Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review

Table 1 Glucose abnormalities and hepatitis C virus infection

Ref.	Year	Country	Study design	Patients	Patients number	Controls	Controls number	Testing for HCV Ab or RNA	Endpoint	Statistical methods	Association	Statistics
HCV infection markers in patients with type 2 diabetes mellitus
Sangiorgio et al[4]	2000	Italy	Retrospective	DM	1514	HV	1300	Ab	HCV	Univariate	Yes	P < 0.0001
Chen et al[5]	2006	Taiwan	Cross sectional	DM	820	HV	905	Ab	HCV	Univariate adjusted	Yes	OR = 2.87 [1.51, 5.46]; P < 0.001
Huang et al[6]	2007	Taiwan	Cross sectional	DM	1237	HV	8595	RNA	HCV	Univariate	Yes	6.9% vs 4.5%; P < 0.001
Jadoon et al[7]	2010	Pakistan	ND	DM	3000	HV	10000	Ab	HCV	Univariate	Yes	OR = 3.03 [2.64, 3.48]; P = 0.001
Balogun et al[53]	2006	Nigeria	case-control	DM	90	HV2	90	Ab	HCV	Univariate	No	NS
Costa et al[54]	2008	Brazil	Case-control	DM	206	HV	206	RNA	HCV	Multivariate	No	NS
Glucose abnormalities in HCV infected patients vs different control groups
Vs healthy volunteers
Knobler et al[17]	2000	Israel	Case-control	HCV	45	HV2	88	RNA	DM	Univariate	Yes	33% vs 5.6%; P < 0.001
Mehta et al[8]	2000	United States	Cross sectional	HCV	230	HV	9611	Ab	DM	Multivariate	Yes	OR = 3.77 [1.8, 7.87]
Marzouk et al[18]	2007	Egypt	Cross sectional	HCV	190	HV	575	RNA	DM	Multivariate	Yes	HR = 3.05 [1.19, 7.81]
Shaheen et al[19]	2007	United States	ND	HCV	239	HV	10144	ND	IR	Univariate adjusted	Yes	OR = 1.68; P = 0.02
Huang et al[6]	2007	Taiwan	Cross sectional	HCV	478	HV2	7927	RNA	DM	Multivariate	Yes	OR = 1.53 [1.18, 1.98]; P <0.001
Huang et al[21]	2008	Taiwan	ND	HCV	683	HV2	515	RNA	DM/IGT1	Univariate	Yes	OR = 3.51 [2.7, 4.56]; P < 0.001
Park et al[20]	2008	South Korea	Prospective	HCV1	62	HV2	172	RNA	IR	Univariate	Yes	22.5% vs 5.2%; P < 0.001
Mohamed et al[22]	2009	Egypt	Cross sectional	HCV1	38	HV2	12	RNA	IR	Univariate	Yes	HOMA-IR = 3.98 (normal ALT) and 2.69 (a normal ALT) vs 1.92; P < 0.001
Duseja et al[23]	2009	India	ND	HCV1	85	HV2	25	RNA	IR	Univariate	Yes	62% vs 16%; P = 0.0002
Lonardo et al[24]	2009	Italy	ND	HCV1	97	HV	182	RNA	IR	Univariate	Yes	P < 0.001
Huang et al[25]	2009	Taiwan	ND	HCV1	93	HV	144	Ab	IR	Univariate	Yes	HOMA-IR 2.2 vs 1.6; P = 0.02
Mostafa et al[26]	2010	Egypt	ND	HCV	329	HV	173/795	RNA	DM	Univariate adjusted	Yes	OR = 1.35 [1.06, 1.73]; P = 0.02
