Insulin Resistance and Type 2 Diabetes in High-Fat–Fed Mice Are Linked to High Glycotoxin Intake

Abstract

Dietary advanced glycosylation end products (AGEs) have been linked to insulin resistance in db/db(؉؉) mice. To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets, normal C57/BL6 mice were randomly assigned to high-fat diets (35% g fat), either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6 months. Age-matched C57/BL6 and db/db (؉؉) mice fed regular diet (5% g fat, 117.4 units/mg AGE) served as controls. After 6 months, 75% of HAGE-HF mice were diabetic and exhibited higher body weight (P < 0.001), fasting glucose (P < 0.001), insulin (P < 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids. The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice, in which findings resembled those of control mice. The HAGE-HF group had more visceral fat (by two-and fourfold) and more AGE-modified fat (by two-and fivefold) than LAGE-HF and control mice, respectively. In the HAGE-HF group, plasma 8-isoprostane was higher (P < 0.01) and adiponectin lower (P < 0.001) than control mice, while in the LAGE-HF group, these were more modestly affected (P < 0.05). These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets. Diabetes 54: 2314 -2319, 2005

Advanced Glycation End Products (Ages) in Food: Focusing on Mediterranean Pasta

“…Positive correlation between dAGE content and serum/tissue AGE levels have been also confirmed by several animal study [17,27,28]. For example Peppa et al [29] to assess the role of dAGEs on type 1 diabetes, exposed the genetically susceptible NOD mice to a high-AGE diet and to a nutritionally similar diet with approximate fivefold-lower levels of CML and MG and demonstrated that after 44 weeks of treatment, NOD mice fed with Low-AGE diet showed almost half of serum AGE levels respect to High-AGE diet fed NOD mice.…”

Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice

“…Adiponectin is a 30 kDa protein exclusively secreted by adipose tissue and plays a protective role against the development of diabetes and atherosclerosis (14,23,26,30,48,53). Plasma levels of APN are markedly reduced in diabetic patients as well as rodent models of diabetes (21,25,40,45). In addition, numerous epidemiological studies showed that reduced APN levels correlate with CVD (16,56).…”

Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice

“…In the present study we explored the effect of GSK3 inhibition on glucose metabolism in an environmentally induced (high-fat [HF] diet) insulin-resistant obese mouse model of type 2 diabetes. Several studies have indicated that the C57BL/6J mouse strain on an HF diet is a suitable model for noninsulin-dependent diabetes mellitus and hypertension [18][19][20][21]. We chose this model because it closely mimics the common form of obesity and insulin resistance associated with human type 2 diabetes.…”