<p>Metformin Decreases Insulin Resistance in Type 1 Diabetes Through Regulating p53 and RAP2A in vitro and in vivo</p>

Abstract

Purpose: Patients with type 1 diabetes (T1D) are associated with a high risk of multiple complications, so the development of T1D treatment is urgently needed. This study was set out to explore the molecular mechanism of metformin in the treatment of T1D insulin resistance.Patients and Methods: Subcutaneous adipose tissues were collected from 68 T1D patients and 51 healthy controls. Insulin resistance model rats and cells were constructed and treated with metformin respectively. Western blot was used to detect p53 and RAP2A protein levels, and qPCR was utilized to measure p53 and RAP2A mRNA levels. SiRNA and RAP2A siRNA vectors were constructed to observe their effects on insulin resistance model cells. Results: In T1D, p53 was up-regulated, while RAP2A was down-regulated. Metformin could effectively improve insulin resistance and inflammatory response while downregulating p53 and up-regulating RAP2A. P53 induced insulin resistance and inflammatory response by inhibiting RAP2A and promoted apoptosis. Conclusion: Metformin improves T1D insulin resistance and inflammatory response through p53/RAP2A pathway, and the regulation of p53/RAP2A pathway is conducive to improving the efficacy of metformin in the treatment of insulin resistance.

High expression of CD52 in adipocytes: a potential therapeutic target for obesity with type 2 diabetes

“…Among the 20 molecules, the up-regulated (P <0.05 and FC ≥ 2) genes included: (1) genes involved in insulin resistance such as APOC3 [ 28 ], PPARD [ 29 ], CASP9 [ 30 ], and CBR3 [ 31 ]; (2) risk loci for type 2 diabetes such as MTHFR [ 32 ] and CDKN2B [ 33 ]; (3) genes correlated with complications of T2DM; for instance, casp-9, which mediates high-glucose-induced diabetic neuropathies [ 34 ]; EBF1, which is a cardiovascular and metabolic risk gene [ 35 ]; and APOM, which is associated with lipid disturbances and rheumatoid arthritis [ 36 ]; (4) BCL11A, which is a candidate regulator of pancreatic endocrine cells, downregulates target genes Ins2, glucagon, and Ppy [ 37 ]. The down-regulated genes (P <0.05 and FC ≤ 0.5) included: (1) genes modulating the lipolytic program and promoting brown adipose tissue function, such as JAK2 [ 38 ]; (2) genes downregulating insulin resistance, such as PCNT [ 39 ], RAP2A [ 40 ], AQP9 [ 41 ], MCL1 [ 42 ], AGTRAP [ 43 ], TF [ 44 ] and FASLG [ 45 ]; and (3) TCF7L2, which plays an important role in glucose homeostasis [ 46 ]; (4)Human GDPD5 restores insulin expression in Gdpd5a-depleted zebrafish embryos [ 47 ]. These up-regulated genes and down-regulated genes are respectively presented in Supplementary Tables 1 , 2 .…”

The Impact of Metformin in Pediatric Type-1 Diabetes Mellitus in Addition to Insulin Therapy; Literature Review

“…Besides, in T1DM, Gao-Fei ran et al have found that metformin improves insulin resistance and inflammatory response through P53/RAP2A pathway [9]. Consequently, the P53/RAP pathway regulation was associated with improving the efficacy of metformin in the treatment of insulin-resistant [9].…”