Although an increase in insulin resistance is frequently associated with liver cirrhosis, a condition sometimes referred to as hepatogenic diabetes (HD), the pathophysiology is still poorly understood. Moreover, the management of patients with HD, both diagnostically and therapeutically, is complex. In this article, we present the case of a cirrhotic patient, initially not known to have diabetes or prediabetes, who developed fulminant diabetes overnight, with massive resistance to subcutaneous insulin treatment. Management during hospitalization was extremely complicated, leading to significant staggering of the insulin doses until the liver transplant, which allowed complete normalization of the glycemic profile.

The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.

Cirrhosis is associated with insulin resistance and impaired glucose tolerance, which may be caused by impairments at different tissue levels (liver, skeletal muscle, and/or beta cell).

Here, glucose kinetics at whole-body and skeletal muscle level in patients with cirrhosis (Child-Pugh A and B) were studied during parenteral nutrition using the isotope dilution technique and arteriovenous balance approach across the leg. As opposed to the euglycemic hyperinsulinemic clamp or glucose tolerance tests applied in previous studies, this approach provides a nutrient composition more similar to a normal meal while circumventing any possible portal-systemic shunting, impaired hepatic uptake and incretin effect.

We confirmed the presence of hepatic and peripheral insulin resistance in our patient population. Endogenous glucose production was less suppressed in response to parenteral nutrition. However, glucose uptake in skeletal muscle was increased.

Our results suggests that in our study participants with cirrhosis, the hepatic and peripheral insulin resistance is compensated for by increased insulin secretion and thus, increased glucose uptake in muscle. Hereby, glucose homeostasis is maintained.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

An 85-year-old woman was admitted to our hospital because of hypoglycemia and impairment of consciousness several hours after breakfast. Because the hypoglycemia predominantly occurred 2-4 h after meals, we diagnosed reactive hypoglycemia. An oral glucose tolerance test showed prolonged hyperinsulinemia following the postprandial hyperglycemia, with a subsequent rapid decrease in blood glucose concentration. The post-stimulus plasma C-peptide concentration was relatively low compared to the plasma insulin concentration. Abdominal computed tomography revealed an intrahepatic congenital portosystemic shunt (CPSS). On the basis of these findings, we concluded that the reactive hypoglycemia was induced by the CPSS, via a reduction in hepatic insulin extraction. Treatment with an alpha-glucosidase inhibitor resolved the reactive hypoglycemia. CPSS comprises anomalous vascular connections between the portal vein and the systemic venous circulation, and reactive hypoglycemia is a rare complication of this malformation, which has most frequently been reported in children, with only a few cases reported in adults. However, this case indicates that even in adult patients, imaging studies should be conducted to rule out CPSS as the cause of the reactive hyperglycemia.

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with chronic liver disease (CLD) and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and complications. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover wherein changes in various metabolic factors such as hyperammonemia, amino acid deprivation, hormonal imbalance, gut dysbiosis, insulin resistance, chronic inflammation, etc. have important roles. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α-ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Skeletal muscle is a major organ of insulin-induced glucose metabolism, and sarcopenia is closely linked to insulin resistance and metabolic syndrome. Patients with liver cirrhosis are in a hypermetabolic state that is associated with catabolism and depletion of amino acids, particularly branched-chain amino acids. Sarcopenia can have significant implications for nonalcoholic fatty liver disease, the most common form of CLD worldwide, because of the close link between metabolic syndrome and sarcopenia. This review discusses the potential metabolic derangement as a cause or effect of sarcopenia in CLD, as well as interorgan crosstalk, which that might help identifying a novel therapeutic strategies.

The diabetogenic potential of liver cirrhosis (LC) has been known for a long time, and the name "hepatogenous diabetes" (HD) was coined in 1906 to define the condition. Diabetes mellitus (DM) that develops as a consequence of LC is referred to as HD. In patients with LC, the prevalence rates of HD have been reported to vary from 21% to 57%. The pathophysiological basis of HD seems to involve insulin resistance (IR) and pancreatic β-cell dysfunction. The neurohormonal changes, endotoxemia, and chronic inflammation of LC initially create IR; however, the toxic effects eventually lead to β-cell dysfunction, which marks the transition from impaired glucose tolerance to HD. In addition, a number of factors, including sarcopenia, sarcopenic obesity, gut dysbiosis, and hyperammonemia, have recently been linked to impaired glucose metabolism in LC. DM is associated with complications and poor outcomes in patients with LC, although the individual impact of each type 2 DM and HD is unknown due to a lack of categorization of diabetes in most published research. In fact, there is much skepticism within scientific organizations over the recognition of HD as a separate disease and a consequence of LC. Currently, T2DM and HD are being treated in a similar manner although no standardized guidelines are available. The different pathophysiological basis of HD may have an impact on treatment options. This review article discusses the existence of HD as a distinct entity with high prevalence rates, a strong pathophysiological basis, clinical and therapeutic implications, as well as widespread skepticism and knowledge gaps.

The prevalence of glucose intolerance in chronic liver disease patients is high, but glucose intolerance may be overlooked in a single blood test. The purpose of this study is to evaluate blood glucose variability in patients with chronic liver disease by a continuous glucose monitoring system (CGMS) and to examine the discrepancy between hemoglobin A1c (HbA1c) levels estimated from average blood glucose levels and HbA1c.

This study included 335 patients with chronic liver disease associated with glucose intolerance. A fasting blood test and 72-h CGMS were performed. The estimated HbA1c was calculated from the average blood glucose level, and the correlation between hepatic functional reserve and blood glucose-related parameters was analyzed. From the obtained data, we created a new formula to calculate HbA1c without using CGMS.

