JNK1 ablation improves pancreatic β-cell mass and function in db/db diabetic mice without affecting insulin sensitivity and adipose tissue inflammation.

Abstract

The cJun N‐terminal Kinases (JNK) emerged as a major link between obesity and insulin resistance, but their role in the loss of pancreatic β‐cell mass and function driving the progression from insulin resistance to type‐2 diabetes and in the complications of diabetes was not investigated to the same extent. Furthermore, it was shown that pan‐JNK inhibition exacerbates kidney damage in the db/db model of obesity‐driven diabetes. Here we investigate the role of JNK1 in the db/db model of obesity‐driven type‐2 diabetes. Mice with systemic ablation of JNK1 (JNK1−/−) were backcrossed for more than 10 generations in db/+ C57BL/KS mice to generate db/db‐JNK1−/− mice and db/db control mice. To define the role of JNK1 in the loss of β‐cell mass and function occurring during obesity‐driven diabetes we performed comprehensive metabolic phenotyping, evaluated steatosis and metabolic inflammation, performed morphometric and cellular composition analysis of pancreatic islets, and evaluated kidney function in db/db‐JNK1−/− mice and db/db controls. db/db‐JNK1−/− mice and db/db control mice developed insulin resistance, fatty liver, and metabolic inflammation to a similar extent. However, db/db‐JNK1−/− mice displayed better glucose tolerance and improved insulin levels during glucose tolerance test, higher pancreatic insulin content, and larger pancreatic islets with more β‐cells than db/db mice. Finally, albuminuria, kidney histopathology, kidney inflammation and oxidative stress in db/db‐JNK1−/− mice and in db/db mice were similar. Our data indicate that selective JNK1 ablation improves glucose tolerance in db/db mice by reducing the loss of functional β‐cells occurring in the db/db mouse model of obesity‐driven diabetes, without significantly affecting metabolic inflammation, steatosis, and insulin sensitivity. Furthermore, we have found that, differently from what previously reported for pan‐JNK inhibitors, selective JNK1 ablation does not exacerbate kidney dysfunction in db/db mice. We conclude that selective JNK1 inactivation may have a superior therapeutic index than pan‐JNK inhibition in obesity‐driven diabetes.