==== Front Indian J Endocrinol MetabIndian J Endocrinol MetabIJEMIndian Journal of Endocrinology and Metabolism2230-82102230-9500Medknow Publications & Media Pvt Ltd India IJEM-22-55210.4103/ijem.IJEM_79_18Review ArticleHepatogenous Diabetes: An Underestimated Problem of Liver Cirrhosis Kumar Ramesh Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Bihar, IndiaAddress for correspondence: Dr. Ramesh Kumar, Department of Gastroenterology, All India Institute of Medical Sciences, Patna - 801 505, Bihar, India. E-mail: docrameshkr@gmail.comJul-Aug 2018 22 4 552 559 Copyright: © 2018 Indian Journal of Endocrinology and Metabolism2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.The prevalence of diabetes mellitus in cirrhotic patients is much higher than that in the general population. Two types of diabetes are usually seen in patients with cirrhosis: type 2 diabetes mellitus and hepatogenous diabetes (HD). The HD is an acquired condition which is believed to be caused by impaired insulin clearance and pancreatic β-cell dysfunction in cirrhotic patients. Increased levels of advanced glycation end products and hypoxia-inducible factors have been implicated in the pathogenesis of HD. Patients with HD typically present with normal fasting glucose, but abnormal response to an oral glucose tolerance test, which is required for the diagnosis. Because the level of glycated hemoglobin is often falsely low in patients with cirrhosis, it does not help in the early diagnosis of HD. HD is associated with an increased rate of complications of cirrhosis, decreased 5-year survival rate, and increased risk of hepatocellular carcinoma. The major complications of cirrhosis associated with HD include hepatic encephalopathy (HE), spontaneous bacterial peritonitis, sepsis, variceal hemorrhage, and renal dysfunction. Treatment of HD may be difficult as many antihyperglycemic therapies are associated with increased risk of complications in cirrhosis, particularly hypoglycemia. Biguanides, alpha-glucosidase inhibitors, and new medications such as dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter 2 inhibitors appear to be safe in patients with cirrhosis. Though insulin therapy is currently advocated, requirement of insulin is variable and is difficult to predict. The liver transplantation usually results in reversal of HD. This review article provides an overview of magnitude, patients' characteristics, clinical implications, pathophysiological mechanisms, diagnosis, and management of HD. Keywords: Cirrhosisdiabetes mellitushepatogenous diabetesinsulin resistance ==== Body INTRODUCTION The liver has a major role in the control of glucose homeostasis in the body.[1] The association between chronic liver disease (CLD) and diabetes mellitus (DM) is known since long. Such association may be due to a common mechanism that leads to both diseases such as non-alcoholic fatty liver disease (NAFLD), hemochromatosis, autoimmune liver diseases, and chronic hepatitis C.[23] A 10-year follow-up study of Veteran Affairs cohort revealed 2-fold increased risk of CLD in the subjects with type 2 DM (T2DM) compared to those without T2DM, after adjusting the confounding variables.[4] However, more commonly, CLD per se can lead to diabetes as known as hepatogenous diabetes (HD).[5] The term HD was first used by Megyesi et al.[6] in the 60's. This term did not get attention, as the entity was then poorly understood. Though, enough data now exist to support HD as a separate entity, it is still a neglected condition and surprisingly even American Diabetes Association does not recognize it. HD appears after the onset of liver disease in individuals without risk factors of T2DM such as high body mass index, hyperlipidemia, and previous or family history of DM. CHARACTERISTICS AND DIFFERENTIAL PREVALENCE OF T2DM AND HD IN CIRRHOSIS The prevalence of DM in cirrhotic subjects is higher than that in general population. The prevalence of DM in general population in India is estimated to be 6.1–16.6%,[7] whereas the reported prevalence rates of DM among cirrhotic patients across the world vary from 35 to 71% [Table 1]. Moreover, the prevalence rates of abnormal glucose regulation (AGR), which includes increased fasting glucose (IFG), impaired glucose tolerance (IGT), and DM, are much higher among cirrhotic patients and vary from 58 to 96% [Table 1]. Such a high prevalence rate of AGR and DM in cirrhotic patients, compared to normal population, suggests that substantial number of cirrhotic with diabetes have HD. However, many studies have not clarified as to what proportions of cirrhotic patients with DM have true HD. The discrimination between T2DM and HD is frequently not possible especially when DM is overt [Table 2]. The onset of DM after development of cirrhosis usually indicates HD. However, considering both conditions having long and variable natural history of pathogenesis, using a cut-off such as “before or after” onset of cirrhosis could be impractical at times. HD should be suspected in non-obese patients without family history of DM, hypertension, or hyperlipidemia.