Liver fat accumulation is associated with reduced hepatic insulin extraction and beta cell dysfunction in healthy older individuals

Diabetology & Metabolic Syndrome

Nicholas J Wareham⁴  Simon J Griffin⁴  Cyrus Cooper²  Avan Aihie Sayer²  Ema De Lucia Rolfe⁴  Alison Sleigh³  Mensud Hatunic⁵  Stephen J Sharp⁴  Francis M Finucane¹ 

[1] Galway Diabetes Research Centre, HRB Clinical Research Facility, School of Medicine, NUI Galway, Galway, Ireland;MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton SO166YD, UK;Wolfson Brain Imaging Centre, University of Cambridge, Cambridge CB20QQ, UK;MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital, Box 285, Hills Road, Cambridge CB20QQ, UK;Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, Cambridge CB20QQ, UK

关键词: Non-alcoholic fatty liver disease;    Intrahepatic lipid;    Insulinogenic index;    Hepatic insulin extraction;    Disposition index;    C-peptide-genic index;    Beta cell dysfunction;    Adaptation index;   

Others  :  820487
DOI  :  10.1186/1758-5996-6-43

 received in 2013-07-30, accepted in 2014-03-11,  发布年份 2014

【 摘 要 】

Background

There is a well-established association between type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) secondary to excess accumulation of intrahepatic lipid (IHL), but the mechanistic basis for this association is unclear. Emerging evidence suggests that in addition to being associated with insulin resistance, NAFLD may be associated with relative beta-cell dysfunction. We sought to determine the influence of liver fat on hepatic insulin extraction and indices of beta-cell function in a cohort of apparently healthy older white adults.

Methods

We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin and C-Peptide levels measured every 30 minutes over two hours. The areas under the concentration curve for glucose, insulin and C-Peptide were used to quantify hepatic insulin extraction (HIE), the insulinogenic index (IGI), the C-Peptide increment (CGI), the Disposition Index (DI) and Adaptation Index (AI). Visceral fat was quantified with magnetic resonance (MR) imaging and IHL with MR spectroscopy. Insulin sensitivity was measured with the Oral Glucose Insulin Sensitivity (OGIS) model.

Results

29 of 70 participants (41%) exceeded our arbitrary threshold for NAFLD, i.e. IHL >5.5%. Compared to those with normal IHL, those with NAFLD had higher weight, BMI, waist and MR visceral fat, with lower insulin sensitivity and hepatic insulin extraction. Alcohol consumption, age, HbA1c and alanine aminotransferase (ALT) levels were similar in both groups. Insulin and C-Peptide excursions after oral glucose loading were higher in the NAFLD group, but the CGI and AI were significantly lower, indicating a relative defect in beta-cell function that is only apparent when C-Peptide is measured and when dynamic changes in glucose levels and also insulin sensitivity are taken into account. There was no difference in IGI or DI between the groups.

Conclusions

Although increased IHL was associated with greater insulin secretion, modelled parameters suggested relative beta-cell dysfunction with NAFLD in apparently healthy older adults, which may be obscured by reduced hepatic insulin extraction. Further studies quantifying pancreatic fat content directly and its influence on beta cell function are warranted.

