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Differentiated Mouse Adipocytes in Primary Culture: A Model of Insulin Resistance
Published on: February 17, 2023
mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome
Jordi Rovira1, María Jose Ramírez-Bajo1, Elisenda Banon-Maneus1
1Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.
Background:
Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β -cell toxicity.
Methods:
Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression.
Results:
After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated.
Conclusions:
In conditions that require adaptive β -cell proliferation, SRL might reveal harmful effects by blocking β -cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy.
Insights
Sirolimus (SRL) impairs insulin secretion and beta-cell function, particularly in obese models. These harmful effects on insulin production and secretion are reversible upon therapy cessation.
Area of Science:
- Endocrinology
- Pharmacology
- Transplantation Immunology
Background:
- Sirolimus (SRL) is linked to new-onset diabetes mellitus post-transplantation.
- Investigating SRL's impact on insulin resistance and beta-cell toxicity is crucial.
Purpose of the Study:
- To determine the effect of Sirolimus (SRL) on insulin resistance.
- To assess SRL's impact on beta-cell toxicity and function.
Main Methods:
- Lean Zucker rats (LZR) and obese Zucker rats (OZR) received vehicle or SRL (0.25–1.0 mg/kg) for 12 or 28 days.
- Intraperitoneal glucose tolerance tests (IPGTT), islet morphometry, proliferation, apoptosis, insulin content, secretion, and gene expression were analyzed.
- Specific gene expression analysis included Neurod1, Pax4, and Ins2.
Main Results:
- SRL dose-dependently impaired IPGTT in OZR after 12 days.
- Prolonged SRL treatment increased IPGTT area under the curve in both LZR and OZR, with LZR normalizing glucose levels.
- SRL reduced pancreas weight, islet proliferation, and insulin content in both rat types; insulin secretion was affected only in OZR. OZR + SRL islets showed downregulated Neurod1, Pax4, and Ins2.
Conclusions:
- SRL may harm beta-cells by inhibiting proliferation and insulin production/secretion, especially when adaptive beta-cell proliferation is needed.
- These detrimental effects are reversible upon discontinuation of SRL therapy.
- SRL's impact on beta-cell function necessitates careful monitoring in transplant patients.
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