[8] In a recent study, the ratios of postprandial plasma glucose to fasting plasma glucose (FPG), fasting plasma insulin, and insulin resistance (IR) were significantly higher in cirrhotic patients with HD as compared to those with T2DM.[9] The prevalence of retinopathy and cardiovascular disease are lower in HD patients compared to cirrhotic patients with T2DM.[10] Table 1 Prevalence of abnormalities of glucose regulation among patients with cirrhosis Table 2 Differential characteristics of cirrhotic patients with Type 2 DM or HD The diagnostic methods greatly influence the detection rates of HD in cirrhotic patients. In patients with cirrhosis the levels of FPG and glycated hemoglobin (HbA1c) may be falsely low.[111213] In a study, the FPG levels were normal in 23% of the cirrhotic patients with overt diabetes.[13] However, postprandial blood glucose in these patients were >200 mg/L. Also, the HbA1c levels in cirrhotic patients frequently fall within normal range (4–6%).[12] The falsely low levels of HbA1c are believed to be due to shortened erythrocyte life span caused by hypersplenism in cirrhotic patients. Therefore, an oral glucose tolerance test (OGTT) is needed to detect the IGT or DM in patients with cirrhosis. Patients with normal FPG (and HbA1c) and abnormal OGTT likely to be those with HD, while in most subjects with increased FPG levels; diabetes is usually T2DM. Using combination of tests, the prevalence of DM in patients with CLD were: 48.3% in study by García-Compeán et al.[14], 71.1% in study by Holstein et al.[10], 59.6% in study by Grancini et al.[15], and 55.4% in study by Jeon et al.[16] The corresponding prevalence rates of AGR were much higher: 86.9%, 96.1%, 88.3%, and 86.7%, respectively. García-Compeán et al.[14] reported that, out of 36 cirrhotic subjects with increased FPG levels, 69.4% had a pre-existing T2DM, whereas only 30.6% could fit into criterion for HD. Jeon et al.[16] using OGTT in 195 consecutive cirrhotic liver patients who had no history of DM found HD in 55.4%. About 62% of HD patients in this study had normal FPG level. The severity of liver disease also determines the prevalence of DM in cirrhotic patients. In a study, DM was present in 20.5%, 56.1%, and 61.2% of Child-Pugh Class A, B, and C, respectively.[15] Müller et al.[17] reported 37% prevalence of DM among 108 cirrhotic patients at baseline. But, after 1-year and 4-year follow-up, the prevalence rates of DM increased by 4.4% and 21.2%, respectively. Thus in patients with cirrhosis, a transition from IR and IGT to DM may indicate progression of liver disease from early to advanced stage. The etiologies are also an important risk factor for DM in cirrhosis. DM is more frequent among those with hepatitis C virus (HCV), alcoholic, and cryptogenic etiology.[5] A large study on population at low risk of diabetes found that serological evidence of hepatitis B virus (HBV) and HCV infection was associated with prevalence of diabetes.[18] A recent meta-analysis also established that patients with HBV infection are at higher risk of developing DM.[19] Therefore, infection with HBV or HCV must be ruled out in patients with DM and liver disease. Iron overload in patients with hemochromatosis can lead to the development of both DM and liver disease. Therefore, screening for abnormal iron indices must be done in patients with concomitant DM and CLD. Pathophysiology The pathophysiology of HD is complex and is not precisely known. Multiple factors are responsible for the development of peripheral IR and β-cell dysfunction in cirrhotic patients. Hyperinsulinemia Reduction in liver cell mass and presence of portosystemic collaterals in cirrhotic patients result in decreased extraction of insulin by the liver, leading to systemic hyperinsulinemia.[20] An exaggerated insulin secretion, which occurs lately in cirrhotic patients due to pancreatic islet hypertrophy, also contributes to hyperinsulinemia.[21] Hyperinsulinemia can lead to IR through down-regulation of insulin receptors of target cells.[22] Indeed, reduction in hyperinsulinemia has been found to normalize insulin sensitivity.[23] Disease-specific glucose intolerance In NAFLD, IR is mediated by multiple mechanisms such as altered secretion of adipokines and pro-inflammatory cytokines, increased free fatty acid release, and the reduced incretin effect.