CD36 dependent redoxosomes promotes ceramide-mediated pancreatic β-cell failure via p66Shc activation

The Multifunctionality of CD36 in Diabetes Mellitus and Its Complications—Update in Pathogenesis, Treatment and Monitoring

“…The mechanism underlying the positive association between the sCD36 and T2DM is not clearly defined, but current reports implicate that CD36 contributes to the development of T2DM on two levels: insulin resistance [ 5 , 7 , 8 , 10 ] and pancreatic β-cell dysfunction and damage [ 11 , 12 ]. Insulin resistance and defects in pancreatic β-cell function are major pathophysiologic events in the pathogenesis of T2DM [ 13 ].…”

“…PDX1 is an important regulator of insulin gene expression and β-cell development, differentiation, and survival. In a subsequent study, they found that CD36 activates of Src tyrosine kinase which mediates redoxosome (Vav2-Rac1- NADPH oxidase (NOX)) formation in response to C2-CER [ 11 ]. The activated complex initiates two different signaling pathways promoting pancreatic β-cell dysfunction and damage.…”

“…TXNIP promotes a range of effects, including modulation of the gene expression by altering the cellular redox state [ 159 ]. The second involves sequential activation of JNK, phosphorylation of serine36 of p66Shc, and hyperoxidation of peroxiredoxin-3 [ 11 ]. In both cases, the triggered mitochondrial stress initiates the reduction of glucose-stimulated insulin secretion and the intrinsic mitochondrial death pathway in β-cells.…”

“…CD36 is important in prediabetes when it participates in the development of insulin resistance in adipose tissue [ 5 , 6 ], the liver [ 7 ], skeletal muscles [ 8 , 9 ], and the heart [ 10 ]. CD36 also mediates both pancreatic β-cell dysfunction and β-cell mass reduction [ 11 , 12 ], contributing to the reduction of insulin secretion and progression to DM [ 13 ]. Conditions such as hyperglycemia and dyslipidemia significantly change CD36 expression, its function, and its signaling pathways.…”

“…Importantly, CD36 disrupts the functions of organs in a tissue-specific manner by several different mechanisms. The abnormalities of carbohydrate and lipid metabolism correlate with changes to CD36 expression and subcellular localization [ 8 , 10 , 14 , 15 , 16 , 25 , 27 , 28 , 29 , 30 , 31 , 32 ] and contribute to an increase in uptake of fatty acids (FAs) and modified lipoproteins; intracellular accumulation of lipids such as triacylglycerols (TAGs), diacylglycerols (DAGs), and ceramides (CERs); and oxidative and endoplasmic reticulum (ER) stress—and thus activation of a number of signaling pathways that initiate inflammation, modulate insulin response and the utilization of energy substrates, and stimulate cell death and fibrosis leading to progressive, often irreversible organ dysfunction [ 5 , 7 , 9 , 10 , 11 , 14 , 15 , 16 , 18 , 19 , 22 , 23 , 26 ].…”