Nutrient regulation of pancreatic β-cell proliferation

Abstract

Excess consumption of energy-dense foods combined with a sedentary lifestyle is driving an obesity epidemic. Although obesity is closely associated with insulin resistance, most individuals meet the insulin demand by increasing their functional β-cell mass. Those who eventually develop type 2 diabetes are distinguished by a failure in this compensatory process. Although a causal role of insulin resistance in compensatory β-cell responses has received considerable experimental support, precisely how the β cell senses changes in the metabolic environment is still unknown. As metabolism of glucose, lipids and amino acids is profoundly altered in obesity, it is not surprising that these nutrients are conspicuous among the factors proposed to contribute. In this review we summarise our understanding of the role of nutrients, in particular glucose, fatty acids and amino acids in β-cell compensation with a particular emphasis on their relation to insulin resistance-induced factors and their underlying mechanism of action. Finally, we describe the concept of epigenetic programming and review recent studies illustrating how the status of the β cell epigenome is a product of its nutrient environment, and how metabolic programming of the β cell contributes to diabetes risk.

Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes

“…After cross the cell membrane via CD36, fatty acids are activated by fatty acyl-CoA synthetase to generate acyl-CoA which undergoes β-oxidation. Acyl-CoA also enters the glycerolipid/free fatty acid cycle or participates in sphingolipid synthesis to generate metabolites such as ceramides and sphingosine-1 phosphate ( 19 ). The binding of long chain FFA to CD36 stimulates the tyrosine phosphorylation of downstream proteins, including proinflammatory response associated with diabetes ( 20 ).…”

VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake

“…Upon entry into β-cells, FFAs either undergo β-oxidation, or they will be directed to enter the glycerolipid/ FFA cycle to generate triacylglycerol (TAG) which promote lipid droplet (LD) formation or, alternatively, participate in sphingolipid synthesis to generate a number of different metabolites, such as ceramide 18 . To address whether VEGF-B mediated fatty acid transport machinery operate in pancreatic islets and particularly to what extent VEGF-B is involved in β-cell fatty acid uptake, we measured islet ceramide content and Plin2 expression (a marker for LD formation) as indicators for islet fatty acid uptake.…”

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…72,73 There are several reports indicating that cultures of rat islets with FA, and the infusion of FA over 2-4 days in rats, increases beta cell proliferation. To support the increase demands of insulin secretion for a sustained period, the expansion of beta cell mass becomes critical.…”

“…While it is well accepted that glucose stimulates beta cell proliferation, there have been conflicting data about whether FA directly increase beta cell proliferation. 72,73 There are several reports indicating that cultures of rat islets with FA, and the infusion of FA over 2-4 days in rats, increases beta cell proliferation. [72][73][74][75] The activation of mammalian target of rapamycin complex 1 (mTORC1) has been implicated in supporting proliferation by FA in one study of rat beta cells.…”

“…72,73 There are several reports indicating that cultures of rat islets with FA, and the infusion of FA over 2-4 days in rats, increases beta cell proliferation. [72][73][74][75] The activation of mammalian target of rapamycin complex 1 (mTORC1) has been implicated in supporting proliferation by FA in one study of rat beta cells. 76 However, in another report, fatty acid infusion blocked glucose-induced proliferation of beta cells in mice.…”