[24] Both direct and cytokine-mediated interference with insulin signalling such as inactivation or degradation of the insulin receptor and their downstream target contributes to HCV-mediated IR.[252627] HCV may impair β-cell function through auto-immune effect by molecular mimicry, as it shares structural homology with glutamic acid decarboxylase.[28] DM in patients with alcoholic cirrhosis and hemochromatosis has been related to the simultaneous injury to hepatocytes and pancreatic β-cells caused by alcohol and iron, respectively.[829] Reduced incretin effects The incretins play important roles in the maintenance of glycemic control. The two naturally occurring incretin hormones are glucose-dependent insulinotropic polypeptide and glucagon-like peptide (GLP-1).[30] GLP-1 is a gut-derived incretin hormone that stimulates insulin secretion and suppresses glucagon secretion. These peptides are rapidly hydrolyzed by dipeptidyl peptidase-4 (DPP-4). The inactivation of GLP-1 results in the development of IGT, DM, and hepatic steatosis.[31] Serum DPP-4 activity and hepatic expression of DPP-4 are up-regulated in cirrhotic patients which reduce incretin effects.[32] Role of advanced glycation endproducts Hyperglycemia cultivates the advanced glycation endproducts (AGEs), and the liver is the main catabolic site for these AGEs. In patients with cirrhosis, plasma levels of AGEs are markedly elevated and correlate with the severity of the liver disease.[3334] The AGEs are thought to induce IR and β-cell injury.[35] A significant decline in the level of serum AGEs is seen after liver transplantation. Role of hypoxia-inducible factors and betatrophin Hypoxia is a common feature in patients with advanced cirrhosis.[36] Hypoxia-inducible factors, a family of transcription factors that mediate tissue response to hypoxia, have been implicated in the development of β-cell dysfunction and DM.[37] Recently, Yi et al.[38] discovered that a hormone named betatrophin, primarily expressed in the hepatocytes, induced β-cell proliferation and improved glucose tolerance in a murine model. A recent study has found a strong correlation between betatrophin levels and IR, more so in non-diabetic subject.[39] Thus, an abnormal hepato-pancreatic axis may be partly responsible for IR in cirrhotic patients. Clinical implications Substantial data suggest that DM in patients with cirrhosis is associated with decreased survival, higher rate of complications of liver cirrhosis, and increased risk of malignancy. However, the comparative data on the adverse impact of T2DM versus HD in cirrhotic patients are not available. Decreased survival DM and IGT in cirrhotic patients are associated with lower survival rate. In a prospective study that included cirrhotic patients with DM (n = 21), IGT (n = 13), and normal glucose tolerance (NGT, n = 22), the cumulative survival rates at 5 years were 94.7%, 68.8%, and 56.6% for patients with NGT, IGT, and DM, respectively.[13] Also, DM was among the most powerful independent negative predictors of survival. Another study reported that compensated cirrhotic patients with subclinical IGT had lower 5-year survival than those with NGT (31.7% vs 71.6%, P = 0.02)[40]. Holstein et al.[10], in a prospective cohort study, which included 52 HD patients, reported that the majority death among 52% patients who died after a mean follow-up of 5.6 years were due to complications of the cirrhosis. There were no diabetes-associated or cardiovascular deaths. This may be because of accelerated liver failure in patients with HD, which might have curtailed the time in which diabetic complications could have developed. Increased risk of cirrhotic complications DM in cirrhosis is associated with HE, variceal hemorrhage, infection, spontaneous bacterial peritonitis, and renal impairment.[8414243] This may be because of the fact that DM causes gastrointestinal dysmotility, immune-suppression, intestinal bacterial overgrowth, and bacterial translocation. In a study, the severity of HE was greater in diabetic (35% mild, 60% severe) than in non-diabetic cirrhotic patients (58% mild, 20% severe), irrespective of the severity of liver disease.[42] Jeon et al. documented that the presence of HD had a significant correlation with high Child-Pugh's score, variceal hemorrhage, and hepatic venous pressure gradient (P < 0.01 each). Postprandial hyperglycemia, in particular, had a significant relationship with variceal hemorrhage.[16] DM has been found to be associated with renal insufficiency and decreased survival in patients with liver cirrhosis and hepatocellular carcinoma (HCC).[43] A study, that included 348 patients with HCV-cirrhosis, found that baseline diabetes was independently associated with ascites (P = 0.05), bacterial infections (P = 0.001), and HE (P < 0.001)[44]. DM in patients with liver cirrhosis itself is a risk factor for the development of diabetes after liver transplant.