As hepatic functional reserve decreased, average blood glucose and insulin resistance increased while HbA1c decreased (P < 0.0001). The discrepancy between the estimated HbA1c calculated from the mean blood glucose level and the serum HbA1c (ΔHbA1c) increased as the liver reserve decreased. Using multiple regression analysis, a formula based on fasting blood glucose, HbA1c, body mass index, albumin, and liver function was constructed, and its validity was demonstrated in a study using a different control group.

Hemoglobin A1c may be underestimated because of decreased hepatic functional reserve. CGMS was useful in assessing accurate glycemic control of blood glucose and in detecting postprandial hyperglycemia and nocturnal hypoglycemia. Patients with chronic hepatic impairment should be corrected for hepatic functional reserve before glycemic control.

Portal hypertension induces pancreatic congestion and impaired insulin secretion in patients with liver cirrhosis (LC). However, its mechanism is unclear, with no established noninvasive imaging method for the evaluation of its pathogeneses. The present study focused on pancreas stiffness, as assessed by shear wave elastography (SWE), and examined its association with portal hypertension and insulin secretion.

Shear wave elastography and contrast-enhanced ultrasonography were utilized to evaluate pancreas stiffness and congestion, respectively. A glucagon challenge test was used for insulin secretion assessment. Furthermore, rat models of carbon tetrachloride (CCl₄ )-induced LC and portal hypertension were used to identify the direct effects of pancreatic congestion. Immunohistochemistry staining of the pancreas was carried out on human autopsy samples.

Pancreas stiffness measured by SWE was higher in patients with LC than in controls and showed significant correlation with pancreatic congestion. The glucagon challenge test indicated a lower value for the change in C-peptide immunoreactivity in the LC group, which was inversely correlated with pancreas stiffness and congestion. Additionally, portal hypertension and insulin secretion dysfunction were confirmed in CCl₄ rat models. Autopsy of human samples revealed congestive and fibrotic changes in the pancreas and the relationship between insulin secretion and their factors in patients with LC.

In patients with LC, pancreas stiffness measured by SWE could be a potential noninvasive test for evaluating pancreatic congestion and fibrosis due to portal hypertension. Moreover, it was associated with impaired insulin secretion, and could aid in guiding the treatment for hepatogenous diabetes.

Diabetes mellitus (DM) negatively affects the development and progression of chronic liver diseases (CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.

Insulin clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate insulin clearance: from the early surrogate indices employing C-peptide:insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the components of insulin clearance (hepatic versus extrahepatic). The methods are explored and interpreted by critically highlighting advantages and limitations.

The feature of blood glucose dynamics in patients with chronic liver disease (CLD) is marked blood glucose fluctuations. However, the detail of blood glucose dynamics is not well known. The aim of the present study was to evaluate glycemic fluctuations by continuous glucose monitoring (CGM).

A total of 105 CLD patients with type 2 diabetes mellitus (T2DM) were enrolled in this study. Various parameters of glycemic variability were evaluated. The association of these parameters with liver functional reserve was examined. The parameters were also evaluated according to glycated hemoglobin A1c (HbA1c) levels.

Data of all patients showed that mean blood glucose (MBG) levels and the difference between highest and lowest blood glucose (ΔBG) increased significantly with worsening of liver functional reserve (P < 0.001 and P = 0.005, respectively). Although many of the cases were being treated for diabetes, postprandial hyperglycemia was seen in 92% of patients. Nocturnal hypoglycemia was seen in 22% of patients. In non-anemic patients with HbA1c levels of < 7.0%, the percentage of patients with mean amplitude of glycemic excursion (MAGE) of ≥ 77.4 mg/dL and that of MBG levels of > 145 mg/dL were higher in liver cirrhosis (LC) patients than in chronic hepatitis (CH) patients. In them, homeostasis model assessment for insulin resistance (HOMA-IR) of > 2.5 and LC were significantly associated with the increase in MAGE. LC was also significantly associated with increased MBG levels.

The CGM systems were useful in finding hidden abnormalities of blood glucose fluctuations in CLD patients with T2DM, especially in non-anemic CLD patients with HbA1c levels of < 7.0%.

There are discrepancies between studies regarding the effect of diabetes mellitus on morbidity and mortality in patients undergoing liver transplantation. The aim of the present study was to compare mortality, risk of liver graft rejection, and cardiovascular events in patients with and without diabetes undergoing liver transplantation over a 10-year follow-up period.

A retrospective study was performed on 183 patients who underwent liver transplantation in 2005 and 2006. Mortality and morbidity data were collected until 2016, including information on mortality and survival time, graft rejection and graft survival time, coronary heart disease, stroke, and peripheral arterial ischemia.

During the follow-up, 41.3% and 27.8% of patients in the groups with and without diabetes, respectively, died. A trend for lower survival time was observed in patients with diabetes, although this effect was not confirmed by the Cox regression model. There was an increased risk of graft rejection in the group with diabetes compared with the group without diabetes ( P  < 0.001). In the survival analysis, diabetes was associated with reduced graft survival time ( P  = 0.001). Cardiovascular events were also more likely in the group with diabetes ( P  = 0.005).

In the present study diabetes was associated with a higher risk of liver graft rejection and cardiovascular events. There was also a trend for higher mortality, although the effect was not statistically significant. These findings suggest that patients with diabetes require a more rigorous pretransplant evaluation and closer monitoring after transplantation in order to try to reduce associated complications.

