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Published in: Digestive Diseases and Sciences 4/2013

01-04-2013 | Original Article

Insulin Sensitivity and Variability in Hepatitis C Virus Infection Using Direct Measurement

Authors: Nizar A. Mukhtar, Peter Bacchetti, Claudia E. Ayala, Jennifer Melgar, Spencer Christensen, Jacquelyn J. Maher, Mandana Khalili

Published in: Digestive Diseases and Sciences | Issue 4/2013

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Abstract

Background and Aims

Studies investigating insulin resistance (IR) in chronic hepatitis C virus (HCV) infection have used surrogate measures of IR that have limited reliability. We aimed to describe the distribution and risk factors associated with IR and its change over time in HCV using direct measurement.

Methods

One hundred two non-cirrhotic, non-diabetic, HCV-infected subjects underwent clinical, histologic, and metabolic evaluation, and 27 completed repeat evaluation at 6 months. Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during the insulin suppression test.

Results

Three subjects with diabetes were excluded and 95 completed all testing. SSPG ranged from 39 to 328 mg/dL (mean 135 mg/dL) and was stable over time (mean SSPG change −0.3 mg/dL). SSPG was associated with Latino ethnicity (Coef 67, 95 % CI 37–96), BMI (Coef 19 per 5 kg/m2, 95 % CI 5–32), ferritin (Coef 1.4 per 10 ng/ml, 95 % CI 0.2–2.5), male gender (Coef −48, 95 % CI −80 to −16), and HDL (Coef −16, 95 % CI −28 to −5 mg/dL). Current tobacco use (Coef 55, 95 % CI 19–90), steatosis (Coef −44, 95 % CI −86 to −3), and increases in BMI (Coef 30 per 5 kg/m2, 95 % CI 6–53) and triglyceride (Coef 3.5 per 10 mg/dL, 95 % CI 0.3–6.7) predicted change in SSPG.