[45] Increased risk of malignancy There is a strong association between DM and HCC. Yang et al.[46] in a recent study, found that diabetes increases the risk of HCC in patients with non-HCV cirrhosis. In HCV cirrhosis patients who already have very high risk, diabetes may not increase the risk any further. Presence of glucose intolerance lowers the survival of male HCC patients.[47] In a prospective study of large European-cohort (n = 363 426), Schlesinger et al.[48] found the incidence of bile tract cancer (BTC) and HCC in 204 and 176 cases during 8.5 years follow-up. Independent of body mass index, diabetes status was associated with higher risk of BTC and HCC [1.77 (1.00-3.13) and 2.17 (1.36-3.470).[48] Treatment The management of diabetes in cirrhotic patients is challenging because of a lack of concrete guidelines, physio-pathological changes in the body due to cirrhosis, and alteration in pharmacokinetic properties of many oral hypoglycemic agents (OHA) rendering patients to increased risk of adverse events [Table 3].[49] In non-cirrhotic patients with DM, a good glycemic control plays an important role in preventing or delaying diabetic complications. However, it is unclear as to whether a similar approach would result in improved outcome in cirrhotic patients with DM. Lifestyle modification, which include low-caloric diet and physical exercise, may not be appropriate in all cirrhotic patients with DM. A hypocaloric diet may aggravate a pre-existing malnutrition, and generalized weakness, oedema, and ascites may hinder physical exercise. In general, therapy is usually started with OHA with advancement to insulin if blood sugar control is not achieved or liver function deteriorates further. Once on treatment, the glycemic targets in patients with HD should be based on postprandial glucose levels and not on FPG or HbA1c. Serum fructosamine, which reflects glycemic status over a period of 2–4 weeks, is better than HbA1c for long-term monitoring glycemic control in such patients.[50] Finally, liver transplantation rapidly normalizes glucose homeostasis, and cures HD in approximately 67% of patients.[51] Table 3 Challenges in the management of DM in cirrhosis patients OHA For patients with cirrhosis, an ideal OHA should have insignificant hepatic metabolism, low binding to plasma protein, non-hepatic rout of elimination, relatively shorter half-life, and no risk of hypoglycemia or hepatoxicity [Table 4]. Table 4 Characteristics of oral hypoglycaemic agents in relation to cirrhotic patients BIGUANIDE Metformin, a biguanide, remains unmetabolized in the body, does not bind to plasma protein, has a short half-life (~5 hours), and is eliminated via kidney.[52] Moreover, metformin has cardio-protective and anti-cancer effects. Metformin has been found to be associated with decreased risk of HCC [HR 0.19] and liver-related death in cirrhotic patients with DM.[53] Paradoxically, the majority of physicians are hesitant to recommend metformin in cirrhotic patients due to undue apprehension about an increased risk of lactic acidosis. However, systematic review and meta-analysis of 194 comparative trials has revealed no significant risk of lactic acidosis in metformin group compared to non-metformin group.[54] Another study revealed that none of diabetic patients who continued metformin after diagnosis of cirrhosis (n = 172) developed lactic acidosis. Moreover, the median survival among patients who received metformin was longer than those who discontinued metformin (11.8 vs. 5.6 years).[55] Metformin is inexpensive and has low risk of hypoglycemia. Though, it may cause mild gastrointestinal disturbances after initiation, this too is unusual with extended release preparations. Thus, metformin appears to be reasonably safe in patients with cirrhosis, and the risk of metformin-induced lactic acidosis is extremely rare unless patients have concomitant renal dysfunction or hypoxemia. Sulfonylureas (SUs) Glyburide/glibenclamide, glipizide, gliclazide, and glimepiride are SUs belonging to second and third generation, respectively. The liver is the major site of metabolism for all SUs. SUs are extensively bound to serum proteins and excreted mainly through kidney.[56] The risk of hypoglycemia is high with all SUs. This happens because of the stimulation of insulin secretion from the pancreatic β-cell, and reduced inactivation of SUs in liver, and enhanced free drug plasma concentrations due to hypoalbuminemia.