By definition, hepatogenous diabetes is directly caused by loss of liver function, implying that it develops after cirrhosis onset. Therefore, it should be distinguished from type 2 diabetes developing before cirrhosis onset, in which specific causes of liver disease play a major role, in addition to traditional risk factors. Currently, although hepatogenous diabetes shows distinct pathophysiological and clinical features, it is not considered as an autonomous entity. Recent evidence suggests that the failing liver exerts an independent "toxic" effect on pancreatic islets resulting in β-cell dysfunction. Moreover, patients with hepatogenous diabetes usually present with normal fasting glucose and haemoglobin A_1c levels and abnormal response to an oral glucose tolerance test, which is therefore required for diagnosis. This article discusses the need to separate hepatogenous diabetes from type 2 diabetes occurring in subjects with chronic liver disease and to identify individuals suffering from this condition for prognostic and therapeutic purposes.

Nonalcoholic fatty liver disease (NAFLD) is frequently associated with insulin resistance (IR) and abnormalities in glucose metabolism. Prevalent postprandial hyperinsulinemia along with insulin resistance in NAFLD may lead to hypoglycemia. This study investigated the prevalence of postprandial oxyhypoglycemia in patients with NAFLD.

The oral glucose tolerance test (OGTT) with 75 g glucose was performed in 375 biopsy-proven NAFLD patients with prior unknown type 2 diabetes mellitus (DM). Serum glucose and insulin levels were measured for 3 h after glucose loading and the clinical parameters were compared.

Normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and DM were observed in 36, 36, and 28 %, respectively. Hypoglycemia (≤70 mg/dL) after 3 h was observed in 14.4 % of all patients. The rate of hypoglycemia was significantly higher in NGT (63 % of NGT) than in IGT (30 % of IGT) and DM (7 % of DM) (P < 0.05). In patients with hypoglycemia, the levels of insulin were significantly higher at 30 and 60 min than those without hypoglycemia (P < 0.05). By multivariate analysis, high-LDL cholesterolemia (P < 0.05), low-HDL cholesterolemia (P < 0.05), and fibrosis (P < 0.05) were significant factors that contributed to hypoglycemia after 3 h on 75 g OGTT.

A relatively higher proportion of NAFLD cases exhibited transient postprandial hypoglycemia after 3 h on OGTT, especially in NAFLD patients with early-stage fibrosis. By performing 75 g OGTT for 3 h, hypoglycemia would be diagnosed earlier and the treatment intervention would decrease the progression of NAFLD and deterioration of glucose metabolism.

The analysis of biological specimens for the presence of exogenous insulin is of special interest in select postmortem investigations. Insulin analogues are primarily used to mediate the regulation of blood glucose concentrations; however, their use has also been implicated or suspected as a cause of death in suicides, accidents, and homicides. Toxicological analysis for these compounds is challenging due to the large molecular weight, the limited stability of insulin in whole blood, and complexities associated with sample preparation and instrumental testing. As a consequence, determination of insulin in postmortem specimens is not routinely offered by most forensic toxicology laboratories. Forensic death investigation is further complicated by interpretative difficulties such as the frequent absence of anatomical findings, concentration interpretation in known insulin users, and addressing the impact of chemical instability and postmortem redistribution. There are ongoing efforts, however, to develop and validate robust methods that may be used for this analysis on these challenging samples and that are capable of withstanding scientific and legal scrutiny for forensic use. In this regard, in recent years, methods for the detection of exogenous insulin in postmortem samples have been reported and results of this testing has been published in a handful of cases. The purpose of this article is to review the primary functions of insulin, the disease states associated with the therapeutic use of exogenous insulin, the current state of laboratory testing, and to provide case summaries that summarize the timeline of advancements and underscore the importance of this work.

Portosystemic shunts (PSS) are abnormal vascular connections between the portal vein or its tributaries and the systemic vein that allow mesenteric blood to reach the systemic circulation without first passing through the liver. PSS can be associated with various syndromes and can lead to serious complications. We report a rare case of a child with PSS and recurrent hypoglycaemia.

A 20-month-old girl with Down's syndrome presented with recurrent hypoglycaemic episodes. She had multiple anomalies including a ventricular septal defect, oesophageal atresia and tracheo-esophageal fistula, gastro-oesophageal reflux, and conjugated hyperbilirubinaemia. The initial investigations suggested hyperinsulinaemic hypoglycaemia (HH). She did not respond to diazoxide. An oral glucose tolerance test suggested postprandial HH. Further vascular imaging showed a side-to-side portocaval shunt (Abernethy malformation) with relative hypoperfusion of the liver. Hypoglycaemia resolved following surgical closure of the portocaval shunt.

PSS can rarely be associated with HH, possibly due to lack of insulin degradation in the liver. Surgical closure of the shunt resolves the hypoglycaemia.

The main objective of this study is to demonstrate whether carbohydrate metabolism alterations identified in patients with advanced cirrhosis show any improvement after liver transplant.

The study included 86 patients who underwent liver transplant between March 2010 and February 2011. An oral glucose tolerance test was performed before the liver transplant, and 6 and 12 months after. Beta cell function and insulin resistance were also calculated, applying formulae that use basal plasma glycaemia and insulin, and plasma glycaemia and insulin during an oral glucose tolerance test. Risk factors for pre- and post-transplant diabetes were also studied. The diagnosis of diabetes was based on an OGTT.

The proportion of patients with diabetes before transplant, and at month 6 and 12 after transplant were 70.9%, 48.8% and 39.2%, respectively. Compared to baseline, at month 6 the odds ratio of having diabetes was 0.39 (IC 95% [0.21, 0.73]) and at month 12 it was 0.26 (IC 95% [0.14, 0.50]). The composite insulin sensitivity index values at 6 and 12 months were 1.72 units higher (IC 95% [0.84, 2.58]) and 1.58 units higher (IC 95% [0.68, 2.44)] than baseline. A statistically significant association was found between high MELD values and high body mass index, and risk of pre-transplant diabetes (p=0.001 and p=0.033, respectively). Cirrhosis aetiology did not influence the risk of diabetes.