Miyajima et al[27]	2013	Japan	Cross sectional	HCV	40	HV	1780/88	RNA	IR	Univariate	Yes	HOMA-IR 3.0 vs 1.3; P < 0.001
Younossi et al[28]	2013	United States	Retrospective	HCV	177	HV	19568	RNA	DM and IR	Multivariate	Yes	OR for DM 2.3 [1.18, 4.54] OR for IR 2.06 [1.19, 3.57]
Pothineni et al[29]	2014	United States	Retrospective	HCV	1434	HV2	14799	RNA	DM	Univariate	Yes	11.2% vs 5.1%; P < 0.01
Dai et al[30]	2013	Taiwan	Retrospective	HCV	160	HV2	480	RNA	DM	Multivariate	Yes	OR = 1.208 [1.009, 2.799]; P = 0.004
Mehta et al[10]	2003	United States	Case-control	HCV	12	HV2	1072	RNA	DM	Univariate	No	NS
Stepanova et al[11]	2012	United States	Nationwide survey	HCV	791	HV	38715	RNA	DM and IR	Multivariate	No	NS
Montenegro et al[9]	2013	Italy	Prospective	HCV	616	HV	1856	Ab	DM	Univariate adjusted	No	NS
Ruhl et al[55]	2014	United States	Cross sectional	HCV	277	HV	14571	RNA	DM	Univariate adjusted	No	NS
Vs hepatitis B virus infection
Knobler et al[17]	2000	Israel	Case-control	HCV	45	HBV	90	RNA	DM	Univariate	Yes	33% vs 12%; P = 0.004
Ryu et al[31]	2001	South Korea	Prospective	HCV, F4	68	HBV	157	Ab	DM	Univariate	Yes	24% vs 10.4%; P = 0.001
Wang et al[32]	2007	Taiwan	Longitudinal	HCV	926	HBV	544	Ab	DM	Multivariate	Yes	HR = 1.7
Huang et al[6]	2007	Taiwan	Cross sectional	HCV	478	HBV	1363	RNA	DM	Univariate	Yes	18% vs 11.4%; P < 0.001
Moucari et al[33]	2008	France	Retrospective	HCV	500	HBV2	100	RNA	HOMA-IR	Univariate	Yes	35% vs 5%; P < 0.001
White et al[12]	2008	United States	Meta-analysis	HCV	34 studies	HBV/ HV	-	Ab/RNA	DM	Meta-analysis	Yes	Adjusted OR for HV 1.68 and for HBV 1.80
Rouabhia et al[34]	2010	Algeria	Prospective cross sectional	HCV1	290	HBV	126	RNA	DM	Multivariate	Yes	OR = 4.73 [1.7, 13.2]; P = 0.0029
Petta et al[56]	2011	Italy	Retrospective	HCV	170	HBV2	170	RNA	HOMA-IR and DM	Univariate	Yes	42.2% vs 25.9%, P = 0.002 and 8.8% vs 3.6%, P = 0.04
Imazeki et al[57]	2008	Japan	Retrospective	HCV	544	HBV	286	RNA	DM and IR	Multivariate	No	NS
Tanaka et al[58]	2008	Japan	Case-control	HCV1	30	HBV2	30	RNA	IR	Multivariate	No	NS
Mavrogiannaki et al[59]	2008	Greece	prospective case control	HCV	108	HBV	81	RNA	glucose intolerance	Univariate adjusted	No	NS
Persico et al[60]	2009	Italy	Retrospective	HCV	726	HBV	126	Ab	DM	Univariate adjusted	No	NS

