Early changes in insulin secretion and action induced by high-fat diet are related to a decreased sympathetic tone

Abstract

To evaluate the relationship between the development of obesity, nervous system activity, and insulin secretion and action, we tested the effect of a 2-mo high-fat diet in rats (HF rats) on glucose tolerance, glucose-induced insulin secretion (GIIS), and glucose turnover rate compared with chow-fed rats (C rats). Moreover, we measured pancreatic and hepatic norepinephrine (NE) turnover, as assessment of sympathetic tone, and performed hypothalamic microdialysis to quantify extracellular NE turnover. Baseline plasma triglyceride, free fatty acid, insulin, and glucose concentrations were similar in both groups. After 2 days of diet, GIIS was elevated more in HF than in C rats, whereas plasma glucose time course was similar. There was a significant increase in basal pancreatic NE level of HF rats, and a twofold decrease in the fractional turnover constant was observed, indicating a change in sympathetic tone. In ventromedian hypothalamus of HF rats, the decrease in NE extracellular concentration after a glucose challenge was lower compared with C rats, suggesting changes in overall activity. After 7 days, insulin hypersecretion persisted, and glucose intolerance appeared. Later (2 mo), there was no longer insulin hypersecretion, whereas glucose intolerance worsened. At all times, HF rats also displayed hepatic insulin resistance. On day 2 of HF diet, GIIS returned to normal after treatment with oxymetazoline, an alpha(2A)-adrenoreceptor agonist, thus suggesting the involvement of a low sympathetic tone in insulin hypersecretion in response to glucose in HF rats. In conclusion, the HF diet rapidly results in an increased GIIS, at least in part related to a decreased sympathetic tone, which can be the first step of a cascade of events leading to impaired glucose homeostasis.

A free-choice high-fat high-sugar diet induces glucose intolerance and insulin unresponsiveness to a glucose load not explained by obesity

“…36,37 We have to note that the method of presenting our diets (using choice) is distinct from various studies in the literature (using synthetic dry diets), making comparison difficult. Early changes in glucose tolerance have been described for rats on a 40%-fat diet, 12 which is not in agreement with our results in rats on a free-choice HF diet. This could be because of the difference in how the diets were presented (that is, choice HF diet vs a synthetic HF diet); however, caloric intake was also much higher in rats on a synthetic HF diet compared with consumption in our study and rats were much younger when experiments began.…”

“…The brain and its projections to the ANS, however, could also have an important role in dietinduced insulin resistance and glucose intolerance. 12,13 One of the changes in glucose metabolism in rats on HFHS diet is the change in the insulin response to a glucose load. It has been demonstrated that a defect in the acute insulin response, or the early insulin response, occurs early in the development of type 2 diabetes mellitus and it may contribute to the conversion from normal to impaired glucose tolerance and diabetes.…”

“…[9][10][11] On the other hand, it has been proposed that alterations in the brain and its projections to the autonomic nervous system (ANS) could have an important role in diet-induced alterations in glucose metabolism. For example, Cruciani-Gluglielmacci 12 showed that a lard-based high-fat diet in young Wistar rats resulted in rapid changes in insulin secretion and action. These changes were not explained by changes in the levels of plasma lipids, but instead explained by changes in the sympathetic tone, and changes in norepinephrine turnover in the hypothalamus, an area in the brain important for the regulation of glucose metabolism.…”

Differential effects of hypercaloric choice diets on insulin sensitivity in rats

“…The molecular drivers involved in the pathogenesis of lower insulin sensitivity in obesity include, but are not limited to, increased concentrations of fatty acids and their intermediates, inflammatory changes, adipose tissue dysfunction, oxidative and ER-stress, and mitochondrial dysfunction (Reaven 2002, Morton & Barrett 2006, Chawla et al 2011. Besides these mechanisms that are mainly related to increased body fat mass, palatable nutrients, that induce obesitylike (saturated) fat and sugar themselves, contribute to insulin resistance (Storlien et al 1987, 1988, Pagliassotti et al 1994, 1996, Cruciani-Guglielmacci et al 2005. The differential impact of dietary fat and sugar on glucose metabolism might provide part of the explanation why not all obese individuals develop insulin resistance and/ or T2DM.…”

Dieta hiperlipídica e capacidade secretória de insulina em ratos

“…Contudo, a administração da dieta por período prolongado tendeu a reduzir os valores de insulina circulantes sem alterar significativamente a glicemia de jejum dos ratos. Embora CrucianiGuglielmacci et al 28 tenham registrado hiperinsulinemia como efeito agudo da administração de dieta hiperlipídica, a insulinemia, após dois meses de dieta, se normalizou. Resultados similares a esses foram relatados por Estadella et al 2 e Chen & Nyomba 29 , mas são contrários àqueles observados por Cheik 26 , nos quais a dieta hipercalórica promoveu aumento significativo nas concentrações plasmáticas de insulina.…”