In this study, we were able to ascertain that alterations in carbohydrate metabolism typical of advanced cirrhosis improve after liver transplant. This improvement is mainly due to an improvement in insulin resistance.

Glucose intolerance in patients with liver cirrhosis (LC), known as hepatogenous diabetes, is thought to be distinct from type 2 diabetes (T2DM) in some aspects. Hyperinsulinemia and/or insulin resistance in liver disease is associated with hepatocarcinogenesis, growth of hepatocellular carcinoma, and poor prognosis. However, the pathophysiological processes in islets that are responsible for hyperinsulinemia in LC are still not precisely known. Therefore, we investigated the histopathological differences in islets of Langerhans cells between LC and T2DM.

A total of 35 human autopsy pancreatic tissue samples were used in this study (control, n = 18; T2DM, n = 6; LC, n = 11). The expression of insulin, glucagon, somatostatin, pancreatic duodenal homeobox-1 (PDX-1), proliferating cell nuclear antigen (PCNA), and Ki-67 was examined using immunohistochemistry and quantitated by image analysis.

Islet hypertrophy and a significant increase in PCNA-positive cells in islets were observed in the tissues from LC cases. The insulin-positive areas in islets were significantly decreased in LC cases compared with control and T2DM cases (P = 0.001, P = 0.035, respectively), whereas the PDX-1-positive area was significantly increased in LC cases (P = 0.001) compared with the control. Furthermore, disorganization of pancreatic endocrine cells and nucleocytoplasmic translocation of PDX-1 were both seen in the LC subjects.

In LC, islets undergo hypertrophy and exhibit paradoxical expression of insulin and PDX-1. In the subjects autopsied, insulin expression was decreased, whereas expression of the pancreatic transcription factor PDX-1 was increased in LC. These results point to important distinctions between LC and T2DM.

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes. Distinctive factors including hepatic parenchymal cell damage, portal-systemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes. Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes, retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure, hepatocellular carcinoma and gastrointestinal hemorrhage. Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes. Moreover, exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis. Thus, pathogenesis, cause of death, assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes. In this article, we review features of insulin resistance in relationship to chronic liver disease. We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.

It is well known that a large portosystemic shunt develops during portal hypertension. In this study, we studied the long-term effects of a large splenorenal shunt (SRS) on liver function and survival.

The subjects were divided into three groups: an SRS (-) group consisting of cirrhotic patients without SRS; an SRS (+) group consisting of patients with gastric fundal varices and SRS; and a balloon-occluded retrograde transvenous obliteration (B-RTO) group with a completely obliterated SRS by B-RTO. We compared the following among these groups: the total bilirubin levels, serum albumin levels, prothrombin times, changes in Child-Pugh scores, and survival rates.

After a 3-year follow-up period the Child-Pugh scores showed significant differences among the SRS (+), SRS (-), and B-RTO groups. The score worsened for the SRS (+) group. The cumulative survival rates were significantly different between the SRS (+) and SRS (-) groups and between the SRS (+) and B-RTO groups. The vital prognosis worsened for the SRS (+) group.

The presence of a large splenorenal shunt (portosystemic shunt) was indicated to lower liver function and vital prognosis. B-RTO, which completely obliterates large splenorenal shunts, inhibited the lowering of hepatic functional reserve and the worsening of vital prognosis, indicating a protective role. Liver pathology and the presence of a large portosystemic shunt each separately result in progressive liver dysfunction and worsen the survival rate. We found that such a pathological condition had occurred due to a large portosystemic shunt, and it should be called 'portosystemic shunt syndrome.'

The contribution of decreased hepatic insulin extraction to the relative hyperinsulinemia after oral glucose load as compared to intravenous glucose load was studied in 6 normal weight male volunteers by means of an analysis of the relationship between peripheral venous concentrations of insulin and C-peptide following similar glycemic stimuli after oral and intravenous glucose administration. The incremental areas under the insulin and C-peptide curves were higher during oral as compared to intravenous glucose administration, 436 (251--762) per cent and 267 (124-378) per cent respectively (mean and range). The ratio between corresponding incremental areas of insulin and C-peptide were 53 (17--103 per cent higher during oral glucose load. These findings suggest that the augmented peripheral insulin levels after oral glucose administration are caused by a combination of increased beta cell secretion and decreased hepatic insulin extraction.

Imbalance of circulating branched chain amino acids (BCAA) versus aromatic amino acids (AAA) and hyperinsulinemia are common metabolic alterations in patients with liver cirrhosis. The aim of this study was to characterize the effect of the carbohydrate component of a protein-rich mixed meal on postprandial plasma concentrations of 21 amino acids, insulin and C-peptide in patients with compensated liver cirrhosis. Furthermore, the effect of a dietary intervention on the metabolic alterations in cirrhotic patients was examined.

Eighteen patients with cirrhosis and 12 healthy volunteers received a protein-rich meal (pork filet 200 g) with or without carbohydrates (bread 50 g, glucose 20 g). A subgroup of four cirrhotic patients received an isoenergetic (117 kJ/kg bw) carbohydrate-enriched (60%) and -restricted (20%) diet for 7 days each.

In the cirrhotic patients, basal plasma insulin and C-peptide concentrations were significantly elevated. The ingestion of a protein-rich meal without additional carbohydrates led to a significantly greater increase of insulin and C-peptide in the cirrhotic patients compared to controls. Postprandial increases of leucine and isoleucine were reduced, whereas those of phenylalanine were higher in cirrhotic patients. The addition of carbohydrates led to higher insulin and C-peptide plasma concentrations in cirrhotic patients. Postprandial BCAA increases were more impaired in the cirrhotic group after additional carbohydrate ingestion (46%vs 82%). After the carbohydrate-restricted diet for 7 days BCAA plasma levels increased but the BCAA/AAA ratio remained unaltered.