¹HCV infection not treated;

²Matched for confounding factors (age and/or gender and/or BMI and/or ALT…). HCV: Hepatitis C virus infection; Ab: Antibody; HV: Healthy volunteers; G1: Genotype 1; SVR: Sustained virological response; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; IR: Insulin resistance; DM: Diabetes mellitus; FPG: Fasting plasma glucose; IGT: Impaired glucose tolerance [after oral glucose tolerance test (OGTT)]; CLD: Chronic liver disease; NAFLD: Non-alcoholic fatty liver disease; NS: Not significant; ND: Not determined.

Table 2 Glucose abnormalities and severe liver fibrosis in hepatitis C virus-infected patients

Ref.	Year	Country	Number of HCV patients	Patient profile	Glucose abnormality	Statistical method	Association with severe fibrosis1	Genotypes	Statistics
Konrad et al[42]	2000	Germany	10	Non DM	FPG	Multivariate	Yes	All	P = 0.01
Sud et al[61]	2004	Australia	170	-	HOMA-IR	Multivariate	Yes	All	OR = 1.47 [1.14, 1.89]; P = 0.003
Muzzi et al[62]	2005	Switzerland	221	Non DM	HOMA-IR	Multivariate	Yes	All (except G3)	OR = 1.57 [1.04, 2.39]
D'souza et al[63]	2005	United Kingdom	59	-	HOMA-IR	Multivariate	Yes	All	P = 0.001
Taura et al[64]	2006	Japan	83	-	HOMA-IR	Multivariate	Yes	All	OR = 7.32 [1.59, 33.73]; P = 0.01
Leandro et al[65]	2006	Italy	3068	-	DM	Multivariate	Yes	G1	OR = 4.52 [1.07, 19.1]; P = 0.011
Bugianesi et al[66]	2006	Italy	132	G3 with steatosis	HOMA-IR	Multivariate	Yes	G3	OR = 2.98 [1.13, 7.89]; P = 0.028
Kita et al[67]	2007	Japan	68	Post tranfusion hepatitis	DM	Multivariate	Yes	All	OR = 8.4 [2.23, 31.54]; P = 0.002
Petta et al[68]	2008	Italy	201	G1	DM	Multivariate	Yes	G1	OR = 2.69 [1.46, 4.95]; P < 0.001
Moucari et al[33]	2008	France	500	-	HOMA-IR	Multivariate	Yes	All	OR = 1.8 [1.16, 2.81]; P = 0.009
Cua et al[69]	2008	Australia	346	G1, G3, untreated	IR	Multivariate	Yes	G3	OR = 3.15 [1.56, 6.35]; P = 0.001
Hsu et al[70]	2009	Taiwan	528	G1, G2	FPG	Multivariate	Yes	G1	OR = 13.72 [2.15, 87.7]; P < 0.05
Moucari et al[71]	2009	France	226	G4	HOMA-IR	Multivariate	Yes	G4	OR = 3.86 [1.859, 8.034]; P < 0.001
Persico et al[60]	2009	Italy	726	-	DM	Multivariate	Yes	All	P < 0.05
Hung et al[14]	2011	Taiwan	1470	-	DM	Univariate	Yes	All	P < 0.001
Patel et al[72]	2011	Asia	263	G2, G3	HOMA-IR	Multivariate	Yes	G2 and G3	OR = 8.42 [2.1, 34.3]; P = 0.003
Mohamed et al[73]	2011	Egypt	50	G4	HOMA-IR	Multivariate	Yes	G4	OR = 3.73; P = 0.001
Miyaaki et al[74]	2011	Japan	171	-	DM	Multivariate	Yes	All	OR = 8.739 [2.85, 26.85]; P = 0.0002
Conjeevaram et al[75]	2011	United States	341	G1	HOMA-IR	Multivariate	Yes	G1	OR = 1.28 [1.07, 1.51]; P = 0.005
Petta et al[56]	2011	Italy	170	G1	HOMA-IR	Multivariate	Yes	G1	OR = 2.64 [1.11, 6.28]; P = 0.02
Khattab et al[76]	2012	Egypt	107	G4	HOMA-IR	Multivariate	Yes	G4	OR = 1.87 [1.09, 8.29]; P = 0.04
Ziada et al[77]	2012	Egypt	140	Non DM	HOMA-IR	Multivariate	Yes	All	OR = 1.92 [0.97, 3.4]; P = 0.049
Thompson et al[13]	2012	United States	1038	Non DM	HOMA-IR	Multivariate	Yes	All	OR = 1.6 [1.1, 2.33]; P = 0.02
Alfaleh et al[78]	2013	Saudi Arabia	157	-	DM	Multivariate	Yes	All (except G4)	OR = 0.37 [0.148, 0.927]; P = 0.034
Dokmeci et al[79]	2014	Turkey	104	-	HOMA-IR	Multivariate	Yes	All	OR = 3.36 [1.32, 31.25]; P = 0.021
Huang et al[80]	2015	Taiwan	1077	-	DM	Multivariate	Yes	All	OR = 1.81 [1.14, 2.65]; P = 0.002
Fartoux et al[81]	2005	France	141	Non DM	HOMA-IR	Univariate	No	No	NS
Elgouhari et al[82]	2008	United States	183	-	DM	Multivariate	No	No	NS
Petta et al[83]	2009	Italy	156	Non DM	HOMA-IR	Multivariate	No	No	NS
Rueger et al[84]	2014	Switzerland	1461	-	DM	Multivariate	No	No	NS

¹Severe liver fibrosis: F3 or F4 in Metavir scoring system. HCV: Hepatitis C virus infection; G1: Genotype 1; SVR: Sustained virological response; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; IR: Insulin resistance; DM: Diabetes mellitus; FPG: Fasting plasma glucose; NS: Not significant.

