Insulin resistance or frank diabetes mellitus in patients with chronic hepatitis C (CHC) may be related to host (metabolic syndrome) or viral factors. The viral factors for HCV and insulin resistance are not very clear and several mechanisms have been suggested. First, insulin resistance may just be a consequence of intracellular fat accumulation occurring as a result of HCV infection. Experimental interventions that increase hepatic triglyceride content in mice result in defective insulin signaling and impairment of the ability of insulin to suppress hepatic glucose production.[1] Likewise, interventions reducing intracellular triglyceride content improve insulin sensitivity. These data suggest that the connection between HCV and insulin resistance may be secondary to the ability of HCV to induce hepatic steatosis. Defects in insulin receptor and insulin-receptor substrates (IRS-1) are associated with insulin resistance and type 2 diabetes. Another possible explanation for insulin resistance in HCV is a direct effect of HCV proteins on insulin signaling pathways. Insulin action is mediated by binding to the cell surface insulin receptor which undergoes autophosphorylation with activation of kinase activity.[2] The signal is transmitted by subsequent tyrosine phosphorylation of a family of insulin-receptor substrates (IRS). In a transgenic mouse model that specifically expresses the HCV core protein at high levels in hepatocytes it was shown that hepatic insulin resistance can be induced solely by expression of the HCV core protein, and that signaling abnormalities in the insulin receptor (IRS 1) pathways are present before the development of steatosis.[1] It was noted that transgenic mice have normal plasma glucose concentrations but have elevated circulating insulin levels and islet cell hyperplasia. When challenged by a high fat diet, the transgenic mice, but not their nontransgenic littermates demonstrated loss of glucose tolerance, as manifested by elevated plasma glucose levels in the fed state. Cytokines like TNF-a may also have a role in virus-induced insulin resistance by disturbing insulin signaling pathways.[3]

It is estimated that by the year 2025, three quarters of the world’s 300 million adults with diabetes will be in the non-industrialised countries with almost a third in India and China alone.[4] India is facing a kind of epidemic of type 2 diabetes mellitus with high prevalence of diabetes mellitus both in urban (4.3-13.9%) and rural (2.7- 3.7%) areas.[5,6] Urbanisation and associated life style changes including sedentary life style and fat rich diet adversely affect the risk factors for diabetes, unmasking the high genetic tendency existing in the Indian population. The problem is complicated by the occurrence of metabolic abnormalities even in children and adolescents in India.[7] Further, low body mass index in infancy may actually be a risk factor for impaired glucose tolerance or diabetes mellitus in young adulthood.[8]

Diabetes mellitus being so common in India, it is difficult to establish an association between DM and HCV short of a good case control study. In an attempt to establish a link between these two conditions, Amrapukar et al [9] in this issue of the journal looked at the prevalence of diabetes mellitus in their cohort of patients of CHC and compared the prevalence of diabetes with patients of chronic hepatitis B (CHB) and irritable bowel syndrome (IBS). A total of 200 patients with HCV were analysed. Of 200 patients, DM was present in 44 (22%) patients with mean duration of DM of 6.1 ± 2.3 years. HCV preceded DM in 29 patients by 10.8 ± 2.3 years. Eighty eight (44%) patients had evidence of cirrhosis and in patients with DM, cirrhosis and steatosis were present in 28 (63.6%) and 20 (45.4%) patients, respectively, as compared to 60 (38.4%) and 35 (22.4%) patients without DM. In 200 patients of CHB and 200 patients of IBS, DM was seen in 24 (12%) and 19 (9.5%) patients, respectively. There was statistically significant difference in prevalence of DM in patients with HCV when compared to CHB or IBS.[9] Though the study by Amarapurkar et al [9] is a welcome step in solving the puzzle of metabolic abnormalities in patients with CHC, certain issues need consideration. It is clearly evident from their study that in patients with CHB and IBS, diabetes mellitus was related to the host-factors of metabolic syndrome like obesity, hypertension and dyslipidemia. In contrast in patients with CHC, there was no difference in the prevalence of metabolic factors between those with and without diabetes mellitus. Importantly, the prevalence ofdiabetes was higher in cirrhotics than in non-cirrhotics in both CHC [31% vs. 14%] & CHB [26% vs. 6%) and patients with DM had significantly higher prevalence of cirrhosis (63% vs. 38%) and hepatic steatosis (45% & 22%) than the non diabetics. Overall out of 200 patients with CHC 88, (44%) were cirrhotics and 112 (56%) were non-cirrhotics. Data is not available on the number of patients with advanced fibrosis in the chronic hepatitis group. Thus it is evident in the study by Amarapurkar et al, [9] that one of the major factors determining the occurrence of diabetes mellitus in CHC was cirrhosis liver. Glucose intolerance, overt diabetes mellitus, and insulin resistance are common in patients with cirrhosis occurring because of various mechanisms.[10] The hyperinsulinemia in cirrhosis results from mainly three abnormalities: diminished hepatic extraction, portosystemic or intrahepatic shunting, and enhanced insulin secretion. Insulin secretion, although increased in absolute terms, is insufficient to offset the presence of insulin resistance. The defect in insulin-mediated glucose disposal involves peripheral tissues, primarily muscle, and most likely reflects a disturbance in glycogen synthesis in patients with cirrhosis.[10] Hepatic glucose production is normally sensitive to insulin; and it is unclear whether hepatic glucose uptake is impaired in cirrhosis.