The carbohydrate content of a meal enhances reduction of BCAA plasma concentrations in clinically stable cirrhotic patients. An imbalanced BCAA/AAA ratio cannot be avoided by a carbohydrate-reduced diet alone, supporting mandatory BCAA supplementation.

The liver plays a key-role in carbohydrates metabolism. Glucose intole-rance, overt diabetes mellitus and insulin resistance are characteristic features of patients with cirrhosis. Central hyperinsulinemia and peripheral insulin-resistance are the main explanations for the high prevalence of diabetes in patients with cirrhosis. On the other hand, type 2 diabetes is associated with a wide spectrum of liver diseases ranging from nonalcoholic fatty liver to cirrhosis and hepatocellular carcinoma. Carbohydrate metabolism abnormalities are a major aggravating risk factor in cirrhosis. Diabetes is also an independent negative prognostic factor in cirrhotic patients. This leads to specific diagnostic procedures and therapeutic issues. Patients with diabetes and liver disease frequently need insulin treatment. The presence of liver disease makes the treatment of diabetes complex, and additional research is needed to determine the best treatment strategies in these patients.

Valproate (VPA) treatment has been reported to be associated with obesity and high fasting serum insulin concentrations in parallel with an unfavorable serum lipid profile and hyperandrogenism and polycystic ovaries in women. The pathogenetic mechanism underlying these changes has remained unknown, although several mechanisms have been implicated.

Fifty-one patients receiving monotherapy (31 male and 20 female patients) were included in this study, with 45 (23 male and 22 female) healthy control subjects. These participants were interviewed, clinically examined, and blood samples for fasting plasma glucose, serum insulin, proinsulin, and C-peptide concentrations were taken after an overnight fast.

The valproate-treated patients had fasting hyperinsulinemia (11.30 +/- 6.23 pM vs. 6.28 +/- 4.66 pM in the control subjects; p < 0.001), although the fasting serum proinsulin and C-peptide concentrations were not significantly higher in the patients than in the control subjects. In addition, proinsulin/insulin (0.30 +/- 0.14) and C-peptide/insulin ratios (35.48 +/- 24.09) were lower (p < 0.001) in the VPA-treated patients when compared with the control subjects (0.53 +/- 0.36 and 94.27 +/- 61.85, respectively), and they also had lower fasting plasma glucose concentrations (4.72 +/- 0.35 mM) than the control subjects (5.12 +/- 0.58 mM; p < 0.01).

This study suggests that valproate does not induce insulin secretion but might interfere with the insulin metabolism in the liver, resulting in higher insulin concentrations in the peripheral circulation. These changes are seen irrespective of concomitant weight gain, suggesting that increased insulin concentrations induce weight gain and not vice versa.

Treatment options for advanced hepatocellular carcinoma (HCC) remain limited. Recently, octreotide has been proposed for therapy, although its efficacy remains controversial. Thus, the aim of this open-label pilot study was to evaluate the response of HCC to long-acting octreotide (Sandostatin LAR). Thirty patients were enrolled for this prospective 2-year trial. Initially, patients were given short acting octreotide to ensure drug tolerability. Thereafter, patients received long-acting octreotide 30 mg IM every 4 to 6 weeks. Measurable disease was assessed at 3-month intervals. Five of 30 patients were unable to tolerate the test dose, and 1 patient was reevaluated and underwent hepatic resection. The remaining 24 patients, who received long-acting octreotide, all had advanced stage of disease with multifocal-massive morphology (67%), vascular thrombosis (63%), or extrahepatic spread (17%), but well compensated liver disease. The treatment was well tolerated, except for diarrhea. Median time to tumor progression was 3.6 months, and median survival was 5.1 months. Seven patients (29%) had stable disease (median duration of 8.0 months) with 2 patients demonstrating disease stability for 24 months. In conclusion, although occasional patients appear to have stable disease on long-acting octreotide therapy, overall the beneficial response in terms of time to tumor progression and survival is limited.

Diabetes mellitus (DM) is frequently observed in patients with chronic hepatitis caused by hepatitis C virus infection (CHC). The present study was designed to determine the pathogenic factors responsible for glucose intolerance in CHC patients.

A total of 131 patients with CHC were enrolled in this study. Insulin resistance and beta-cell function were determined after 75 g oral glucose tolerance tests.

Glucose intolerance was detected in 27.5% (36/131) of CHC patients; 10 had DM and 26 impaired glucose tolerance. HOMA-R [insulin 0xglucose 0/22.5] was greater in patients with both impaired glucose tolerance and DM than in those with normal glucose tolerance (P<0.01). Matsuda index [10(4)/ (square root) (mean insulinxmean glucosexglucose 0xinsulin 0)] was lower in diabetic patients than in those with normal glucose tolerance (P<0.05). The insulinogenic index [Deltainsulin 30-0/Deltaglucose 30-0] and DeltaC-peptide 30 [DeltaC-peptide 30-0/Deltaglucose 30-0] were significantly lower even in patients with impaired glucose tolerance than in patients with normal glucose tolerance (P<0.01).

Both insulin resistance and beta-cell dysfunction contribute to glucose intolerance in CHC patients.

Host factors such as increased body mass index (BMI) and genotype-specific viral factors contribute to the development of steatosis in patients with chronic hepatitis C (HCV). We hypothesized that host metabolic factors associated with increased BMI may play a role in disease progression.

Fasting serum was collected from 160 patients with chronic HCV at the time of liver biopsy and 45 age, gender and BMI matched controls, and assessed for levels of insulin, c-peptide and leptin.

