Functional and Molecular Adaptations of Enteroendocrine L-Cells in Male Obese Mice Are Associated With Preservation of Pancreatic α-Cell Function and Prevention of Hyperglycemia

Abstract

Glucose homeostasis depends on the coordinated secretion of glucagon, insulin, and Glucagon-like peptide (GLP)-1 by pancreas and intestine. Obesity, which is associated with an increased risk of developing insulin resistance and type 2 diabetes, affects the function of these organs. Here, we investigate the functional and molecular adaptations of proglucagon-producing cells in obese mice to better define their involvement in type 2 diabetes development. We used GLU-Venus transgenic male mice specifically expressing Venus fluorochrome in proglucagon-producing cells. Mice were subjected to 16 weeks of low-fat diet or high-fat diet (HFD) and then subdivided by measuring glycated hemoglobin (HbA1c) in 3 groups: low-fat diet mice and I-HFD (glucose-intolerant) mice with similar HbA1c and H-HFD (hyperglycemic) mice, which exhibited higher HbA1c. At 16 weeks, both HFD groups exhibited similar weight gain, hyperinsulinemia, and insulin resistance. However, I-HFD mice exhibited better glucose tolerance compared with H-HFD mice. I-HFD mice displayed functional and molecular adaptations of enteroendocrine L-cells resulting in increased intestinal GLP-1 biosynthesis and release as well as maintained pancreatic α- and β-cell functions. By contrast, H-HFD mice exhibited dysfunctional L, α- and β-cells with increased β- and L-cell numbers. Administration of the GLP-1R antagonist Exendin9-39 in I-HFD mice led to hyperglycemia and alterations of glucagon secretion without changes in insulin secretion. Our results highlight the cross-talk between islet and intestine endocrine cells and indicate that a compensatory adaptation of L-cell function in obesity plays an important role in preserving glucose homeostasis through the control of pancreatic α-cell functions.

Enhanced postprandial glucagon-like peptide-1 secretion during obesity development has a protective role against glucose intolerance induction in rats

“…Accordingly, our results illustrate that chronic HFS feeding with continuous Ex9 administration rapidly established postprandial hyperglycaemia, while HFS alone maintained a glycaemic response similar to the control group in both the 2-and 4-week feeding periods. Previous studies demonstrated that Ex9 treatment for 14 d accelerated glucose intolerance in rats assessed by OGTT (24) and intraperitoneal injection of Ex9 prior to OGTT-induced glucose intolerance in rats (48) . Overnight fasting (14-18 h) is generally employed in typical metabolic studies (49,50) , but prolonged fasting may affect glycaemic response and improve insulin sensitivity, compared with relatively shorter (51)(52)(53) .…”

“…The GLP-1 receptor antagonist, Ex9 (analytical grade, purity > 95 %), was purchased from Thermo Fisher Scientific Inc. Ex9 was dissolved in sterile saline and transferred to the Alzet Mini osmotic pump (Model 2006, Durect corporation) following the manufacturer's instructions. According to a previous study, Ex9 impairs glucose tolerance during an oral glucose tolerance test (OGTT) (24) . In our study, 100 μg/day per rat of Ex9 was used to block GLP-1 signalling.…”

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

“…While it is hard to find commonalities in the literature regarding HFD-induced hyperglucagonaemia, our findings suggest that methodological aspects such as time of sampling have a strong influence on the level of circulating glucagon measured. Thus, these findings could potentially explain why measurements of plasma glucagon in HFD fed models differ markedly between studies [26-28, 48] and why it has been difficult relating them to human observations.…”

“…Exposure of whole islets to high levels of palmitate for up to 72h changes both insulin, glucagon and somatostatin secretion [21, 22] as well as whole-islet gene expression [23] and metabolism [24, 25]. Furthermore, isolated islets from HFD mice exhibit elevated glucagon secretion when exposed to high glucose concentrations [26]. However the mechanism by which this elevation occurs remains unresolved and obscured by the conflicting in vivo observations that circulating glucagon is increased [26], decreased [27] or unchanged [28] in HFD mice.…”

“…Furthermore, isolated islets from HFD mice exhibit elevated glucagon secretion when exposed to high glucose concentrations [26]. However the mechanism by which this elevation occurs remains unresolved and obscured by the conflicting in vivo observations that circulating glucagon is increased [26], decreased [27] or unchanged [28] in HFD mice. Here we investigate the effects of HFD feeding on alpha-cell function and the paracrine regulation of glucagon secretion.…”