Conclusions

There was a wide spectrum of insulin resistance in our HCV population. Host factors, rather than viral factors, appeared to more greatly influence insulin action and its change in HCV.
Literature
1.
go back to reference Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556–562.PubMedCrossRef Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556–562.PubMedCrossRef
2.
go back to reference DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88:787–835, ix. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88:787–835, ix.
3.
go back to reference Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab. 2001;86:3574–3578.PubMedCrossRef Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab. 2001;86:3574–3578.PubMedCrossRef
4.
go back to reference Yip J, Facchini FS, Reaven GM. Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J Clin Endocrinol Metab. 1998;83:2773–2776.PubMedCrossRef Yip J, Facchini FS, Reaven GM. Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J Clin Endocrinol Metab. 1998;83:2773–2776.PubMedCrossRef
5.
go back to reference Grasso A, Malfatti F, De Leo P, et al. Insulin resistance predicts rapid virological response in non-diabetic, non-cirrhotic genotype 1 HCV patients treated with peginterferon alpha-2b plus ribavirin. J Hepatol. 2009;51:984–990.PubMedCrossRef Grasso A, Malfatti F, De Leo P, et al. Insulin resistance predicts rapid virological response in non-diabetic, non-cirrhotic genotype 1 HCV patients treated with peginterferon alpha-2b plus ribavirin. J Hepatol. 2009;51:984–990.PubMedCrossRef
6.
go back to reference Petta S, Camma C, Di Marco V, et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol. 2008;103:1136–1144.PubMedCrossRef Petta S, Camma C, Di Marco V, et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol. 2008;103:1136–1144.PubMedCrossRef
7.
go back to reference Romero-Gomez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641.PubMedCrossRef Romero-Gomez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641.PubMedCrossRef
8.
go back to reference Fartoux L, Poujol-Robert A, Guechot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–1008.PubMedCrossRef Fartoux L, Poujol-Robert A, Guechot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–1008.PubMedCrossRef
9.
go back to reference Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416–423.PubMedCrossRef Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416–423.PubMedCrossRef
10.
go back to reference Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology. 2003;125:1695–1704.PubMedCrossRef Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology. 2003;125:1695–1704.PubMedCrossRef
11.
go back to reference Khalili M, Lim JW, Bass N, Ascher NL, Roberts JP, Terrault NA. New onset diabetes mellitus after liver transplantation: the critical role of hepatitis C infection. Liver Transpl. 2004;10:349–355.PubMedCrossRef Khalili M, Lim JW, Bass N, Ascher NL, Roberts JP, Terrault NA. New onset diabetes mellitus after liver transplantation: the critical role of hepatitis C infection. Liver Transpl. 2004;10:349–355.PubMedCrossRef
12.
go back to reference Lam KD, Bacchetti P, Abbasi F, et al. Comparison of surrogate and direct measurement of insulin resistance in chronic hepatitis C virus infection: impact of obesity and ethnicity. Hepatology. 2010;52:38–46.PubMedCrossRef Lam KD, Bacchetti P, Abbasi F, et al. Comparison of surrogate and direct measurement of insulin resistance in chronic hepatitis C virus infection: impact of obesity and ethnicity. Hepatology. 2010;52:38–46.PubMedCrossRef
13.
go back to reference Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers. Diabetes Care. 2000;23:171–175.PubMedCrossRef Yeni-Komshian H, Carantoni M, Abbasi F, Reaven GM. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers. Diabetes Care. 2000;23:171–175.PubMedCrossRef
14.
go back to reference Greenfield MS, Doberne L, Kraemer F, Tobey T, Reaven G. Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes. 1981;30:387–392.PubMedCrossRef Greenfield MS, Doberne L, Kraemer F, Tobey T, Reaven G. Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes. 1981;30:387–392.PubMedCrossRef
15.
go back to reference Vanni E, Abate ML, Gentilcore E, et al. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology. 2009;50:697–706.PubMedCrossRef Vanni E, Abate ML, Gentilcore E, et al. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology. 2009;50:697–706.PubMedCrossRef
16.
go back to reference Milner KL, van der Poorten D, Trenell M, et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology. 2010;138:932–941, e1–3.PubMedCrossRef Milner KL, van der Poorten D, Trenell M, et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology. 2010;138:932–941, e1–3.PubMedCrossRef
17.
go back to reference Brandman D, Bacchetti P, Ayala CE, Maher JJ, Khalili M. Impact of insulin resistance on HCV treatment response and impact of HCV treatment on insulin sensitivity using direct measurements of insulin action. Diabetes Care. 2012;35:1090–1094.PubMedCrossRef Brandman D, Bacchetti P, Ayala CE, Maher JJ, Khalili M. Impact of insulin resistance on HCV treatment response and impact of HCV treatment on insulin sensitivity using direct measurements of insulin action. Diabetes Care. 2012;35:1090–1094.PubMedCrossRef
18.
go back to reference Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26:S5–S20. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26:S5–S20.
19.
go back to reference Marchesini G, Bianchi GP, Forlani G, et al. Insulin resistance is the main determinant of impaired glucose tolerance in patients with liver cirrhosis. Dig Dis Sci. 1987;32:1118–1124.PubMedCrossRef Marchesini G, Bianchi GP, Forlani G, et al. Insulin resistance is the main determinant of impaired glucose tolerance in patients with liver cirrhosis. Dig Dis Sci. 1987;32:1118–1124.PubMedCrossRef
20.
go back to reference Letiexhe MR, Scheen AJ, Gerard PL, et al. Insulin secretion, clearance, and action on glucose metabolism in cirrhotic patients. J Clin Endocrinol Metab. 1993;77:1263–1268.PubMedCrossRef Letiexhe MR, Scheen AJ, Gerard PL, et al. Insulin secretion, clearance, and action on glucose metabolism in cirrhotic patients. J Clin Endocrinol Metab. 1993;77:1263–1268.PubMedCrossRef
21.
go back to reference Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417.PubMedCrossRef Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417.PubMedCrossRef
22.
go back to reference McLaughlin T, Deng A, Gonzales O, et al. Insulin resistance is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women. Diabetologia. 2008;51:2303–2308.PubMedCrossRef McLaughlin T, Deng A, Gonzales O, et al. Insulin resistance is associated with a modest increase in inflammation in subcutaneous adipose tissue of moderately obese women. Diabetologia. 2008;51:2303–2308.PubMedCrossRef