Patients with viral genotype 3 had more severe steatosis (P=0.0001) and developed stages 1 and 2 fibrosis at a younger age (P<0.05) than patients with genotype 1. For both genotypes, overweight patients had significantly more steatosis and increased insulin and leptin levels. In contrast to lean patients, there was a statistically significant increase in circulating insulin levels with increasing fibrosis in overweight patients with chronic HCV (P=0.03). Following multivariate analysis, insulin was independently associated with fibrosis (P=0.046) but not inflammation (P=0.83). There was no association between serum leptin levels and stage of fibrosis.

Increasing circulating insulin levels may be a factor responsible for the association between BMI and fibrosis in patients with HCV, irrespective of viral genotype.

The aim of this study was to investigate the cause of increased incidence of impaired glucose tolerance and diabetes mellitus in patients with alpha-thalassaemia major and chronic hepatitis C virus (HCV) infection without cirrhosis of the liver.

The study included 28 alpha-thalassaemic multi-transfused patients (14 females and 14 males; age, 25.7 +/- 6.3 years) with normal fasting glucose levels. Sixteen were seropositive for HCV and they had biopsy proven chronic hepatitis C without cirrhosis. An oral glucose tolerance test (OGTT) was performed. Glucose, insulin and C-peptide levels were measured every 30 min for 2 h. Fasting insulin resistance index (FIRI) was calculated according to the formula: FIRI = (fasting glucose x fasting insulin)/25.

All patients had a normal OGTT except for two HCV positive and two HCV negative patients who had impaired glucose tolerance. HCV positive patients had higher fasting insulin levels (P = 0.02), higher fasting insulin/fasting glucose ratio (P = 0.017) and higher FIRI (P = 0.016) than HCV negative patients. During the OGTT, peak insulin levels occurred at 30 min in HCV negative patients but at 60 min in HCV positive. HCV infected patients had higher mean value of insulin at 60 (P = 0.017), 90 (P = 0.04), and 120 min (P = 0.04), and higher mean increment above basal at 60 (P = 0.015), 90 (P = 0.018) and 120 min (P = 0.05). The area under the curve (AUC) of insulin was also greater in HCV positive patients as compared to HCV negative (P = 0.04), although the AUC of glucose and the glucose levels at all time points of the OGTT were similar in both groups.

The findings of this study show that alpha-thalassaemic patients with HCV infection without liver cirrhosis are more insulin resistant and have delayed insulin secretion compared to HCV negative alpha-thalassaemic patients. These changes in insulin action and secretion are evident before the development of impaired glucose tolerance and may explain the higher prevalence of diabetes mellitus in this group.

Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinemia. Both increased insulin secretion and decreased insulin clearance appear to contribute to hyperinsulinemia in cirrhotic patients. A decrease in hepatic insulin extraction rate may be due either to hepatocellular dysfunction or to portosystemic shunting with decreased first-pass insulin clearance.

To specifically address the contribution of portosystemic shunting to the pathogenesis of hyperinsulinemia in cirrhotic patients, we analyzed glycemic control and insulin levels in fasting serum in 23 cirrhotic patients before and after transjugular intrahepatic portosystemic shunt (TIPS).

Compared to respective values in healthy controls, C-peptide, insulin and proinsulin concentrations at baseline were increased by 340%, 120% and by 100% in cirrhotic patients (all p<0.05). In cirrhotic patients insulin levels before TIPS averaged 104+/-73 pmol/l and increased by more than 50% to 163+/-118 pmol/l after TIPS (p<0.01), whereas levels of C-peptide and proinsulin showed no significant change. Glucose and fructosamin levels also remained unchanged after TIPS.

Our data demonstrate that TIPS does not impair glycemic control in cirrhotic patients and that an increase in portosystemic shunting augments hyperinsulinemia, most likely by decreasing hepatic insulin clearance.

Four cases of self-injected insulin overdose in nondiabetic individuals are presented. Included are two cases of presumed insulin overdose (no autopsy), one case with elevated vitreous insulin (autopsy), and one case with elevated postmortem blood insulin and low blood C peptide (autopsy). These cases demonstrate the need for a thorough scene investigation, complete autopsy, and proper collection and storage of specimens to certify a death caused by insulin intoxication as well as to determine the manner of death. Appropriate collection and preservation of postmortem blood samples are discussed.

Although basal circulating levels of individual islet cell hormones have been measured, few studies compared the molar ratios of the major hormones secreted by the endocrine pancreas. This study examined the basal levels of four major islet hormones: insulin, C-peptide (C-P), glucagon (G), and pancreatic polypeptide (PP) in normal subjects, in organ donors with brain death, and in the isolated perfused human pancreas. Basal blood samples were taken from normal, fasted control subjects (NCs). Pancreata were obtained from 17 organ donors (ODs) with donor portal vein (DPV) and radial arterial (DRA) blood samples taken before organ procurement. Single-pass perfusion was performed on the procured pancreata, and after rewarming and equilibration, basal samples were collected from the splenic vein (SV) for 30 min. Radioimmunoassays of insulin, C-P, G, and PP were performed on all samples, and basal levels of all hormones were expressed as a common unit, femtomoles per milliliter. The data suggest that in the basal state, these four major islet hormones circulate in a relatively constant molar ratio. The ratio of the hormones is altered in brain death and with in vitro perfusion of the pancreas. The isolated perfused human pancreas secretes a relatively constant molar ratio of these hormones; however, this ratio is markedly different from the circulating ratio seen in either the NC group or the OD group. We conclude that a relatively constant hormonal milieu is secreted from the normal endocrine pancreas, and this hormonal milieu is altered after brain death and with isolation and perfusion of the human pancreas.

