Glucose mediates insulin sensitivity via a hepatoportal mechanism in high-fat-fed rats.

Poor nutrition plays a fundamental role in the development of insulin resistance, an underlying characteristic of type 2 diabetes. We have previously shown that high-fat diet-induced insulin resistance in rats can be ameliorated by a single glucose meal, but the mechanisms for this observation remain unresolved. To determine if this phenomenon is mediated by gut or hepatoportal factors, male Wistar rats were fed a high-fat diet for 3 weeks before receiving one of five interventions: high-fat meal, glucose gavage, high-glucose meal, systemic glucose infusion or portal glucose infusion. Insulin sensitivity was assessed the following day in conscious animals by a hyperinsulinaemic-euglycaemic clamp. An oral glucose load consistently improved insulin sensitivity in high-fat-fed rats, establishing the reproducibility of this model. A systemic infusion of a glucose load did not affect insulin sensitivity, indicating that the physiological response to oral glucose was not due solely to increased glucose turnover or withdrawal of dietary lipid. A portal infusion of glucose produced the largest improvement in insulin sensitivity, implicating a role for the hepatoportal region rather than the gastrointestinal tract in mediating the effect of glucose to improve lipid-induced insulin resistance. These results further deepen our understanding of the mechanism of glucose-mediated regulation of insulin sensitivity and provide new insight into the role of nutrition in whole body metabolism.

Glycaemic Index of Maternal Dietary Carbohydrate Differentially Alters Fto and Lep Expression in Offspring in C57BL/6 Mice.

Maternal diet and gestational hyperglycaemia have implications for offspring health. Leptin (LEP) and fat mass and obesity-associated (FTO) alleles are known to influence body fat mass in humans, potentially via effects on appetite. We hypothesized that expression of Fto, Lep, and other appetite-related genes (Argp, Npy, Pomc, Cart, Lepr) in the offspring of female mice are influenced by the glycaemic index (GI) of carbohydrates in the maternal diet. C57BL/6 mice were randomly assigned to low or high GI diets and mated with chow-fed males at eight weeks of age. Male pups were weaned at four weeks and randomly divided into two groups, one group following their mother's diet (LL and HH), and one following the standard chow diet (LC and HC) to 20 weeks. Fto expression was 3.8-fold higher in the placenta of mothers fed the high GI diet (p = 0.0001) and 2.5-fold higher in the hypothalamus of 20-week old offspring fed the high GI (HH vs. LL, p < 0.0001). By contrast, leptin gene (Lep) expression in visceral adipose tissue was 4.4-fold higher in four-week old offspring of low GI mothers (LC vs. HC, p < 0.0001) and 3.3-fold higher in visceral adipose tissue of 20-week old animals (LL vs. HH, p < 0.0001). Plasma ghrelin and leptin levels, and hypothalamic appetite genes were also differentially regulated by maternal and offspring diet. These findings provide the first evidence in an animal model that maternal high GI dietary carbohydrates that are digested and absorbed faster may contribute to programming of appetite in offspring.

Determining the Glycaemic Index of Standard and High-Sugar Rodent Diets in C57BL/6 Mice.

The glycaemic index (GI) is a useful tool to compare the glycaemic responses of foods. Numerous studies report the favorable effects of low GI diets on long term metabolic health compared with high GI diets. However, it has not been possible to link these effects to the GI itself because of other components such as macronutrients and dietary fibre, which are known to affect GI. This study aimed to create and evaluate isocaloric diets differing in GI independent of macronutrient and fibre content. The GIs of eight diets differing in carbohydrate source were evaluated in mice; cooked cornstarch (CC), raw cornstarch (RC), chow, maltodextrin, glucose, sucrose, isomaltulose, and fructose. A glucose control was also tested. The GIs of all eight diets were different from the GI of the glucose control (GI: 100; p < 0.0001). The GIs of the glucose (mean ± SEM: 52 ± 3), maltodextrin (52 ± 6), CC (50 ± 4), RC (50 ± 6), and chow (44 ± 4) diets were similar, while the GIs of the sucrose (31 ± 4), isomaltulose (24 ± 5), and fructose (18 ± 2) diets were lower than all other diets (p < 0.05). This is the first trial to report GI testing in vivo in mice, resulting in three main findings: chow is relatively high GI, the glucose availability of raw and cooked cornstarch is similar, and the GI of different sugar diets occur in the same rank order as in humans.

Metabolic Effects of High Glycaemic Index Diets: A Systematic Review and Meta-Analysis of Feeding Studies in Mice and Rats.

Low glycaemic index (LGI) diets are often reported to benefit metabolic health, but the mechanism(s) responsible are not clear. This review aimed to systematically identify studies investigating metabolic effects of high glycaemic index (HGI) versus LGI diets in mice and rats. A meta-analysis was conducted to calculate an overall effect size, Hedge's standardised mean differences (hereafter d), for each trait, with moderator variables considered in subsequent meta-regressions. Across 30 articles, a HGI diet increased five of the seven traits examined: body weight (d = 0.55; 95% confidence interval: 0.31, 0.79), fat mass (d = 1.08; 0.67, 1.49), fasting circulating insulin levels (d = 0.40; 0.09, 0.71), and glucose (d = 0.80; 0.35, 1.25) and insulin (d = 1.14; 0.50, 1.77) area under the curve during a glucose tolerance test. However, there was substantial heterogeneity among the effects for all traits and the small number of studies enabled only limited investigation of possible confounding factors. HGI diets favour body weight gain, increased adiposity and detrimentally affect parameters of glucose homeostasis in mice and rats, but these effects may not be a direct result of GI per se; rather they may be due to variation in other dietary constituents, such as dietary fibre, a factor which is known to reduce the GI of food and promote health via GI-independent mechanisms.