Comment on: Turban et al. Optimal Elevation of β-Cell 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism That Prevents High-Fat Diet–Induced β-Cell Failure. Diabetes 2012;61:642–652 (original) (raw)
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Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin
Diabetologia, 2008
In many countries, first-or second-line pharmacological treatment of patients with type 2 diabetes consists of sulfonylureas (such as glibenclamide [known as glyburide in the USA and Canada]), which stimulate the beta cell to secrete insulin. However, emerging evidence suggests that forcing the beta cell to secrete insulin at a time when it is struggling to cope with the demands of obesity and insulin resistance may accelerate its demise. Studies on families with persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI), the primary defect of which is hypersecretion of insulin, have shown that overt diabetes can develop later in life despite normal insulin sensitivity. In addition, in vitro experiments have suggested that reducing insulin secretion from islets isolated from patients with diabetes can restore insulin pulsatility and improve function. This article will explore the hypothesis that forcing the beta cell to hypersecrete insulin may be counterproductive and lead to dysfunction and death via mechanisms that may involve the endoplasmic reticulum and oxidative stress. We suggest that, in diabetes, therapeutic approaches should be targeted towards relieving the demand on the beta cell to secrete insulin.
The effects of a cafeteria diet on insulin production and clearance in rats
British Journal of Nutrition, 2012
The aim of the present study was to determine the effects of a cafeteria diet on the function and apoptosis of the pancreas, and the activity and expression of the insulin-degrading enzyme (IDE). Female Wistar rats were fed either with a cafeteria diet or a control diet for 17 weeks, and blood and tissues were then collected for analysis. The cafeteria diet-treated rats had higher plasma insulin and C-peptide levels (P, 0·05), showing increased insulin secretion by the pancreas. Insulin protein and gene expression levels were higher in the pancreas of obese rats, as was its transcriptional controller, pancreatic duodenal homeobox 1 (P,0·05). Feeding a cafeteria diet downregulated the gene expression of the anti-apoptotic marker B-cell/lymphoma 2 (BCL2), and up-regulated the protein levels of BCL2-associated X protein, a pro-apoptotic marker (P,0·05). The cafeteria diet caused lipid accumulation in the pancreas and modified the expression of key genes that control lipid metabolism. To assay whether insulin clearance was also modified, we checked the activity of the IDE, one of the enzymes responsible for insulin clearance. We found increased liver IDE activity (P, 0·05) in the cafeteria diet-fed animals, which could, in part, be due to an up-regulation of its gene expression. Conversely, IDE gene expression was unmodified in the kidney and adipose tissue; although when the adipose tissue weight was considered, the insulin clearance potential was higher in the cafeteria diet-treated rats. In conclusion, treatment with a cafeteria diet for 17 weeks in rats mimicked a pre-diabetic state, with ectopic lipid accumulation in the pancreas, and increased the IDE-mediated insulin clearance capability. These authors have contributed equally to this work. * Corresponding author: M. Pinent, fax þ34 977 558232, email montserrat.pinent@urv.cat
Journal of Clinical Investigation, 2011
Insulin, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) play key roles in the regulation of b cell growth and function. Although b cells express the GH receptor, the direct effects of GH on b cells remain largely unknown. Here we have employed a rat insulin II promoter-driven (RIP-driven) Cre recombinase to disrupt the GH receptor in b cells (bGHRKO). bGHRKO mice fed a standard chow diet exhibited impaired glucose-stimulated insulin secretion but had no changes in b cell mass. When challenged with a high-fat diet, bGHRKO mice showed evidence of a b cell secretory defect, with further deterioration of glucose homeostasis indicated by their altered glucose tolerance and blunted glucosestimulated insulin secretion. Interestingly, bGHRKO mice were impaired in b cell hyperplasia in response to a high-fat diet, with decreased b cell proliferation and overall reduced b cell mass. Therefore, GH receptor plays critical roles in glucose-stimulated insulin secretion and b cell compensation in response to a high-fat diet.
Endocrinology, 2013
Corticosterone (CORT) and other glucocorticoids cause peripheral insulin resistance and compensatory increases in β-cell mass. A prolonged high-fat diet (HFD) induces insulin resistance and impairs β-cell insulin secretion. This study examined islet adaptive capacity in rats treated with CORT and a HFD. Male Sprague-Dawley rats (age ∼6 weeks) were given exogenous CORT (400 mg/rat) or wax (placebo) implants and placed on a HFD (60% calories from fat) or standard diet (SD) for 2 weeks (N = 10 per group). CORT-HFD rats developed fasting hyperglycemia (>11 mM) and hyperinsulinemia (∼5-fold higher than controls) and were 15-fold more insulin resistant than placebo-SD rats by the end of ∼2 weeks (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR] levels, 15.08 ± 1.64 vs 1.0 ± 0.12, P < .05). Pancreatic β-cell function, as measured by HOMA-β, was lower in the CORT-HFD group as compared to the CORT-SD group (1.64 ± 0.22 vs 3.72 ± 0.64, P < .001) as well as acute insulin ...
The American Journal of Clinical Nutrition, 2012
Background: Caloric restriction in obese diabetic patients quickly improves glucose control, independently from weight loss. However, the early effects of a very-low-calorie diet (VLCD) on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes are still unclear. Objective: The objective was to study the relative contributions of insulin sensitivity, insulin secretion, or both to improvement in glucose metabolism, after 1 wk of caloric restriction, in severely obese diabetic patients. Design: Hyperglycemic clamps were performed in 14 severely obese (BMI, in kg/m 2 : .40) patients with type 2 diabetes in good glucose control (glycated hemoglobin , 7.5%) before and after 7 d of a VLCD (400 kcal/d). Results: The VLCD caused a 3.22 6 0.56% weight loss (P , 0.001), 42.0% of which was fat loss, accompanied by decreases in fasting plasma glucose (P , 0.05) and triglycerides (P , 0.01). In parallel, the Disposition Index, which measures the body's capability to dispose of a glucose load, increased from 59.0 6 6.3 to 75.5 6 6.3 mLÁ min 21 Á m 22 body surface area (P , 0.01), because of improvements in indexes of both first-and second-phase insulin secretion (P , 0.02), but with no changes in insulin sensitivity (P = 0.33). Conclusion: The marked improvement in metabolic profile, observed in severely obese patients with type 2 diabetes after a 7-d VLCD, was primarily due to the amelioration of b cell function, whereas no contribution of insulin sensitivity was shown. This trial was registered at www.clinicaltrials.gov as NCT01447524.
Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene
Diabetes, 2002
autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg tm1Mbl ). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P ؍ 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions. FIG. 5. Plasma insulin and HOMA in WT and KO mice fed LF or HF diets. After an overnight fast, HF-or LF-fed (9 weeks) fetuin KO and WT mice were given an i.p. glucose tolerance test (1.5 mg glucose/g), and blood glucose and plasma insulin concentrations were measured.