Table 3 Impact of glucose abnormalities on virological response after interferon alpha based treatment

Ref.	Year	Country	Patients number	Patient profile	Association	Statistical method	Impact on virological response	Genotypes	Statistics
D'souza et al[63]	2005	United Kingdom	59		HOMA-IR	Multivariate	Yes	All	OR of SVR: 0.44 [0.22, 0.88]; P = 0.02
Tarantino et al[85]	2005	Italy	80		GMI	Univariate	Yes	All	40% vs 7.5%; P = 0.0009
Romero-Gomez et al[86]	2005	Spain	159		HOMA-IR	Multivariate	Yes	All	OR of SVR 0.55 [0.33, 0.93]; P = 0.012
Jian Wu et al[87]	2006	China	98		HOMA-IR	Multivariate	Yes	All	OR of SVR: 0.17; P = 0.015
Backus et al[88]	2007	United States	5944	G1, G2, G3	DM	Multivariates	Yes	All and G1	OR = 0.76 [0.64, 0.71]; P = 0.002
Conjeevaram et al[89]	2007	United States	401	G1	HOMA-IR	Multivariates	Yes	G1	OR = 0.87 [0.77, 0.99]; P = 0.028
Elgouhari et al[82]	2008	United States	183		DM	Multivariate	Yes	All	OR of SVR 0.22 [0.07, 0.55]; P = 0.003
Poustchi et al[90]	2008	Australia	82	G2, G3 non DM	HOMA-IR	Multivariate	Yes	G2, G3	OR of SVR 0.16 [0.03, 0.77]; P = 0.02
Romero-Gomez et al[91]	2008	Spain	1059		FPG	Multivariate	Yes	All	OR of SVR 0.56 [0.34, 0.93]; P < 0.02
Moucari et al[71]	2009	France	226	G4	HOMA-IR	Multivariate	Yes	-	OR of SVR: 0.19 [0.07, 0.51]; P = 0.001
Dai et al[92]	2009	Taiwan	330	G1, G2	HOMA-IR	Multivariate	Yes	G1, G2	OR of SVR 0.872 [0.79, 097]; P = 0.01
Hung et al[115]	2010	Taiwan	1470		DM	Multivariate	Yes	All	OR of SVR 0.69 [0.5, 0.96]; P = 0.029
Khattab et al[93]	2010	Egypt	131	Non DM, G4	HOMA-IR	Multivariate	Yes	G4	OR of SVR 0.07 [0.01, 0.43]; P = 0.004
Deltenre et al[94]	2011	France	2732	G1-6	IR	Meta-analysis	Yes	All	-
Eslam et al[95]	2011		2129	G1-6	IR	Meta-analysis	Yes	All	OR of SVR 0.35 [0.24, 0.51]; P = 0.0004
Del Campo et al[96]	2012	Spain	240	Non DM	HOMA-IR	Multivariate	Yes	G1, G4	OR of SVR 0.44 [0.17, 0.97]; P = 0.04
Ziada et al[77]	2012	Egypt	140	Non DM	HOMA-IR	Multivariate	Yes	All	OR of SVR 0.41 [0.18, 0.9]; P = 0.003
Laurito et al[97]	2013	Brazil	2238	G1-6	IR	Meta-analysis	Yes	All	OR of SVR 0.41 [0.3, 0.56]; P = 0.022
Abd El-Wahab et al[98]	2014	Egypt	392	Non DM	HOMA-IR	Multivariate	Yes	All	OR of virological response: 0.19 [0.1, 0.38]; P = 0.0001
Grasso et al[99]	2009	Italy	90	Non DM, G1	HOMA-IR	Multivariate	No	G1	NS
Fattovich et al[100]	2010	Italy	412		HOMA-IR	Multivariate	No	No	NS
Khattab et al[76]	2012	Egypt	107	G4	HOMA-IR	Multivariate	No	G4	NS
Brandman et al[101]	2012	United States	23	Non DM	IGT, FGP, SSGP	Univariate	No	No	NS
Aghemo et al[102]	2012	Italy	339		HOMA-IR	Univariate	No	No	NS
Fattovich et al[100]	2012	Italy	124	Non DM	HOMA-IR	Multivariate	No	No	NS
Serfaty et al[103]	2012	France	1611	G4	HOMA-IR	Multivariate	No	G4	NS
Alfaleh et al[78]	2013	Saudi Arabia	157		DM	Multivariate	No	No	NS
Younossi et al[104]	2013	United States	5781	G1	HOMA-IR	Univariate adjusted	No	G1	NS
Jung et al[105]	2014	Soutk Korea	60		HOMA-IR	Univariate	No	No	NS

