The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

Abstract

Efficient energy storage in adipose tissues requires optimal function of the insulin-producing ␤-cell, whereas its dysfunction promotes diabetes. The associated paradox related to ␤-cell efficiency is that excessive accumulation of fat in adipose tissue predisposes for type 2 diabetes. Insulin exocytosis is regulated by intracellular metabolic signal transduction, with glutamate dehydrogenase playing a key role in the amplification of the secretory response. Here, we used mice with ␤-cell-selective glutamate dehydrogenase deletion (␤Glud1 ؊/؊ ), lacking an amplifying pathway of insulin secretion. As opposed to control mice, ␤Glud1 ؊/؊ animals fed a high calorie diet maintained glucose tolerance and did not develop diet-induced obesity. Islets of ␤Glud1 ؊/؊ mice did not increase their secretory response upon high calorie feeding, as did islets of control mice. Inhibited adipose tissue expansion observed in knock-out mice correlated with lower expression of genes responsible for adipogenesis. Rather than being efficiently stored, lipids were consumed at a higher rate in ␤Glud1 ؊/؊ mice compared with controls, in particular during food intake periods. These results show that reduced ␤-cell function prior to high calorie feeding prevented diet-induced obesity.

Glutamate pathways of the beta-cell and the control of insulin secretion

“…Such a state may evolve towards frank diabetes in case of a failure of the pancreatic b-cell [1]. However, it has been shown in mice that obesity is prevented by an early limitation of the full secretory potential of the b-cell, either by the reduction of insulin gene dosage [19] or by abrogation of the amplifying pathway [18]. Some available clinical data do support such observations made in rodents.…”

“…Whereas control mice become obese and pre-diabetic, those without GDH in their b-cells are totally resistant to diet-induced obesity [18]. Such a resistance to weight gain is accompanied by the preservation of glucose tolerance and a better use of lipids as a source of energy compared to control mice expressing the Glud1 gene encoding for GDH [18]. Even when Glud1 in the b-cell is deleted following the development of obesity …”

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

“…The latter depends on the cataplerotic activity of GDH (Vetterli et al, 2012) and its genetic abrogation protects against obesity (Vetterli et al, 2016a). In the present study, we tested the pharmacological inhibition of GDH on insulin secretion in mouse and human islets.…”

“…However, ß-cell-targeted genetic intervention in mice protects against obesity, either by the reduction of insulin gene dosage (Mehran et al, 2012) or by the ablation of the amplifying pathway of glucose-stimulated insulin secretion (Vetterli et al, 2016a). Clinical data have shown that pharmacological inhibition of insulin secretion in obese subjects can promote weight loss (Lustig et al, 2006;van Boekel et al, 2008), although drugs used in these studies are associated with undesired side effects, such as hyperglycemia.…”

“…Moreover, GDH is allosterically regulated by leucine as well as pyridine, adenine and guanine nucleotides; being inhibited by GTP and activated by ADP (Fisher, 1985;Smith et al, 2001). In pancreatic ß-cells, cataplerosis participates in the amplifying pathway of insulin secretion (Vetterli et al, 2016b). Conversely, GDH-mediated anaplerosis, evoked for instance by glutamine, is not favoured in ß-cells but can be prompted by the allosteric activator BCH (2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid) resulting in insulin release (Carobbio et al, 2004;Sener et al, 1981) or by activating mutations causing a syndrome of hyperinsulinism (Stanley et al, 1998).…”