Diabetes mellitus frequently complicates cirrhosis but the pathogenic mechanisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic-diabetic patients waiting for liver transplant because of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the beta-cell function and an insulin clamp combined with [3-(3)H]glucose infusion to measure whole body glucose metabolism before and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a profound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P <.05) and insulin deficiency during the OGTT (P <.05). Liver transplantation normalized endogenous glucose production and insulin sensitivity but failed to cure diabetes in 8 of the 24 patients because a markedly low insulin response during the OGTT. Age, body mass index, family history of diabetes, immunosuppressive drugs, and pathogenesis of cirrhosis did not predict in whom liver transplant was going to cure diabetes. On the contrary, a reduced secretory response characterized the patients in whom the transplant would not be curative. In summary, insulin resistance was a primary event complicating cirrhosis but additional beta-cell secretory defects were crucial for development of diabetes. Liver transplantation, lessening insulin resistance, cured hepatogenous diabetes in 67% of cirrhotic-diabetic patients; nevertheless 33% were still diabetics because the persistence of a reduced beta-cell function, which makes these patients eventually eligible for combined islet transplantation.

Nonalcoholic fatty liver disease is frequently associated with type 2 diabetes mellitus, obesity, and dyslipidemia, but some patients have normal glucose tolerance or normal weight. We tested the hypothesis that there is an association between nonalcoholic fatty liver disease and insulin resistance that is independent of diabetes and obesity.

We measured anthropometric and metabolic variables in 46 patients with chronically elevated serum aminotransferase levels, "bright liver" on ultrasound scan, and normal glucose tolerance. Indexes of insulin resistance and secretion were determined using the homeostasis model assessment method. They were compared with 92 normal subjects who were matched for age and sex.

Patients with nonalcoholic fatty liver disease were characterized by fasting and glucose-induced hyperinsulinemia, insulin resistance, postload hypoglycemia, and hypertriglyceridemia. Insulin resistance [odds ratio (OR) = 15 per percent increase, 95% confidence interval (CI): 3.0 to 70], fasting triglyceride level (OR = 3.1 per mmol/liter increase, 95% CI: 1.1 to 8.9), 180-minute blood glucose level (OR = 4.3 per mmol/ liter decrease, 95% CI: 1.6 to 12), and average insulin concentration in response to oral glucose (OR = 3.0 per 100 pmol/liter increase, 95% CI: 1.5 to 6.2) were independently associated with nonalcoholic fatty liver disease. The exclusion of overweight and obese subjects did not change the results.

Nonalcoholic fatty liver disease is associated with insulin resistance and hyperinsulinemia even in lean subjects with normal glucose tolerance. Genetic factors that reduce insulin sensitivity and increase serum triglyceride levels may be responsible for its development.

Non-insulin-dependent diabetes mellitus (NIDDM) may be associated with chronic hepatitis C virus (HCV) infection. This was studied further in two parts. First, 1,151 patients with HCV-related cirrhosis and 181 patients with hepatitis B virus (HBV)-related cirrhosis, well matched for age, sex, and severity of cirrhosis, were reviewed retrospectively. The prevalence of diabetes mellitus was higher in HCV-related cirrhosis (23.6%) than in HBV-related cirrhosis (9.4%; odds ratio [OR], 2.78; 95% confidence interval [CI], 1.6-4.79; P =.0002). The prevalence of diabetes mellitus was associated closely with the Child-Pugh score (OR, 3.83; 95% CI, 2. 38-6.17; P <.0001) and increasing age (OR, 1.02; 95% CI, 1.00-1.03; P =.0117). Second, 235 patients with biopsy confirmed chronic HBV or HCV underwent an oral glucose tolerance test. Only 1 of 70 patients with chronic viral hepatitis without cirrhosis was diabetic. However, 31 of 127 patients with HCV-related cirrhosis (24.4%) were diabetic compared with 3 of 38 patients with HBV-related cirrhosis (7.9%, P =.0477). The major variables associated with NIDDM were cirrhosis (OR, 14.39; 95% CI, 1.91-108; P =.0096) and male sex (OR, 4.64; 95% CI, 1. 32-16.18; P =.0161). Fasting insulin levels in 30 patients with HCV-related cirrhosis and diabetes mellitus were elevated significantly, which was consistent with insulin resistance. However, acute insulin responsiveness was reduced in all patients with HCV infection and diabetes suggesting concomitant B-cell dysfunction. This study confirms an association between HCV and NIDDM.

Patients with liver cirrhosis are insulin-resistant and frequently glucose-intolerant. Although peripheral glucose uptake has been shown to be impaired in liver cirrhosis, little is known about the significance of splanchnic (hepatic) glucose uptake after oral glucose load.

We performed an oral glucose tolerance test and euglycemic hyperinsulinemic clamp with oral glucose load for eight patients with liver cirrhosis and eight patients with chronic active hepatitis. The patients with liver cirrhosis had higher plasma glucose levels 2 h after glucose load than those with chronic active hepatitis (228+/-22 mg/dl vs. 102+/-9 mg/dl, p<0.01). Using the euglycemic hyperinsulinemic clamp with oral glucose load, we simultaneously measured peripheral and splanchnic glucose uptake. Peripheral glucose uptake in liver cirrhosis was 6.1+/-0.7 mg x kg(-1) x min(-1), which was lower than that in healthy volunteers (10.5+/-0.9 mg x kg(-1) x min(-1), p<0.05) and in chronic active hepatitis (8.4+/-0.3 mg x kg(-1) x min(-1), p<0.05). Furthermore, splanchnic glucose uptake in liver cirrhosis was much lower (20.1+/-3.4%) than in healthy volunteers (36.0+/-4.0%, p<0.05) and in chronic active hepatitis (37.2+/-3.1%, p<0.05).

These results suggest that glucose intolerance in patients with liver cirrhosis is caused by a defect of the glucose uptake of both splanchnic and peripheral tissues.