[57] Therefore, SUs should be better avoided in patients with cirrhosis; however, the ones with short half-life such as glipizide or glyburide may be used with caution. Meglitinides Repaglinide and nateglinide are the two currently available meglitinides for clinical use. No specific guidelines are available pertaining to meglitinides. However, meglitinides may be used alternative to SUs, with a preference for nateglinide compared to repaglinide. Thiazolidinediones (TZD) TZDs improve insulin sensitivity through varied mechanisms. The first commercialized thiazolidinedione, troglitazone, was withdrawn from the market because of idiosyncratic hepatotoxicity.[58] Pioglitazone is the only TZD available for clinical use in India. It is extensively metabolized in liver and is excreted via bile and feces. Pioglitazone has a good hepatic safety profile; however, no published study investigated the pharmacokinetic (PK) of pioglitazone in patients with CLD.[59] The peroxisome proliferator-activated receptor-γ (PPARγ) is the functioning receptor for TZD. Activation of PPARγ inhibits collagen production from hepatic stellate cells. In a meta-analysis of eight RCT that included patients of NASH with advanced fibrosis (F3–F4), TZD was associated with improved fibrosis score (OR, 3.15).[60] Also, TZD has negative impact on oxidative stress and pro-inflammatory cytokines. Though pioglitazone appears to be safe, the dose, in view of absence of evidence, should be kept on lower the side (maximum of 30 mg/day) in CLD patients, and liver function should be monitored periodically during treatment. Alpha-glucosidase inhibitors (AGI) AGIs available for the treatment of patients with DM are: voglibose, acarbose, and miglitol. AGIs are metabolized within the gastrointestinal tract.[61] Due to a low systemic bioavailability and lack of hepatic metabolism, AGIs appear to be safe, useful, and well tolerated in CLD patients.[6263] AGI causes delayed carbohydrate digestion and absorption, with reduction of postprandial hyperglycemia. Because carbohydrate absorption is only delayed, and is not incomplete, there are no nutritional caloric losses. Also, acarbose stimulates the gut peristalsis and proliferation of the saccarolytic bacteria which result in the reduction of blood ammonia levels. In a randomized controlled trial, acarbose significantly decreased blood ammonia levels, FPG, PPG, and improved encephalopathy scores compared with placebo (P < 01).[62] However, acarbose may cause mild transient transaminitis requiring monitoring of liver function tests.[64] Miglitol is not metabolized by liver; therefore, no influence of hepatic function on the kinetics of miglitol can be expected. Voglibose is more potent and better tolerated as compared to acarbose or migitol. Rare cases of hepatitis with severe cholestasis attributed to voglibose hypersensitivity have been reported.[65] DPP-4 inhibitors DDP-4 inhibitors are the therapeutic approaches for increasing incretin action. The currently available DPP-4 inhibitors are sitagliptin, saxagliptin, vidagliptin, linagliptin, and alogliptin. Their PK characteristics in patients with different degrees of hepatic insufficiency (HI) are better known as compared to older OHAs[666768] [Table 4]. However, no clinical study with a long-term administration of a DPP-4 inhibitor in patients with CLD is yet available. In a case–control study, sitagliptin was found to be effective and safe for the treatment of T2DM in HCV-related CLD patients.[69] PK study of vildagliptin and linagliptin revealed no significant difference in drug exposure in patients with mild, moderate, or severe HI compared to healthy controls. Thus, dose adjustment with vildagliptin or linagliptin is not required in patients with HI. On the other hand, saxagliptin is primarily metabolized in liver and thus requires dose adjustment in presence of HI.[70] Sodium-glucose co-transporter 2 (SGLT2) inhibitors Canagliflozin, dapagliflozin, and empagliflozin are SGLT2 inhibitors currently available in India. SGLT2 inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2.[7172] In addition to robust glucose control, SGLT2 inhibitors have multiple non-glycemic benefits that include weight loss and reduction of high blood pressure, dyslipidemia, and hyperuricemia. The PK characteristics of SGLT2 inhibitors are similar and are not significantly affected by HI.[7374] Studies have found none of SGLT2 inhibitors to be hepatotoxic. Thus, SGLT-2 inhibitors can be used in CLD patients. The adverse events of SGLT2 inhibitors are due to their effect of increasing urinary glucose excretion and osmotic dieresis. Insulin Insulin therapy is believed to be the safest and most effective therapy in patients with CLD. It is frequently prescribed in patients with cirrhosis, although clinical studies are scant in the literature. Study have found no clinically significant impact of HI on PKs of insulin aspart.