Trial registration

ISRCTN60986572

【 授权许可】

   
2014 Finucane et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Stefan N, Kantartzis K, Haring HU: Causes and metabolic consequences of fatty liver. Endocr Rev 2008, 29:939-960.
• [2]Duckworth WC, Kitabchi AE: Insulin metabolism and degradation. Endocr Rev 1981, 2:210-233.
• [3]Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, Cassader M, David E, Cavallo-Perin P, Rizzetto M: Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002, 35:367-372.
• [4]Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 2005, 365:1415-1428.
• [5]Kotronen A, Vehkavaara S, Seppala-Lindroos A, Bergholm R, Yki-Jarvinen H: Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab 2007, 293:E1709-E1715.
• [6]Wiesenthal SR, Sandhu H, McCall RH, Tchipashvili V, Yoshii H, Polonsky K, Shi ZQ, Lewis GF, Mari A, Giacca A: Free fatty acids impair hepatic insulin extraction in vivo. Diabetes 1999, 48:766-774.
• [7]Poitout V, Robertson RP: Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 2008, 29:351-366.
• [8]van der Zijl NJ, Goossens GH, Moors CC, van Raalte DH, Muskiet MH, Pouwels PJ, Blaak EE, Diamant M: Ectopic fat storage in the pancreas, liver, and abdominal fat depots: impact on beta-cell function in individuals with impaired glucose metabolism. J Clin Endocrinol Metab 2011, 96:459-467.
• [9]Wang L, Zhang J, Wang B, Zhang Y, Hong J, Zhang Y, Wang W, Gu W: New evidence for an association between liver enzymes and pancreatic islet β-cell dysfunction in young obese patients. Endocrine 2013, 44(3):688-95.
• [10]Finucane FM, Sharp SJ, Purslow LR, Horton K, Horton J, Savage DB, Brage S, Besson H, De Lucia Rolfe E, Sleigh A, Martin HJ, Aihie Sayer A, Cooper C, Ekelund U, Griffin SJ, Wareham NJ: The effects of aerobic exercise on metabolic risk, insulin sensitivity and intrahepatic lipid in healthy older people from the Hertfordshire Cohort Study: a randomised controlled trial. Diabetologia 2010, 53(4):624-31.
• [11]Syddall HE, Aihie Sayer A, Dennison EM, Martin HJ, Barker DJ, Cooper C: Cohort profile: the Hertfordshire cohort study. Int J Epidemiol 2005, 34:1234-1242.
• [12]Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ: A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 2001, 24:539-548.
• [13]Finucane FM, Horton J, Purslow LR, Savage DB, Brage S, Besson H, Horton K, Rolfe Ede L, Sleigh A, Sharp SJ, Martin HJ, Sayer AA, Cooper C, Ekelund U, Griffin SJ, Wareham NJ: Randomized controlled trial of the efficacy of aerobic exercise in reducing metabolic risk in healthy older people: The Hertfordshire Physical Activity Trial. BMC Endocr Disord 2009, 9:15. BioMed Central Full Text
• [14]Franks PW, Ekelund U, Brage S, Wong MY, Wareham NJ: Does the association of habitual physical activity with the metabolic syndrome differ by level of cardiorespiratory fitness? Diabetes Care 2004, 27:1187-1193.
• [15]Tura A, Kautzky-Willer A, Pacini G: Insulinogenic indices from insulin and C-peptide: comparison of beta-cell function from OGTT and IVGTT. Diabetes Res Clin Pract 2006, 72:298-301.
• [16]Tura A, Ludvik B, Nolan JJ, Pacini G, Thomaseth K: Insulin and C-peptide secretion and kinetics in humans: direct and model-based measurements during OGTT. Am J Physiol Endocrinol Metab 2001, 281:E966-E974.
• [17]Ahren B, Pacini G: Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies. Eur J Endocrinol 2004, 150:97-104.
• [18]Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL: Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005, 288:E462-E468.
• [19]Yki-Jarvinen H, Westerbacka J: The fatty liver and insulin resistance. Curr Mol Med 2005, 5:287-295.
• [20]Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003, 112:1821-1830.
• [21]Bonadonna RC, Groop LC, Simonson DC, DeFronzo RA: Free fatty acid and glucose metabolism in human aging: evidence for operation of the Randle cycle. Am J Physiol 1994, 266:E501-E509.
• [22]Koutsari C, Basu R, Rizza RA, Nair KS, Khosla S, Jensen MD: Nonoxidative free fatty acid disposal is greater in young women than men. J Clin Endocrinol Metab 2011, 96:541-547.