23.
go back to reference Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–848.PubMedCrossRef Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–848.PubMedCrossRef
24.
go back to reference Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38:1384–1392.PubMed Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38:1384–1392.PubMed
25.
go back to reference Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–1508.PubMedCrossRef Kawaguchi T, Yoshida T, Harada M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–1508.PubMedCrossRef
26.
go back to reference Imazeki F, Yokosuka O, Fukai K, Kanda T, Kojima H, Saisho H. Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver Int. 2008;28:355–362.PubMedCrossRef Imazeki F, Yokosuka O, Fukai K, Kanda T, Kojima H, Saisho H. Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver Int. 2008;28:355–362.PubMedCrossRef
27.
go back to reference Tsochatzis E, Manolakopoulos S, Papatheodoridis GV, et al. Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study. Aliment Pharmacol Ther. 2009;30:947–954.PubMedCrossRef Tsochatzis E, Manolakopoulos S, Papatheodoridis GV, et al. Serum HCV RNA levels and HCV genotype do not affect insulin resistance in nondiabetic patients with chronic hepatitis C: a multicentre study. Aliment Pharmacol Ther. 2009;30:947–954.PubMedCrossRef
28.
go back to reference Yazicioglu G, Isitan F, Altunbas H, et al. Insulin resistance in chronic hepatitis C. Int J Clin Pract. 2004;58:1020–1022.PubMedCrossRef Yazicioglu G, Isitan F, Altunbas H, et al. Insulin resistance in chronic hepatitis C. Int J Clin Pract. 2004;58:1020–1022.PubMedCrossRef
29.
go back to reference Carter JS, Pugh JA, Monterrosa A. Non-insulin-dependent diabetes mellitus in minorities in the United States. Ann Intern Med. 1996;125:221–232.PubMed Carter JS, Pugh JA, Monterrosa A. Non-insulin-dependent diabetes mellitus in minorities in the United States. Ann Intern Med. 1996;125:221–232.PubMed
30.
go back to reference Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: national health and nutrition examination survey 1999–2002. Diabetes Care. 2006;29:1263–1268.PubMedCrossRef Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: national health and nutrition examination survey 1999–2002. Diabetes Care. 2006;29:1263–1268.PubMedCrossRef
31.
go back to reference Furutani M, Nakashima T, Sumida Y, et al. Insulin resistance/beta-cell function and serum ferritin level in non-diabetic patients with hepatitis C virus infection. Liver Int. 2003;23:294–299.PubMedCrossRef Furutani M, Nakashima T, Sumida Y, et al. Insulin resistance/beta-cell function and serum ferritin level in non-diabetic patients with hepatitis C virus infection. Liver Int. 2003;23:294–299.PubMedCrossRef
32.
go back to reference D’Souza RF, Feakins R, Mears L, Sabin CA, Foster GR. Relationship between serum ferritin, hepatic iron staining, diabetes mellitus and fibrosis progression in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2005;21:519–524.PubMedCrossRef D’Souza RF, Feakins R, Mears L, Sabin CA, Foster GR. Relationship between serum ferritin, hepatic iron staining, diabetes mellitus and fibrosis progression in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2005;21:519–524.PubMedCrossRef
33.
go back to reference Sumida Y, Kanemasa K, Fukumoto K, Yoshida N, Sakai K. Hepatic iron accumulation may be associated with insulin resistance in patients with chronic hepatitis C. Hepatol Res. 2007;37:932–940.PubMedCrossRef Sumida Y, Kanemasa K, Fukumoto K, Yoshida N, Sakai K. Hepatic iron accumulation may be associated with insulin resistance in patients with chronic hepatitis C. Hepatol Res. 2007;37:932–940.PubMedCrossRef
34.
go back to reference Facchini F, Humphreys MH, Jeppesen J, Reaven GM. Measurements of insulin-mediated glucose disposal are stable over time. J Clin Endocrinol Metab. 1999;84:1567–1569.PubMedCrossRef Facchini F, Humphreys MH, Jeppesen J, Reaven GM. Measurements of insulin-mediated glucose disposal are stable over time. J Clin Endocrinol Metab. 1999;84:1567–1569.PubMedCrossRef
35.
go back to reference Reaven G, Tsao PS. Insulin resistance and compensatory hyperinsulinemia: the key player between cigarette smoking and cardiovascular disease? J Am Coll Cardiol. 2003;41:1044–1047.PubMedCrossRef Reaven G, Tsao PS. Insulin resistance and compensatory hyperinsulinemia: the key player between cigarette smoking and cardiovascular disease? J Am Coll Cardiol. 2003;41:1044–1047.PubMedCrossRef
36.
go back to reference Ryan MC, Fenster FHM, Abbasi F, Reaven GM. Comparison of waist circumference versus body mass index in diagnosing metabolic syndrome and identifying apparently healthy subjects at increased risk of cardiovascular disease. Am J Cardiol. 2008;102:40–46.PubMedCrossRef Ryan MC, Fenster FHM, Abbasi F, Reaven GM. Comparison of waist circumference versus body mass index in diagnosing metabolic syndrome and identifying apparently healthy subjects at increased risk of cardiovascular disease. Am J Cardiol. 2008;102:40–46.PubMedCrossRef
37.
go back to reference Howard BV, Mayer-Davis EJ, Goff D, et al. Relationships between insulin resistance and lipoproteins in nondiabetic African Americans, Hispanics, and non-Hispanic whites: the insulin resistance atherosclerosis study. Metabolism. 1998;47:1174–1179.PubMedCrossRef Howard BV, Mayer-Davis EJ, Goff D, et al. Relationships between insulin resistance and lipoproteins in nondiabetic African Americans, Hispanics, and non-Hispanic whites: the insulin resistance atherosclerosis study. Metabolism. 1998;47:1174–1179.PubMedCrossRef
38.
go back to reference Cena H, Fonte ML, Turconi G. Relationship between smoking and metabolic syndrome. Nutr Rev. 2011;69:745–753.PubMedCrossRef Cena H, Fonte ML, Turconi G. Relationship between smoking and metabolic syndrome. Nutr Rev. 2011;69:745–753.PubMedCrossRef
39.
go back to reference Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–1645.PubMedCrossRef Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–1645.PubMedCrossRef
Metadata
Title
Insulin Sensitivity and Variability in Hepatitis C Virus Infection Using Direct Measurement
Authors
Nizar A. Mukhtar
Peter Bacchetti
Claudia E. Ayala
Jennifer Melgar
Spencer Christensen
Jacquelyn J. Maher
Mandana Khalili
Publication date
01-04-2013
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 4/2013
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-012-2438-3

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