Effects of Losartan on Insulin Sensitivity and Secretion in Type 2 Diabetes and Nephropathy

Condition(s) targeted: Type 2 Diabetes; Diabetic Nephropathy

Intervention: losartan (Drug)

Phase: N/A

Status: Completed

Sponsored by: Shanghai Jiao Tong University of Medicine

Official(s) and/or principal investigator(s):
Hui M Jin, MD, Principal Investigator, Affiliation: Shanghai NO.3 people's Hospital
Hui M Jin, MD, Principal Investigator, Affiliation: Shanghai No.3 people's hospital

Angiotensin type-1 receptor (AT1R) blockers (ARBs) have been recognized recently as regulators of glucose and lipid metabolism in adipocytes and adipose tissue. Moreover telmisartan and irbesartan have been recognized recently as regulators of glucose metabolism. For ARB losartan, the results were controversial. To confirm its effect on glucose metabolism, we designed and performed a prospective, randomized and controlled study in subjects with type 2 diabetes and nephropathy.

Official title: Effects of Angiotensin Type 1 Receptor Blockade With Losartan on Insulin Sensitivity and Secretion in Subjects With Type 2 Diabetes and Nephropathy

Study design: Treatment, Randomized, Open Label, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Detailed description: Angiotensin II (AngII), the main effector peptide of the rennin-angiotensin system (RAS), is implicated in the development of vascular, cardiac, and renal pathologies. Several lines of evidence have suggested that AngII can impair insulin sensitivity. Angiotensin type-1 receptor (AT1R) blockers (ARBs) have been recognized recently as regulators of glucose and lipid metabolism in adipocytes and adipose tissue. Recent clinical trials suggest that blockade of the RAS, either by inhibiting the angiotensin-converting enzyme (ACE) or by blocking AT1R, may substantially lower the risk for type 2 diabetes. In the Heart Outcomes Prevention Evaluation (HOPE) trial, there was 34% reduction in relative risk for the development of type 2 diabetes. Similarly, in the Intervention For Endpoint Reduction in Hypertension study (LIFE), the incidence of type 2 diabetes was reduced by 25% in the losartan group compared with other antihypertensive therapies. Previous study demonstrated that AT1R blockade improved insulin sensitivity in animal models of insulin resistance. The underlying mechanism of the insulin sensitizing and anti-diabetic effect of ARBs is incompletely clear.

The nuclear hormone receptor peroxisome proliferator activated receptor- (PPAR-γ) plays an important role in the regulation of insulin sensitivity. Several studies have shown the ARBs telmisartan and irbesartan potently induces PPAR-γ activity, promoting PPAR-γ-dependent differentiation in adipocytes. However, not all ARBs own PPAR-γ activating properties. In vitro studies have shown that significant differences among PPAR-γ activating ARBs are likely caused by their physicochemical properties, and high lipophilicity is required to obtain sufficiently high penetration rates to bind to intracellular PPAR-γ. Losartan at high concentrations could activate PPAR-γ and behaved like partial PPAR-γ agonists. Nevertheless the results of losartan on insulin sensitivity remain controversial.

To elucidate the underlying effects of losartan on insulin sensitivity, we investigated the effects of losartan on insulin sensitivity and secretion in patients with type 2 diabetes and nephropathy.

Minimum age: 17 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Fasting plasma glucose (FPG) level of 3. 3-9. 0mmol/L

- 2h plasma glucose level of 7. 5-13 mmol/L

- Body mass index (BMI) of 22 kg/m2

- Two occasions of a ratio of urinary albumin to urinary creatinine≥300 or 24 hours

urinary protein concentration is ＞150mg.

- Informed consent

Exclusion Criteria:

- Type1 diabetes or nondiabetic renal disease

Starting date: January 2006
Ending date: July 2006
Last updated: August 4, 2006