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JNK1 ablation improves pancreatic ?-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 ?-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 ?-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 ?-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 ?-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.

SUBMITTER: Mazzoli A

PROVIDER: S-EPMC7876705 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Mazzoli Arianna A Sardi Claudia C Breasson Ludovic L Theilig Franziska F Becattini Barbara B Solinas Giovanni G

FASEB bioAdvances 20201230 2

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-d ...[more]

PMID: 33615154

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Project description:What is already known about this subjectNew onset diabetes after transplantation is related to treatment with immunosuppressive medications. Clinical studies have shown that risk of new onset diabetes is greater with tacrolimus compared with ciclosporin. The diabetogenicity of ciclosporin and tacrolimus has been attributed to both beta cell dysfunction and impaired insulin sensitivity.What this study addsThis is the first trial to investigate beta cell function and insulin sensitivity using gold standard methodology in healthy human volunteers treated with clinically relevant doses of ciclosporin and tacrolimus. We document that both drugs acutely increase insulin sensitivity, while first phase and pulsatile insulin secretion remain unaffected. This study demonstrates that ciclosporin and tacrolimus have similar acute effects on glucose metabolism in healthy humans. AIM The introduction of calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) cause impairment of survival rates. The relative contribution of each CNI to the pathogenesis and development of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects.MethodsTen healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double-blind, crossover study. During infusion glucose metabolism was investigated using following methods: a hyperinsulinaemic-euglycemic clamp, an intravenous glucose tolerance test (i.v.GTT), glucose-stimulated insulin concentration-time series and indirect calorimetry.ResultsClamp derived insulin sensitivity was increased by 25% during CsA (P < 0.0001) and 13% during Tac administration (P = 0.047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were observed in circulating glucagon, FFA or adiponectin concentrations. Mean blood concentrations of CNIs were 486.9 ± 23.5 µg l(-1) for CsA and 12.8 ± 0.5 µg l(-1) for Tac.ConclusionsAcute effects of i.v. CsA, and to a lesser degree Tac infusions, in healthy volunteers include increased insulin sensitivity, without any effect on first phase or pulsatile insulin secretion.

Dataset Information

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

Publications

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

Similar Datasets

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