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.
Highlights
The prevalence of non-alcoholic fatty liver disease (NAFLD) is 80% in obese adults, 30%–50% in patients with type 2 diabetes mellitus (T2DM), up to 90% in patients with hyperlipidemia [1,2], and 19% in non-obese subjects [3]
The current study indicates that reduced hepatic insulin clearance is not the only mechanism responsible for hyperinsulinemia, and increased insulin gene-expression parallels the increase of serum glucose levels
Merging alcohol-plus-fructose with high-fat diet (HFD) induced hepatomegaly, which is not related to changes in the Body weight (BW) and cannot be only explained as a result of the increased deposition of fat in hepatocytes
Summary
The prevalence of non-alcoholic fatty liver disease (NAFLD) is 80% in obese adults, 30%–50% in patients with type 2 diabetes mellitus (T2DM), up to 90% in patients with hyperlipidemia [1,2], and 19% in non-obese subjects [3]. Factors responsible for hyperglycemia and hyperinsulinemia are not fully understood. Both insulin clearance and insulin sensitivity correlate inversely with dietary fat/carbohydrate ratio [7,8]. Data suggest that increased liver fat impairs insulin clearance and hepatic and adipose tissue insulin resistance (IR) characterizes of T2DM [9]. NAFLD could inhibit hepatic insulin clearance in patients, which is associated with reduced insulin sensitivity [12]. Partial ablation of hepatic ApoA5 in mice fed a high-fat diet (HFD) reduced triglyceride accumulation in liver, skeletal muscles, and protected them from HFD-induced IR [13]
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