β-cell failure as a complication of diabetes

Abstract

Type 2 diabetes mellitus is a complex disease characterized by β-cell failure in the setting of insulin resistance. In early stages of the disease, pancreatic β-cells adapt to insulin resistance by increasing mass and function. As nutrient excess persists, hyperglycemia and elevated free fatty acids negatively impact β-cell function. This happens by numerous mechanisms, including the generation of reactive oxygen species, alterations in metabolic pathways, increases in intracellular calcium and the activation of endoplasmic reticulum stress. These processes adversely affect β-cells by impairing insulin secretion, decreasing insulin gene expression and ultimately causing apoptosis. In this review, we will first discuss the regulation of β-cell mass during normal conditions. Then, we will discuss the mechanisms of β-cell failure, including glucotoxicity, lipotoxicity and endoplasmic reticulum stress. Further research into mechanisms will reveal the key modulators of β-cell failure and thus identify possible novel therapeutic targets.

Macrophages and islet inflammation in type 2 diabetes

“…In vitro studies have shown that β-cell lipotoxicity is directly induced by palmitate, at least in part via pathways primarily involving ER stress and ROS [42][43][44].…”

“…Palmitate is the most abundant saturated FFA in blood, and the deleterious effects of palmitate, collectively termed as 'lipotoxicity', on β-cells are well documented [41]. In vitro studies have shown that β-cell lipotoxicity is directly induced by palmitate, at least in part via pathways primarily involving ER stress and ROS [42][43][44].…”

“…Clinically, FFA levels are an independent predictor of future T2D [39], and high intake of saturated fatty acids has been linked to higher risks of T2D [40]. Palmitate is the most abundant saturated FFA in blood, and the deleterious effects of palmitate, collectively termed as 'lipotoxicity', on β-cells are well documented [41].In vitro studies have shown that β-cell lipotoxicity is directly induced by palmitate, at least in part via pathways primarily involving ER stress and ROS [42][43][44].To test the effects of palmitate on β-cells in vivo, we developed a method to increase non-esterified palmitate levels in the serum by infusing emulsified ethyl palmitate [35]. This model revealed that palmitate induces chemokines, including CCL2 and CXC11, in β-cells via TLR4 activation.…”

Postprandial platelet aggregation: effects of different meals and glycemic index

“…4 --6 Chronic hyperglycaemia as observed in type-2 diabetes, or acute hyperglycaemia, as a result of ingestion of a meal causing postprandial glucose and insulin excursions, may increase platelet activation and reactivity. 7,8 Foods such as garlic, cocoa, tomatoes, kiwi fruit, berries and so on have been shown to have anti-platelet properties that may help reduce the risk of thrombosis. 9 --12 We have previously reported 13 a postprandial reduction in platelet aggregation, in healthy men and women, in response to a high carbohydrate, low fat meal (69% energy from carbohydrate, 16% from protein and 15% from fat).…”

The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker

“…At the beginning of the disease, pancreatic beta cells adapt to insulin resistance by increasing their mass and secretory function. Nevertheless, the sustained hyperglycaemia and hyperlipidaemia eventually exert a negative impact on beta cell function and lead to impaired insulin secretion and decreased insulin gene expression, ultimately causing beta cell apoptosis [1,2]. Moreover, the follow-up of beta cell mass in diabetic patients and in people strongly at risk for diabetes and their response to pharmacological treatment may be crucial for early diagnosis and treatment selection, making the search for beta cell mass markers a high priority for investigation [3].…”