Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake

Abstract

Coate KC, Scott M, Farmer B, Moore MC, Smith M, Roop J, Neal DW, Williams P, Cherrington AD. Chronic consumption of a high-fat/ high-fructose diet renders the liver incapable of net hepatic glucose uptake. Am J Physiol Endocrinol Metab 299: E887-E898, 2010. First published September 7, 2010; doi:10.1152/ajpendo.00372.2010.-The objective of this study was to assess the response of a large animal model to high dietary fat and fructose (HFFD). Three different metabolic assessments were performed during 13 wk of feeding an HFFD (n ϭ 10) or chow control (CTR, n ϭ 4) diet: oral glucose tolerance tests (OGTTs; baseline, 4 and 8 wk), hyperinsulinemic-euglycemic clamps (HIEGs; baseline and 10 wk) and hyperinsulinemic-hyperglycemic clamps (HIHGs, 13 wk). The ⌬AUC for glucose during the OGTTs more than doubled after 4 and 8 wk of HFFD feeding, and the average glucose infusion rate required to maintain euglycemia during the HIEG clamps decreased by Ϸ30% after 10 wk of HFFD feeding. These changes did not occur in the CTR group. The HIHG clamps included experimental periods 1 (P1, 0 -90 min) and 2 (P2, 90 -180 min). During P1, somatostatin, basal intraportal glucagon, 4 ϫ basal intraportal insulin, and peripheral glucose (to double the hepatic glucose load) were infused; during P2, glucose was also infused intraportally (4.0 mg·kg Ϫ1 ·min Ϫ1). Net hepatic glucose uptake during P1 and P2 was Ϫ0.4 Ϯ 0.1 [output] and 0.2 Ϯ 0.8 mg · kg Ϫ1 · min Ϫ1 in the HFFD group, respectively, and 1.8 Ϯ 0.8 and 3.5 Ϯ 1.0 mg · kg Ϫ1 · min Ϫ1 in the CTR group, respectively (P Ͻ 0.05 vs. HFFD during P1 and P2). Glycogen synthesis through the direct pathway was 0.5 Ϯ 0.2 and 1.5 Ϯ 0.4 mg·kg Ϫ1 · min Ϫ1 in the HFFD and CTR groups, respectively (P Ͻ 0.05 vs. HFFD). In conclusion, chronic consumption of an HFFD diminished the sensitivity of the liver to hormonal and glycemic cues and resulted in a marked impairment in NHGU and glycogen synthesis. impaired glucose tolerance; glycogen synthesis; hyperinsulinemic euglycemic clamp; hyperinsulinemic hyperglycemic clamp; portal signal CHRONIC CONSUMPTION OF A WESTERN DIET, characterized by foods rich in sugar and abundant in total and saturated fat, has been suggested to play a role in the development of type 2 diabetes (9, 37, 38). Numerous studies have delineated the effects of dietary fat on whole body insulin sensitivity. For example, 3 days of high-fat feeding (59% of kcal from fat) was sufficient to produce hepatic insulin resistance in rats, as evidenced by a diminished ability of hyperinsulinemia to suppress hepatic glucose production (HGP) in the absence of an alteration in peripheral (skeletal muscle and white adipose tissue) insulin sensitivity (20,22,31). These findings were supported in a canine model, in which hepatic insulin resistance was also found to be the primary metabolic consequence associated with 12 wk of moderate-fat (44% of kcal from fat) feeding (18). However, other studies have demonstrated that peripheral insulin resistance precedes liver resistance in response to high dietar...

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding

“…In support of findings in animals [7,19,21,23,24] and humans [25,30,31], our data show that an HFD rapidly impairs the ability of insulin to suppress hepatic glucose output, with peripheral insulin resistance developing subsequently. Furthermore, our data suggest that the liver quantitatively has the most significant impact on postprandial glycaemia, as both peak glucose intolerance and hepatic insulin resistance occurred within 3-7 days of HFD, despite the absence of muscle insulin resistance at this time.…”

“…Furthermore, consistent with our hypothesis, we show that an increase in lipid metabolites are associated with defects in tissue insulin action, suggesting that lipotoxicity is a generalised mechanism associated with the induction of insulin resistance in individual tissues of mice. Studies in rodents [7,[19][20][21]23], dogs [24] and humans [25][26][27], have shown that short-term exposure to HFD/overfeeding (3-28 days) results in the rapid development of insulin resistance and glucose intolerance. Often these changes occur with only modest increases in fat mass, highlighting that metabolic defects occur prior to the onset of obesity and do not require extensive periods of fat feeding.…”

An interaction effect between glucokinase gene variation and carbohydrate intakes modulates the plasma triglyceride response to a fish oil supplementation

“…The induction of GCK gene expression by insulin may be modulated by dietary components such as dietary PUFA which decrease GCK gene expression induction (Jump et al 1994). Moreover, the long-term consumption of a diet high in fat and in fructose among dogs has shown to also decrease GCK protein and its activity in the liver as well as glycogen storage, but not mRNA abundance (Coate et al 2010(Coate et al , 2011Moore et al 2012). It has been observed that GCK mRNA abundance is positively correlated with the liver TG content (Peter et al 2011).…”

Canine body composition quantification using 3 tesla fat–water MRI

“…Following each scanning session the animals were allowed to recover from the anesthesia. Details on the animal study design can be found in previously published work by Coate et al (7). Table positions for the thorax, chest, and abdomen were performed with breath-holding by temporarily deactivating the ventilator.…”

“…Though used often in human studies, whole-body FWMRI remains underutilized in large animal models such as dogs. The canine model is particularly valuable for obesogenic diet studies (7,8) that would be difficult to perform in a human cohort.…”