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. 2017 Feb 1;312(2):E109-E116.
doi: 10.1152/ajpendo.00279.2016. Epub 2016 Dec 27.

Reduced Islet Function Contributes to Impaired Glucose Homeostasis in Fructose-Fed Mice

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Reduced Islet Function Contributes to Impaired Glucose Homeostasis in Fructose-Fed Mice

Zeenat A Asghar et al. Am J Physiol Endocrinol Metab. .
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Abstract

Increased sugar consumption, particularly fructose, in the form of sweetened beverages and sweeteners in our diet adversely affects metabolic health. Because these effects are associated with features of the metabolic syndrome in humans, the direct effect of fructose on pancreatic islet function is unknown. Therefore, we examined the islet phenotype of mice fed excess fructose. Fructose-fed mice exhibited fasting hyperglycemia and glucose intolerance but not hyperinsulinemia, dyslipidemia, or hyperuricemia. Islet function was impaired, with decreased glucose-stimulated insulin secretion and increased glucagon secretion and high fructose consumption leading to α-cell proliferation and upregulation of the fructose transporter GLUT5, which was localized only in α-cells. Our studies demonstrate that excess fructose consumption contributes to hyperglycemia by affecting both β- and α-cells of islets in mice.

Figures

Fig. 1.
Fig. 1.
High fructose consumption increases adiposity. Beginning at 6–8 wk of age, male mice were fed standard chow diet and water [control (Con); ● and black bars] or 60% fructose diet + 30% fructose water (HFr; ○ and open bars) for 6 wk. A: body weights of HFr and control mice; n = 8–10. B: %body fat and lean mass; n = 7 mice in each group. CE: fasting serum uric acid (C), triglyceride (D), and free fatty acid (E) levels; n = 7 in each group. ***P < 0.001 by Student's t-test.
Fig. 2.
Fig. 2.
High-fructose consumption impairs glucose homeostasis. A, left: blood glucose levels over time following an intraperitoneal injection of 2 mg/g glucose; n = 16 in each group. A, right: area under the curve (AUC). B: insulin response during the glucose tolerance test; n = 11–12 mice. C: blood glucose levels following an intraperitoneal injection of 0.5 U insulin; n = 6 in each group. D and E: fed, fasting, and refed plasma insulin (D) and glucagon (E) levels; n = 4–6. Data are presented as means ± SE. *P < 0.05, ***P < 0.01, and ****P < 0.0001 by Student’s t-test.
Fig. 3.
Fig. 3.
High fructose consumption leads to decreased glucose-stimulated insulin secretion and impaired mitochondrial response. A: glucose-stimulated insulin secretion in freshly isolated islets; n = 6–7 replicates of islet batches from ≥4 mice in each group. B: insulin secretion simulated with 10 mM leucine and 10 mM glutamine under nonstimulatory (2.8 mM) glucose conditions; n = 7 replicates of islet batches from 3 mice in each group. C: oxygen consumption rates in the basal (b) state, after glucose stimulation (+20 mM glc), after addition of the mitochondrial uncoupler FCCP (F), and after addition of the electron transport chain inhibitors oligomycin (O) and rotenone/antimycin (R/A). D: mitochondrial bioenergetics parameters were calculated based on measurements from those in C. Results are expressed as means ± SE; n = 4–7/group. **P < 0.01, ***P < 0.001, and ****P < 0.0001 by Student’s t-test.
Fig. 4.
Fig. 4.
High fructose consumption leads to increases in glucagon secretion and α-cell expansion. A: glucagon secretion from cultured islets under low (1 mM) and high glucose (16.7 mM) with or without 20 mM l-arginine; n = 5 replicates of islet batches from 4 mice in each group. B: total islet glucagon content; n = 12 batches of islets. C: representative immunofluorescence image of control and HFr islets. Green, insulin; red, glucagon. D: quantification of Ki-67-positive red stained α-cells (left) and representative image (right). Red, glucagon; yellow, Ki-67; Dapi, blue (n = 3 mice pancreata examined by pancreatic sections separated by 80 µm from each of 3 mice). **P < 0.01 and ***P < 0.001 by Student’s t-test.
Fig. 5.
Fig. 5.
GLUT5 is expressed in α-cells and is upregulated in response to high fructose consumption. A: mRNA expression of GLUT5 (normalized to β-actin) in islets from control and HFr-exposed mice. B: representative immunofluorescence image of control islets at low and high magnification. Cyan, insulin; red, glucagon; green, GLUT5 (n = 4 replicates from 4 mice). *P< 0.05 by Student’s t-test.

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