¹Treated with peginterferon/ribavirin telaprevir. HCV: Hepatitis virus infection; G1: Genotype 1; SVR: Sustained virological response; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; IR: Insulin resistance; IGT: Impaired glucose tolerance; DM: Diabetes mellitus; FPG: Fasting plasma glucose; SSGP: Steady-state plasma glucose; GMI: Glucose metabolism impairment; NS: Not significant; ND: Not determined.

Table 4 Glucose abnormalities after interferon alpha based treatment

Ref.	Year	Country	Number of HCV patients	Patient profile	Glucose metabolism parameter	Statistical method	Significant association or difference	Genotypes	Statistics
Improvement of glucose abnormalities after HCV treatment
Konrad et al[42]	2000	United States	13		FPG and FI	Univariate	Yes	All	P < 0.05 and P < 0.01
Romero-Gomez et al[86]	2005	Spain	50		HOMA-IR	Univariate	Yes	All	In SVR; P < 0.05
Kawaguchi et al[106]	2007	Japan	89		HOMA-IR	Univariate	Yes	All	In SVR; P < 0.01
Chehadeh et al[107]	2009	Kuwait	181	G4	FPG	Univariate	Yes	G4	In SVR; P < 0.001
Kim et al[108]	2009	Korea	28	G1, G2	HOMA-IR	Multivariate	Yes	G1, G2	In SVR, OR of decreased IR 50 [3.74, 668.35]; P = 0.003
Conjeevaram et al[75]	2011	United States	341	G1	HOMA-IR	Univariate	Yes	G1	In SVR; P < 0.001
Khattab et al[76]	2012	Egypt	107	G4, non cirrhotic	HOMA-IR	Univariate	Yes	G4	In SVR ; P = 0.001
Thompson et al[13]	2012	United States	1038		HOMA-IR	Multivariate1	Yes	All	In G1 SVR; P = 0.007
Serfaty et al[103]	2012	France	161	G1, non cirrhotic	HOMA-IR	Univariate	Yes	G1	In SVR ; P < 0.05
Ziada et al[77]	2012	Egypt	140	Non DM, non cirrhotic	HOMA-IR	Univariate	Yes	All	P = 0.009
Chan et al[109]	2013	Australia	86	Non DM	HOMA-IR	Univariate	Yes	All	In SVR; P = 0.04
Jung et al[105]	2014	South Korea	60		HOMA-IR	Univariate	Yes	All	In SVR; P = 0.036
Mello et al[110]	2006	Brazil	30	G1, G3	HOMA-IR	Univariate	No	All	NS
Kawaguchi et al[111]	2009	Japan	72	Non DM, non cirrhotic	HOMA-IR, SI and ISI	Univariate1	No	No	HOMA-IR: NS In SVR, SI P = 0.002 and ISI P = 0.009
Brandman et al[101]	2012	United States	23	Non cirrhotic	SSGP	Univariate	No	No	NS
Occurrence of glucose abnormalities after HCV treatment
Simó et al[112]	2006	Spain	234	Non DM	DM or IGT	Multivariate1	Yes	All	In SVR, OR = 0.48 [0.24, 0.48]; P = 0.04
Romero-Gomez et al[91]	2008	Spain	1059		DM or IGT	Multivariate1	Yes	All	In SVR, OR = 0.44 [0.2, 0.97]; P = 0.04
Arase et al[113]	2009	Japan	2842		DM	Multivariate1	Yes	All	In SVR, HR = 0.36 [0.24; 0.56]
Aghemo et al[102]	2012	Italy	339	Non DM	HOMA-IR	Multivariate1	Yes	All	In SVR, OR = 0.36 [0.18, 0.72]; P = 0.004
Giordanino et al[114]	2008	Italy	202	Non DM	DM or IGT	Multivariate1	No	No	NS

