitazones, GLP-1 analogues or DPP-IV inhibitors
2. Anti-hypertensive therapy with beta-blockers, ACE-inhibitors and/or angiotensin-II receptor blockers
3. Significant microvascular complications e.g. nephropathy (GFR<60), proliferative retinopathy and symptomatic neuropathy e.g. postural hypotension
4. Previous significant vascular disease including angina pectoris and myocardial infarction, cerebral artery disease e.g. history of transient ischemic attacks and peripheral artery disease with no palpable pulses
5. Smoking > 10 cig/day and/or smokeless tobacco > one can per 2 days
6. Concurrent use of nitrates or NO donors, or an apparent risk that there may be a need of such medication
7. Cardiac failure (stages NYHA II-IV)
8. Uncontrolled hypertension > 170/105 mm Hg
9. Apparent ECG-pathology indicating current or previous myocardial ischemia;
10. Males with erectile dysfunction
11. Hemophilia or a history of bruises or hepatic failure (> 2-fold increase upper limit normal values of ASAT/ALAT)
12. Hypotension
13. Treatment with doxazosin
14. Anything in the contact with the patient that makes the doctor to believe that he/she will be uncompliant to the protocol.