Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

OBJECTIVE—Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic β-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation

An inhibitor of phospholipase A2 group IIA modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats

Obesity, type 2 diabetes, and cardiovascular disease correlate with infiltration to adipose tissue of different immune cells, with uncertain influences on metabolism. Rats were fed a diet high in carbohydrates and saturated fats to develop diet-induced obesity over 16 weeks. This nutritional overload caused overexpression and secretion of phospholipase A2 group IIA (pla2g2a) from immune cells in adipose tissue rather than adipocytes, whereas expression of adipose-specific phospholipase A2 (pla2g16) was unchanged. These immune cells produce prostaglandin E2 (PGE2), which influences adipocyte signaling. We found that a selective inhibitor of human pla2g2a (5-(4-benzyloxyphenyl)-(4S)-(phenyl-heptanoylamino)-pentanoic acid [KH064]) attenuated secretion of PGE2 from human immune cells stimulated with the fatty acid, palmitic acid, or with lipopolysaccharide. Oral administration of KH064 (5 mg/kg/day) to rats fed the high-carbohydrate, high-fat diet prevented the overexpression of pla2g2a and the increased macrophage infiltration and elevated PGE2 concentrations in adipose tissue. The treatment also attenuated visceral adiposity and reversed most characteristics of metabolic syndrome, producing marked improvements in insulin sensitivity, glucose intolerance, and cardiovascular abnormalities. We suggest that pla2g2a may have a causal relationship with chronic adiposity and metabolic syndrome and that its inhibition in vivo may be a valuable new approach to treat obesity, type 2 diabetes, and metabolic dysfunction in humans

Life and death of β cells in Type 1 diabetes: A comprehensive review

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic β cells. Immune modulators have achieved some success in modifying the course of disease progression in T1D. However, there are parallel declines in C-peptide levels in treated and control groups after initial responses. In this review, we discuss mechanisms of β cell death in T1D that involve necrosis and apoptosis. New technologies are being developed to enable visualization of insulitis and β cell mass involving positron emission transmission that identifies β cell ligands and magnetic resonance imaging that can identify vascular leakage. Molecular signatures that identify β cell derived insulin DNA that is released from dying cells have been described and applied to clinical settings. We also consider changes in β cells that occur during disease progression including the induction of DNA methyltransferases that may affect the function and differentiation of β cells. Our findings from newer data suggest that the model of chronic long standing β cell killing should be reconsidered. These studies indicate that the pathophysiology is accelerated in the peridiagnosis period and manifest by increased rates of β cell killing and insulin secretory impairments over a shorter period than previously thought. Finally, we consider cellular explanations to account for the ongoing loss of insulin production despite continued immune therapy that may identify potential targets for treatment. The progressive decline in β cell function raises the question as to whether β cell failure that is independent of immune attack may be involved