Direct renin inhibition improved insulin resistance and adipose tissue dysfunction in type 2 diabetic KK-A(y) mice.
OBJECTIVE
The renin-angiotensin system affects insulin sensitivity mainly through the angiotensin II type 1 receptor. In this study, the effects of renin inhibition on insulin resistance and adipose tissue dysfunction were explored in type 2 diabetic KK-A(y) mice.


RESULTS
Male KK-A mice were treated with a direct renin inhibitor, aliskiren, administered subcutaneously at a dose of 50 mg/kg per day for 14 days using an osmotic minipump. This dose of aliskiren strongly inhibited plasma renin activity and lowered blood pressure about 17% in KK-A(y) mice. Aliskiren decreased body weight and plasma glucose level, and increased plasma insulin level in a fed condition. Aliskiren also lowered the plasma levels of cholesterol, fatty acids and triglycerides. In the oral glucose tolerant test, the plasma glucose elevation after glucose load was reduced by aliskiren, without a significant change in insulin level. Insulin tolerance test showed that aliskiren enhanced insulin's effect on plasma glucose. Aliskiren also reduced the epididymal adipose tissue mass by 25% and retroperitoneal adipose tissue mass by 35%. In adipose tissue, expression of the insulin receptor was not changed by aliskiren; however, expression of insulin receptor substrate-1, glucose transporter type 4, adiponectin, peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding proteindelta was increased by aliskiren. Moreover, NADPH oxidase activity and expression of inflammatory factors were reduced in adipose tissue. Aliskiren increased the pancreatic beta-cell area in KK-A(y) mice.


CONCLUSIONS
These results suggest that renin inhibition by aliskiren improved insulin resistance and adipose tissue dysfunction in type 2 diabetic mice through an increase in insulin sensitivity, insulin secretion and adipocyte differentiation, and a reduction of oxidative stress.
Iwai
Masaru
M
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan.
Kanno
Harumi
H
Tomono
Yumiko
Y
Inaba
Shinji
S
Senba
Izumi
I
Furuno
Megumi
M
Mogi
Masaki
M
Horiuchi
Masatsugu
M
D052242:Adiponectin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005650:Fumarates / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D012083:Renin / Q000378:metabolism / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects; D000092502:Renin Inhibitors
D052242:Adiponectin; D000577:Amides; D005650:Fumarates; D005947:Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047495:PPAR gamma; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren