JNK1 ablation improves pancreatic β-cell mass and function in db/db diabetic mice without affecting insulin
Arianna Mazzoli1, Claudia Sardi1, Ludovic Breasson1
1The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden.
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.
Insights
Selective JNK1 ablation improves glucose tolerance in obesity-driven diabetes by preserving pancreatic beta-cell function. This approach avoids exacerbating kidney damage, unlike broader JNK inhibition, suggesting a better therapeutic index for type-2 diabetes.
Area of Science:
- Metabolic diseases
- Endocrinology
- Molecular biology
Background:
- cJun N-terminal Kinases (JNK) link obesity and insulin resistance.
- The specific role of JNK1 in pancreatic beta-cell loss and diabetes complications remains unclear.
- Pan-JNK inhibition has been shown to worsen kidney damage in obesity models.
Purpose of the Study:
- To investigate the role of JNK1 in obesity-driven type-2 diabetes using the db/db mouse model.
- To determine if JNK1 ablation affects pancreatic beta-cell mass and function.
- To assess the impact of JNK1 ablation on kidney function and metabolic parameters.
Main Methods:
- Generated db/db mice lacking JNK1 (db/db-JNK1-/-) through extensive backcrossing.
- Conducted comprehensive metabolic phenotyping, including glucose tolerance tests and insulin level assessments.
- Analyzed pancreatic islet morphology, beta-cell content, liver steatosis, metabolic inflammation, and kidney function (albuminuria, histopathology).
Main Results:
- db/db-JNK1-/- mice showed improved glucose tolerance and insulin levels compared to db/db controls.
- Selective JNK1 ablation led to larger pancreatic islets with increased beta-cell numbers and higher insulin content.
- No significant differences were observed in insulin resistance, fatty liver, metabolic inflammation, or kidney dysfunction between groups.
Conclusions:
- Selective JNK1 ablation ameliorates glucose intolerance in obesity-driven diabetes by protecting beta-cell function and mass.
- JNK1 inactivation does not worsen metabolic inflammation, steatosis, or insulin sensitivity.
- Targeting JNK1 offers a potentially safer therapeutic strategy than pan-JNK inhibition for obesity-driven diabetes, avoiding kidney complications.