Amarapurkar et al [9] also showed that HCV infection antedated the development of DM in 29 patients by 10.8 ± 2.3 years. This study however did not highlight the length of time advanced fibrosis or cirrhosis antedated the  development of DM. They had taken one of the risk factors (blood transfusion, hemodialysis etc) as the possible time of HCV infection which may or may not be true. In our experience, we have not observed this kind of antedating of HCV infection before DM, rather the reverse has been more common and it has always been difficult to establish if the diabetes is due to hepatic fibrosis/ cirrhosis or cirrhosis is due to diabetes mellitus in patients with both HCV infection and DM.
 

Since a possibility remains that higher prevalence of DM in patients with CHC may be related to cirrhosis per se, ideally the authors should have separately analysed the data regarding the prevalence of diabetes mellitus in non-cirrhotic patients with CHC. Our study which included 65 non cirrhotic patients with CHC found a prevalence of diabetes mellitus in 12.3% (8 patients), almost similar to the prevalence in urban India.[11] Recently we analysed 85 non cirrhotic patients with CHC without metabolic syndrome for the prevalence of insulin resistance and found that patients with CHC had higher HOMA values and more number of CHC patients had insulin resistance in comparison to healthy volunteers.[12] Our results suggest that HCV possibly does lead to insulin resistance as a first step and depending upon the degree of insulin resistance and duration, may later lead on to glucose intolerance and frank diabetes mellitus. Only a good case control study can establish this link in a population with high prevalence of DM.

Another important issue is regarding the genotype specificity of HCV in causing insulin resistance and DM. There is some data to suggest that though hepatic steatosis is seen more commonly with genotype 3, insulin resistance may be more commonly associated with genotype 1. In spite of being a prospective study, HCV genotype was known in only 80 out of 200 patients in the study by Amarapurkar et al [9] and DM was present in 11/47 (23.4%) with genotype 3, and in 6/31 (19.3%)patients with genotype 1 with no significant difference between two genotypes. Hui et al observed that patients with genotype 3 had higher prevalence of steatosis, but lower HOMA-IR in comparison to other genotypes.[13] Similarly in a recent study, Fartoux et al observed that steatosis and fibrosis were more severe in patients with genotype 3 patients, and median HOMAIR was significantly higher in patients with genotype 1.[14] They also noted that increased insulin levels in genotype 1 patients was a risk factor for increased fibrosis through insulin resistance induced steatosis.[14] Though not significant, we also found in our data that patients with genotype 3 less commonly had insulin resistance in comparison to genotype 1 (57.4% Vs 66.6%, p= 0.67).[12]

 In conclusion, Amarapurkar et al need to be complimented for their work but a larger number of patients with CHC with different genotypes and especially non cirrhotics may have to be studied to clarify the genotype specificity and relation between HCV and diabetes mellitus.

References

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2.    White MF, Kahn CR. The insulin signaling system. J Biol Chem. 1994;269:1–4.

3.    Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;162:840–8.

4.    Mohan V. Why are Indians more prone to diabetes? J Assoc Physicians India. 2004;52:468–74.

5.    Ramachandran A, Snehalatha C, Satyavani K, Vijay V. Impaired fasting flucose in impaired glucose tolerance test in urban population in India. Diabet Med. 2003; 20:220–4.

6.    Sadikot SM, Nigam A, Das S, Bajaj S, Zargar AH, Sosale A, et al. The burden of diabetes and impaired glucose tolerance in India using the WHO 1999 criteria: prevalence of diabetes in India Study (PODIS). Diabetes Res Clin Pract.  2004;66:301–7.

7.    Bhatia V; IAP International taskforce for Childhood Prevention of Adult Diseases. IAP International taskforce for Childhood Prevention of Adult diseases: insulin resistance and type 2 diabetes mellitus in childhood. Indian Pediatr. 2004;41:443–57.

8.    Bhargava SK, Sachdev HS, Fall CH, Osmond C, Lakshmy R, Barker DJ, et al. Relation of serial changes in childhood body mass index to impaired glucose tolerance in young adulthood. N Eng J Med. 2004;350:865–75.

9.    Amarapurkar DN, Patel ND. Increased prevalence of type II diabetes mellitus in hepatitis C virus infection in Western India. Trop Gastroenterol. 2008;29:148-52.

10. Petrides AS, DeFronzo RA. Glucose and insulin metabolism in cirrhosis. J Hepatol. 1989;8:107–14.

11. Duseja A, Sharma S, Nitin, Chaudhry S, Dhiman RK, Chawla Y, et al. Prevalence of diabetes mellitus in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol. 2004;19:A711.

12. Duseja A, Dhiman RK, Chawla Y, Thumburu KK, Kumar A, Das A, et al. Insulin resistance is common in patients with predominant genotype 3 chronic hepatitis C. In Press

13. Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, et al. Insulin resistance is associated with chronic hepatitis C virus infection and f ibrosis progression. Gastroenterology. 2003;125:1695–704.

14. Fartoux L, Poujal-Robert A, Guechot J, Wendum D, Roupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–8.