[75] Insulin requirement may vary in patients with cirrhosis and is difficult to predict. It may be decreased due to reduced capacity for gluconeogenesis and reduced hepatic clearance of insulin; however, it may become higher to compensate for IR.[76] Furthermore, beta-blockers, which are commonly used for portal hypertension, may make hypoglycemic episodes less symptomatic, leading to more worsening of mental state. A close monitoring of blood glucose levels is required during the initiation of insulin therapy in cirrhotic patients. In conclusions, though enough data exist to support the fact that liver disease per se can lead to diabetes, HD is still a neglected condition. There is a need to separate HD from type-2 DM. HD appears to constitute a significant proportion of DM in cirrhotic patients. Differentiating HD from type-2 DM is often difficult, and an OGTT is required for its diagnosis. HD is associated with increased risk of cirrhotic complications, including HCC. Treatment of HD is not well defined. Because India falls in the intermediate endemicity zone of HBV infection which is an important cause of CLD, HBV vaccination might be an important step towards diabetes prevention. Additional works are needed to gain a better understanding of disease process and treatment of this condition. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.77 ==== Refs REFERENCES 1 Han HS Kang G Kim JS Choi BH Koo SH Regulation of glucose metabolism from a liver-centric perspective Exp Mol Med 2016 48 e218 26964834 2 Williams KH Shackel NA Gorrell MD McLennan SV Twigg SM Diabetes and nonalcoholic fatty liver disease: A pathogenic duo Endocr Rev 2013 34 84 129 23238855 3 Garcia-Compean D Jaquez-Quintana JO Gonzalez-Gonzalez JA Maldonado-Garza H Liver cirrhosis and diabetes: Risk factors, pathophysiology, clinical implications and management World J Gastroenterol 2009 15 280 3 19140227 4 El-Serag HB Everhart JE Diabetes increases the risk of acute hepatic failure Gasteroenterology 2002 122 1822 8 5 García-Compean D Jaquez-Quintana JO Maldonado-Garza H Hepatogenous diabetes. Current views of an ancient problem Ann Hepatol 2009 8 13 20 19221528 6 Megyesi C Samols E Marks V Glucose tolerance and diabetes in chronic liver disease Lancet 1967 2 1051 6 4168535 7 Kaveeshwar SA Cornwall J The current state of diabetes mellitus in India AMJ 2014 1 45 8 8 Orsi E Grancini V Menini S Aghemo A Pugliese G Hepatogenous diabetes: Is it time to separate it from type 2 diabetes? Liver Int 2017 37 950 62 27943508 9 Kim MG Choi WC Differential diagnosis of diabetes mellitus caused by liver cirrhosis and other type 2 diabetes mellitus Korean J Hepatol 2006 12 524 9 17237630 10 Holstein A Hinze S Thiessen E Plaschke A Egberts E-H Clinical implications of hepatogenous diabetes in liver cirrhosis J Gastroenterol Hepatol 2002 17 677 81 12100613 11 Imano E Nishida T Shibata M Kanda T Significance of oral glucose tolerance test for the diagnosis of diabetes mellitus in patients with liver cirrhosis Intern Med 1999 38 918 10563758 12 Lahousen T Hegenbarth K Ille R Lipp RW Krause R Little RR Determination of glycated hemoglobin in patients with advanced liver disease World J Gastroenterol 2004 10 2284 6 15259084 13 Nishida T Tsuji S Tsujii M Arimitsu S Haruna Y Imano E Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis Am J Gastroenterol 2006 101 70 5 16405536 14 García-Compeán D Jáquez-Quintana JO Lavalle-González FJ Reyes-Cabello E González-González JA Muñoz-Espinosa LE The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study Ann Hepatol 2012 11 240 8 22345342 15 Grancini V Trombetta M Lunati ME Zimbalatti D Boselli ML Gatti S Contribution of β-cell dysfunction and insulin resistance to cirrhosis-associated diabetes: Role of severity of liver disease J Hepatol 2015 63 1484 90 26297917 16 Jeon HK Kim MY Baik SK Park HJ Choi H Park SY Hepatogenous diabetes in cirrhosis is related to portal pressure and variceal hemorrhage Dig Dis Sci 2013 58 3335 41 23912248 17 Müller MJ Pirlich M Balks HJ Selberg O Glucose intolerance in liver cirrhosis: Role of hepatic and non-hepatic influences Eur J Clin Chem Clin Biochem 1994 32 74958 18 Hong YS Chang Y Ryu S Cainzos-Achirica M Kwon MJ Zhang Y Hepatitis B and C virus infection and diabetes mellitus: A cohort study Sci Rep 2017 7 4606 28676706 19 Cai C Zeng J Wu H Shi R Wei M Gao Y Association between hepatitis B virus infection and diabetes mellitus: A meta-analysis Exp Ther Med 2015 10 693 98 26622377 20 Greco AV Mingrone G Mari A Capristo E Manco M Gasbarrini G Mechanisms of hyperinsulinaemia in child's disease grade B liver cirrhosis investigated in free living conditions Gut 2002 51 870 75 12427792 21 Saitoh M Studies on histopathology of pancreas in portal hypertension Nippon Shokakibyo Gakkai Zasshi 1984 81 144452 22 Shanik MH Xu Y Skrha J Dankner R Zick Y Roth J Insulin resistance and