¹association with SVR. HCV: Hepatitis C virus infection; G1: Genotype 1; SVR: Sustained virological response; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; IR: Insulin resistance; DM: Diabetes mellitus; FPG: Fasting plasma glucose; FI: Fasting insulin; IGT: Impaired glucose tolerance; ISI: Insulin sensitivity index; SI: Serum insulin; SSGP: Steady-state plasma glucose; NS: Not significant.

Table 5 Glucose abnormalities and hepatocellular carcinoma in hepatitis C virus-infected patients

Ref.	Year	Country	Patient number	Patient profile	Association	Statistical method	Association DM and HCC	Statistics
Diabetes mellitus/insulin resistance in HCV-related HCC
K-Kutala et al[15]	2014	France	162	HCC, not treated for HCV	DM and HCC	Multivariate	Yes3	HR = 3.13 [1.17, 8.38]; P = 0.0223
Hung et al[115]	2010	Taiwan	188	59 HCC; 129 non-HCC	DM and HCC	Multivariate	Yes	OR = 11.6 [2.500, 53.800]; P = 0.002
Hung et al[115]	2010	Taiwan	188	59 HCC; 129 non-HCC	HOMA-IR and HCC	Multivariate	Yes	OR = 2.0 [1.35, 3]; P = 0.001
Khattab et al[116]	2012	Egypt	294	147 HCC; 147 non-HCC	HOMA-IR and HCC	Multivariate	Yes	OR = 2.5 [1.7, 3.69]; P = 0.001
Mohamed et al[73]	2011	Egypt	100	50 HCC; 50 non-HCC; 20 non HCV	HOMA-IR and HCC	Univariate	No	NS
Diabetes mellitus/insulin resistance and development of HCC in HCV-infected patients
Chen et al[117]	2008	Taiwan	1095	-	DM and HCC	Multivariate	Yes	OR = 3.52 [1.29, 9.24]
Veldt et al[16]	2008	Europe	541		DM and HCC	Multivariate	Yes3	OR = 3.28 [1.35, 7.97]; P = 0.0093
Konishi et al[118]	2009	Japan	197	Non DM, treated for HCV	DM1 and HCC	Multivariate	Yes	HR = 4.63 [1.677, 12.766]; P = 0.003
Hung et al[14]	2010	Taiwan	1470	Treated for HCV	DM and HCC	Multivariate	Yes2	HR = 4.32 [1.23, 15.25]; P = 0.0232
Nkontchou et al[119]	2010	France	248	Cirrhotics	HOMA-IR and HCC	Multivariate	Yes	HR = 1.10 [1.01, 1.21]; P = 0.026
Takahashi et al[120]	2011	Japan	203	Non DM, treated for HCV	DM1 and HCC	Multivariate	Yes	HR = 6.9 [1.7, 28.4]; P < 0.05
Arase et al[121]	2013	Japan	4302	Non treated for HCV	DM and HCC	Multivariate	Yes	HR = 1.73 [1.3, 2.3]; P < 0.001
Elkrief et al[45]	2014	France	348	Cirrhotics	DM	Multivariate	Yes	HR = 1.938 [1.129 , 3.328]; P = 0.016
Toyoda et al[122]	2015	Japan	522	Patients with SVR	DM and HCC	Multivariate	Yes	HR = 2.08 [1.0170, 4.0133]; P = 0.045
Lai et al[123]	2006	Taiwan	2141	-	DM and HCC	Multivariate	No	NS
Chen et al[124]	2013	Taiwan	5186	-	DM and HCC	Multivariate	No	NS

¹Association of abnormal post-challenge hyperglycaemia and HCC;

²Only in SVR patients without cirrhosis;

³Only in advanced liver fibrosis. HCV: Hepatitis virus infection; HCC: Hepatocellular carcinoma; SVR: Sustained virological response; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; IR: Insulin resistance; DM: Diabetes mellitus; NS: Not significant.