Insulin Production and Resistance in Different Models of Diet-Induced Obesity and Metabolic Syndrome

Abstract

The role of the liver and the endocrine pancreas in development of hyperinsulinemia in different types of obesity remains unclear. Sedentary rats (160 g) were fed a low-fat-diet (LFD, chow 13% kcal fat), high-fat-diet (HFD, 35% fat), or HFD+ 30% ethanol+ 30% fructose (HF-EFr, 22% fat). Overnight-fasted rats were culled after one, four or eight weeks. Pancreatic and hepatic mRNAs were isolated for subsequent RT-PCR analysis. After eight weeks, body weights increased three-fold in the LFD group, 2.8-fold in the HFD group, and 2.4-fold in the HF-EFr (p < 0.01). HF-EFr-fed rats had the greatest liver weights and consumed less food during Weeks 4–8 (p < 0.05). Hepatic-triglyceride content increased progressively in all groups. At Week 8, HOMA-IR values, fasting serum glucose, C-peptide, and triglycerides levels were significantly increased in LFD-fed rats compared to that at earlier time points. The greatest plasma levels of glucose, triglycerides and leptin were observed in the HF-EFr at Week 8. Gene expression of pancreatic-insulin was significantly greater in the HFD and HF-EFr groups versus the LFD. Nevertheless, insulin: C-peptide ratios and HOMA-IR values were substantially higher in HF-EFr. Hepatic gene-expression of insulin-receptor-substrate-1/2 was downregulated in the HF-EFr. The expression of phospho-ERK-1/2 and inflammatory-mediators were greatest in the HF-EFr-fed rats. Chronic intake of both LFD and HFD induced obesity, MetS, and intrahepatic-fat accumulation. The hyperinsulinemia is the strongest in rats with the lowest body weights, but having the highest liver weights. This accompanies the strongest increase of pancreatic insulin production and the maximal decrease of hepatic insulin signaling, which is possibly secondary to hepatic fat deposition, inflammation and other factors.

Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism

“…Visceral fat mass increases with fructose diet in humans [53] as well as in experimental models [18,54]. This suggests either a direct fructose metabolism in visceral adipocytes, which may be exposed to higher fructose concentrations than subcutaneous adipocytes due to anastomosis between portal hepatic and systemic splanchnic circulation, or an indirect effect through an accumulation of lipid originating from the liver.…”

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

“…The pH-buffering capacity of the interstitial fluid is much lower compared with that in the blood and in the cytosol ( Figure 1 and Figure 3 ), meaning that interstitial fluid pH in metabolic tissues is variable depending on metabolic conditions. One of the most serious problems in glucose metabolism caused by the lowered pH value of the interstitial fluid [ 1 , 108 , 109 , 110 , 113 , 160 , 161 , 162 , 163 , 164 , 165 , 166 ] is occurrence of the insulin resistance [ 1 , 108 , 109 , 110 , 113 ]. The lowered interstitial fluid (extracellular) pH diminishes insulin action on glucose uptake in rat skeletal model cells [ 110 , 167 ].…”

Adipokines in Liver Cirrhosis

“…High fat diets, Western-type diets, diets enriched in fructose and light to moderate alcohol intake could trigger the onset and progression of NAFLD [ 3 , 4 , 5 ]. Excess dietary fructose is connected to hepatic ATP depletion in type 2 diabetes patients and thus may contribute to NAFLD pathogenesis [ 6 ].…”