Endoplasmic reticulum stress in the adipose tissue and monocyte chemoattractant protein-1 are involved in tacrolimus-induced diabetes mellitus.
Xiaoxia SunHongyang WangJingwei ChiKui CheYangang WangPublished in: Pharmacology research & perspectives (2023)
Tacrolimus is an independent risk factor for new-onset diabetes after transplantation (NODAT). This study aimed to identify the mechanisms underlying tacrolimus-induced NODAT. About 80 kidney-transplant patients receiving tacrolimus were divided into NODAT and non-NODAT groups after 1 year. Binary logistic regression was used to identify risk factors for NODAT. Insulin resistance indices were estimated using the homeostasis model assessment. The blood levels of 13 adipocytokines were measured 1 week after transplantation. A tacrolimus-induced diabetes mouse model was used to reveal the underlying mechanisms. The cumulative NODAT incidence was 12.7% at 1 year (median, 6 months; range, 3-12 months). Tacrolimus trough levels ≥10 ng/mL during the first 3 months (odds ratio: 2.54, p = .012) were related to NODAT. Insulin resistance indices were higher in NODAT patients than in non-NODAT patients at 3, 6, and 12 months. Monocyte chemoattractant protein (MCP)-1 was overexpressed in blood in NODAT patients. In the animal experiments, postprandial blood glucose and insulin levels, insulin pathway protein levels in adipose tissue, MCP-1 expression in blood and adipose tissue, and number of macrophages in adipose tissue were markedly higher in tacrolimus-treated mice than in control mice, and these increases were dose-dependent. The expression of endoplasmic reticulum (ER) stress proteins in adipose tissue was increased in a tacrolimus dose-dependent manner. In conclusion, tacrolimus-induced insulin resistance. Tacrolimus trough levels ≥10 ng/mL during the first 3 postoperative months were an independent risk factor for NODAT. ER stress and MCP-1 underlie tacrolimus-induced diabetes.
Keyphrases
- adipose tissue
- insulin resistance
- type diabetes
- glycemic control
- blood glucose
- high fat diet
- high glucose
- diabetic rats
- high fat diet induced
- end stage renal disease
- cardiovascular disease
- mouse model
- metabolic syndrome
- randomized controlled trial
- drug induced
- ejection fraction
- poor prognosis
- endothelial cells
- peritoneal dialysis
- chronic kidney disease
- weight loss
- prognostic factors
- gene expression
- dendritic cells
- dna methylation
- oxidative stress
- long non coding rna
- risk factors
- cell therapy
- mesenchymal stem cells
- ionic liquid
- skeletal muscle
- immune response
- protein protein
- small molecule
- blood pressure
- double blind
- patient reported