hyperinsulinemia: Is hyperinsulinemia the cart or the horse? Diabetes Care 2008 31 S262–8 18227495 23 Petrides AS Stanley T Matthews DE Vogt C Bush AJ Lambeth H Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity Hepatology 1998 28 141 9 9657106 24 Gariani K Philippe J Jornayvaz FR Non-alcoholic fatty liver disease and insulin resistance: From bench to bedside Diabetes Metab 2013 39 16 26 23266468 25 Lecube A Hernández C Genescà J Simó R Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case- control study Diabetes Care 2006 29 1096 1101 16644643 26 Bugianesi E Salamone F Negro F The interaction of metabolic factors with HCV infection: Does it matter? J Hepatol 2012 56 Suppl 1 S56 65 22300466 27 Bose SK Shrivastava S Meyer K Ray RB Ray R Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance J Virol 2012 86 6315 22 22457523 28 Christen V Treves S Duong FH Heim MH Activation of endoplasmic reticulum stress response by hepatitis viruses up-regulates protein phosphatase 2A Hepatology 2007 46 558 5 17526027 29 Rahier J Loozen S Goebbels RM Abrahem M The haemochromatotic human pancreas: A quantitative immunohistochemical and ultrastructural study Diabetologia 1987 30 5 12 3552822 30 Drucker DJ Nauck MA The incretin system: Glucagonlike peptide-1 receptor agonists and dipeptidyl peptidase4 inhibitors in type 2 diabetes Lancet 2006 368 1696 705 17098089 31 Balaban YH Korkusuz P Simsek H Gokcan H Gedikoglu G Pinar A Dipeptidyl peptidase IV (DDP IV) in NASH patients Ann Hepatol 2007 6 242 50 18007554 32 Itou M Kawaguchi T Taniguchi E Sata M Dipeptidyl peptidase-4: A key player in chronic liver disease World J Gastroenterol 2013 19 2298 306 23613622 33 Yagmur E Tacke F Weiss C Lahme B Manns MP Kiefer P Elevation of Ne-(carboxymethyl) lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis Clin Biochem 2006 39 39 45 16321365 34 Sebekova K Kupcova V Schinzel R Heidland A Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis-amelioration by liver transplantation J Hepatol 2002 36 66 71 11804666 35 Vlassara H Uribarri J Advanced glycation end products (AGE) and diabetes: Cause, effect, or both? Curr Diab Rep 2014 14 453 24292971 36 Moreau R Lee SS Soupison T Roche-Sicot J Sicot C Abnormal tissue oxygenation in patients with cirrhosis and liver failure J Hepatol 1988 7 98 105 3183357 37 Cheng K Ho K Stokes R Scott C Lau SM Hawthorne WJ Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets J Clin Invest 2010 120 2171 83 20440072 38 Yi P Park J-S Melton DA Betatrophin: A hormone that controls pancreatic b cell proliferation Cell 2013 153 747 58 23623304 39 Abu-Farha M Abubaker J Al-Khairi I Cherian P Noronha F Hu FB Higher plasma betatrophin/ANGPTL8 level in type 2 diabetes subjects does not correlate with blood glucose or insulin resistance Sci Rep 2015 5 10949 26077345 40 García-Compeán D Jáquez-Quintana JO Lavalle-González FJ González-González JA Muñoz-Espinosa LE Villarreal-Pérez JZ Subclinical abnormal glucose tolerance is a predictor of death in liver cirrhosis World J Gastroenterol 2014 20 7011 18 24944496 41 Wlazlo N van Greevenbroek MM Curvers J Schoon EJ Friederich P Twisk JW Diabetes mellitus at the time of diagnosis of cirrhosis is associated with higher incidence of spontaneous bacterial peritonitis, but not with increased mortality Clin Sci (Lond) 2013 125 341 8 23566037 42 Sigal SH Stanca CM Kontorinis N Bodian C Ryan E Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis Am J Gastroenterol 2006 101 1490 96 16863551 43 Huo TI Hsu CY Huang YH Hsia CY Lin HC Lee PC Diabetes mellitus as an independent prognostic predictor and its association with renal dysfunction in patients with hepatocellular carcinoma Liver Int 2010 30 198 207 19849777 44 Elkrief L Chouinard P Bendersky N Hajage D Larroque B Babany G Diabetes mellitus is an independent prognostic factor for major liver-related outcomes in patients with cirrhosis and chronic hepatitis C Hepatology 2014 60 823 83 24841704 45 Lunati ME Grancini V Agnelli F Gatti S Masserini B Zimbalatti D Metabolic syndrome after liver transplantation: Shortterm prevalence and pre- and post-operative risk factors Dig Liver Dis 2013 45 833 83 23816695 46 Yang JD Mohamed HA Cvinar JL Gores GJ Roberts LR Kim WR Diabetes mellitus heightens the risk of hepatocellular carcinoma except in patients with hepatitis C cirrhosis Am J Gastroenterol 2016 111 1573 80 27527741 47 Sumie S Kawaguchi T Komuta M Kuromatsu R Itano S Okuda K Significance of glucose intolerance and SHIP2 expression in hepatocellular carcinoma patients with HCV infection Oncol Rep 2007 18 545 52 17671700 48 Schlesinger S Aleksandrova K Pischon T Jenab M Fedirko V Trepo E Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort Ann Oncol 2013 24 2449 55 23720454 49 Hamed AE Abas B Shaltout I Esmt G