So what makes a FFAR

So what makes a FFAR1 agonist different and interesting? As shown in the , the cellular mechanism is different from those of present insulin-releasing pharmacotherapies—namely the secretion initiators (sulphonylureas and meglitinides) and the incretin-based secretion potentiators (glucagon-like peptide-1 [GLP-1] receptor agonists and dipeptidyl peptidase-4 [DPP-4] inhibitor). FFAR1 is one of several long-chain fatty acid-activated receptors expressed by pancreatic β cells. Selective agonists of FFAR1 activate the G-protein subunit Gαq, which acts via phospholipase Cβ to raise cytosolic Ca by redistribution from endoplasmic stores and to activate various isoforms of protein kinase C. Protein kinase C isoforms exert diverse cellular effects that include augmentation of distal steps in the insulin secretory pathway. Thus, selective FFAR1 agonists might be capable of restricted initiation of insulin secretion, and will mainly potentiate nutrient-induced insulin secretion, which will favour enhanced prandial insulin secretion and reduce the risk of interprandial hypoglycaemia., Perhaps unexpectedly, the insulin response to an oral glucose tolerance test was not significantly raised by TAK-875, possibly due in part to lower glucose concentrations and large variations between individuals. However, this result might disguise a beneficial change in the timing of insulin release because the C-peptide:glucose ratio during the first 30 min of an oral glucose tolerance test was improved, suggesting a greater initial insulin response relative to the glycaemic challenge. Consistent with agents that mainly potentiate nutrient-induced insulin secretion, TAK-875 produced no more hypoglycaemia than did placebo and much less than glimepiride. Whereas free fatty acids can acutely amplify insulin secretion, chronic exposure to raised concentrations of fatty acids has harmful lipotoxic effects on the viability of β cells. However, FFAR1 does not transport fatty acids and does not appear to contribute to chronic lipotoxicity. Various enteroendocrine ABT-263 express FFAR1, including L cells, which secrete GLP-1. This link raises the possibility that FFAR1 agonists could augment prandial insulin secretion partly via an enhanced incretin response—something for future investigation. GLP-1 might be expected to exert a satiety effect that restricts weight gain; however, in Burant and colleagues' study, TAK-875 increased bodyweight relative to placebo (>0·6 kg), an effect not dissimilar to that of glimepiride. The question of durability looms large over insulin-releasing pharmacotherapies. The stimulatory effect of sulphonylureas seems to wear off and restrict long-term efficacy in many patients. This outcome might reflect desensitisation to the drug, ongoing β-cell deterioration, or even accelerated functional exhaustion through overstimulation—the jury is still out after 50 years of widespread use., The durability of incretin-mediated treatments awaits thorough evaluation, and now FFAR1 agonists join that waiting list. Insulin resistance was apparently unaffected by TAK-875, although this outcome was not examined in detail. This finding revisits the therapeutic conundrum in type 2 diabetes—namely, that chronically increased insulin concentrations can aggravate insulin resistance, which might offset early benefits of enhanced insulin secretion. Evidence to date suggests no particular effects of TAK-875 on cardiovascular function via the circulating lipid profile or blood pressure, although the significance of FFAR1 receptors in brain, osteoclasts, and monocytes is uncertain. On the journey to approval of a new class of treatment for type 2 diabetes, many questions will be asked of the FFAR1 agonists. Can they unlock the secretion-shy β cells, provide durable efficacy, and avoid off-target safety issues? We travel hopefully.
Introduction The incidence of type 2 diabetes mellitus (T2DM) has been on the increase, making it a serious health care problem. It was estimated that about 415 million adults were living with diabetes globally in 2015 [1]. Although several synthetic drugs such as sulfonylureas, biguanides, alpha-glucosidase inhibitors and others are currently being used for the treatment/management of T2DM, some of them have been associated with adverse effects such as hypoglycemia, liver damage, gastrointestinal symptoms, and weight gain. This therefore underscores the need for new and safer treatment options for T2DM.