Gomez R Managing diabetes and liver disease association, guidelines (consensus) development J Endocrinol Diabetes Obes 2015 3 1 19 50 Trenti T Cristani A Cioni G Pentore R Mussini C Ventura E Fructosamine and glycated hemoglobin as indices of glycemic control in patients with liver cirrhosis Ric Clin Lab 1990 20 261 7 2075378 51 Shetty A Wilson S Kuo P Laurin JL Howell CD Johnson L Liver transplantation improves cirrhosis-associated impaired oral glucose tolerance Transplantation 2000 69 2451 54 10868659 52 Graham GG Punt J Arora M Day RO Doogue MP Duong JK Clinical pharmacokinetics of metformin Clin Pharmacokinet 2011 50 12 53 Nkontchou G Cosson E Aout M Mahmoudi A Bourcier V Charif I Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients J Clin Endocrinol Metab 2011 96 2601 8 21752887 54 Salpeter SR Greyber E Pasternak GA Salpeter EE Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: Systematic review and meta-analysis Arch Intern Med 2003 163 2594 602 14638559 55 Zhang X Harmsen WS Mettler TA Kim WR Roberts RO Therneau TM Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes Hepatol 2014 60 2008 16 56 Balant L Clinical pharmacokinetics of sulphonylurea hypoglycaemic drugs Clin Pharmacokinet 1981 6 215 41 7016385 57 Ashcroft FM Mechanisms of the glycaemic effects of sulfonylureas Horm Metab Res 1996 28 456 63 8911983 58 Scheen AJ Hepatotoxicity with thiazolidinediones: Is it a class effect? Drug Saf 2001 24 873 88 11735645 59 Kawamori R Kadowaki T Onji M Seino Y Akanuma Y PRACTICAL Study Group. Hepatic safety profile and glycemic control of pioglitazone in more than 20,000 patients with type 2 diabetes mellitus: Postmarketing surveillance study in Japan Diabetes Res Clin Pract 2007 76 229 35 17109986 60 Musso G Cassader M Paschetta E Gambino R Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: A meta-analysis JAMA Intern Med 2017 177 633 40 28241279 61 Balfour JA McTavish D Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus Drugs 1993 46 1025 54 7510610 62 Gentile S Guarino G Romano M Alagia IA Fierro M Annunziata S A randomized controlled trial of acarbose in hepatic encephalopathy Clin Gastroenterol Hepatol 2005 3 184 91 15704053 63 Kihara Y Ogami Y Tabaru A Unoki H Otsuki M Safe and effective treatment of diabetes mellitus associated with chronic liver diseases with an alpha-glucosidase inhibitor, acarbose J Gastroenterol 1997 32 777 9430016 64 Hsiao SH Liao LH Cheng PN Wu TJ Hepatotoxicity associated with acarbose therapy Ann Pharmacother 2006 40 151 4 16317107 65 Kawakami S Arima T Harada K Miyazono H Oketani M Miyazaki H Hepatic necrosis with cholestasis induced by long-term voglibose administration Intern Med 2001 40 484 8 11446671 66 Migoya EM Stevens CH Bergman AJ Luo WL Lasseter KC Dilzer SC Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin Can J Clin Pharmacol 2009 16 e165 70 19221403 67 Graefe-Mody U Rose P Retlich S Ring A Waldhauser L Cinca R Pharmacokinetics of linagliptin in subjects with hepatic impairment Br J Clin Pharmacol 2012 74 75 85 22242621 68 Golightly LK Drayna CC McDermott MT Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors Clin Pharmacokinet 2012 51 501 14 22686547 69 Arase Y Suzuki F Kobayashi M Suzuki Y Kawamura Y Matsumoto N Efficacy and safety in sitagliptin therapy for diabetes complicated by chronic liver disease caused by hepatitis C virus Hepatol Res 2011 41 524 9 21435130 70 Boulton DW Li L Frevert EU Tang A Castaneda L Vachharajani NN Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin Clin Pharmacokinet 2011 50 253 65 21348538 71 Ferrannini E Solini A SGLT2 inhibition in diabetes mellitus: Rationale and clinical prospects Nat Rev Endocrinol 2012 8 495 502 22310849 72 Ghosh RK Ghosh SM Chawla S Jasdanwala SA SGLT2 inhibitors: A new emerging therapeutic class in the treatment of type 2 diabetes mellitus J Clin Pharmacol 2012 52 457 63 21543663 73 Scheen AJ Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease Clin Pharmacokinet 2015 54 691 708 25805666 74 Kasichayanula S Liu X Zhang W Pfister M LaCreta FP Boulton DW Influence of hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: An open- label, parallel- group, single- dose study Clin Ther 2011 33 1798 808 22030444 75 Holmes G Galitz L Hu P Lyness W Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment Br J Clin Pharmacol 2005 60 469 76 16236036 76 Marselli L De Simone P Morganti R Coletti L Carrai P Catalano G Frequency and characteristics of diabetes in 300 pre-liver transplant patients Nutr Metab Cardiovasc Dis 2016 26 441 2 27089979 77 Tietge UJ Selberg O Kreter A Bahr MJ Pirlich M Burchert W Alterations in glucose metabolism associated with liver cirrhosis persist in the clinically stable long-term course after liver transplantation Liver Transpl 2004 10 1030 40 15390330