Insulin and insulin-like growth factor (IGF-1) are mitogenic for fibroblasts and smooth muscle cells. IGF-1 increases in inflamed and fibrotic tissues and induces proliferation of rat hepatic stellate cells (HSC). This study evaluates the potential roles of these hormones in the development of liver fibrosis. Insulin and IGF-1 receptor expression was evaluated by immunohistochemistry in both cultured human HSC and human liver tissue. Phosphorylation of both 70-kd S6 kinase and extracellular-regulated kinase (ERK), cell proliferation, type I collagen gene expression, and accumulation in HSC culture media were evaluated by Western blot, immunohistochemistry for bromodeoxyuridine (BrdU), Northern blot, and enzyme-linked immunosorbent assay, respectively. Insulin and IGF-1 receptors were detected in HSC in vitro and in liver sections from patients with chronic active hepatitis. Insulin and IGF-1 induced 70-kd S6 kinase phosphorylation in HSC, whereas IGF-1 only induced ERK phosphorylation. Insulin and IGF-1 stimulated HSC proliferation in a dose-dependent fashion, with IGF-1 being four to five times more potent than insulin. Cell exposure to specific inhibitors showed that both phosphatidylinositol 3-kinase (PI3-K) and ERK are involved in IGF-1-induced mitogenesis, whereas insulin stimulated mitogenesis through a PI3-K-dependent ERK-independent pathway. IGF-1 increased type I collagen gene expression and accumulation in HSC culture media through a PI3-K- and ERK-dependent mechanism. In conclusion, insulin and IGF-1, which stimulate HSC mitogenesis and collagen synthesis, may act in concert to promote liver fibrosis in vivo by a differential activation of PI3-K- and ERK1-dependent pathways.

Obesity is a rapidly increasing health problem among US youth. Hyperinsulinemia is associated with obesity and has been found to be a contributory factor for the development of cardiovascular disease in the obese. It has been suggested that hyperinsulinemia of obesity is a result of increased insulin secretion caused by insulin resistance. However, it has been shown in adults that decreased hepatic insulin clearance (HIC) is the primary cause of hyperinsulinemia in this population.

We studied 15 obese children and adolescents (11 F, 4 M; 8.6 to 18.1 years) before and 10 weeks after their enrollment in a multidisciplinary weight reduction program, which included a protein-sparing modified fast, a moderate intensity progressive exercise program, and a behavior-modification intervention.

All patients lost weight (P < 0.05). Measurements of immunoreactive insulin (IRI) and C-peptide reactivity (CPR) were performed before the program and at 10 weeks. IRI levels dropped significantly, whereas CPR levels did not change. CPR/IRI molar ratios, considered an indirect estimation of HIC, rose significantly after weight loss.

Our data suggest that hyperinsulinemia seen in obese children and adolescents is caused by decreased HIC. The cause for this decrease remains unknown, but it is reversible upon weight loss.

Serum insulin, and plasma glucagon and glucose levels were measured in 56 Chinese patients with aplastic anemia (AA) and 40 normal controls. Serum insulin and plasma glucose levels in 18 newly diagnosed cases and 11 previously treated cases with prednisone were significantly higher than those in the controls. Serum insulin and plasma glucose levels in 27 cases previously treated with stanozolol were significantly higher than those in the newly diagnosed cases and the previously treated cases with prednisone. There was no significant difference in plasma glucagon levels between the patients and the controls. Serum insulin and plasma glucose levels were significantly correlated with the amount of blood transfusions and serum ferritin and cortisone concentrations in the AA patients. Our findings suggest that AA patients may have hyperinsulinemia accompanying hyperglycemia, which can be further aggravated by stanozolol and prednisone therapy and iron overload.

Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis.

A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels.

There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group.

These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.

Glucose intolerance and impaired insulin secretion are often associated with obstructive jaundice. Our objective was to determine whether such abnormalities would be ameliorated after jaundice was relieved by biliary drainage.

Twenty-four patients with hepatobiliary malignancy prospectively underwent intravenous glucose tolerance test with femoral and portal blood sampling, and the kinetics of insulin release were determined. Sixteen patients had obstructive jaundice (group A) that had been completely relieved by percutaneous transhepatic biliary drainage by the time of intravenous glucose tolerance testing, and eight patients exhibited no jaundice (group B).

Integrated immunoreactive insulin (sigmaIRI, 10 muU min/ml; mean +/- SD) and integrated C-peptide (sigmaCPR, 10 ng min/ml) in the portal blood in group A were significantly lower than those values in group B (sigmaIRI: group A, 436.0 +/- 260.6; group B, 714.3 +/-287.2; p< 0.01; sigmaCPR; group A, 26 +/- 10.1; group B 49.5 +/- 18.8; p<0.005). The hepatic insulin extraction ratio (portal-femoral difference of sigmaIRI divided by portal sigmaIRI) in group A was significantly higher than that in group B (group A, 0.75 +/- 0.06; group B, 0.55 +/- 0.05; p<0.001), whereas the hepatic CPR extraction ratio did not differ significantly between the two groups (group A, 0.37 +/- 0.10; group B, 0.39 +/- 0.05).

The impaired insulin secretion caused by obstructive jaundice is not fully reversed after percutaneous transhepatic biliary drainage. The high hepatic extraction ratio of insulin in patients who had been treated with percutaneous transhepatic biliary drainage may compensate for the impaired insulin secretion, although its mechanism is still unclear.

Insulin and glucagon are thought to play important roles as hepatotrophic factors in acute viral hepatitis (AVH); however, few reports have investigated the responses and relationships of each of these hormones to liver damage in detail. We studied insulin and glucagon responses during the acute and recovery phases of AVH. We performed a glucose tolerance test (GTT) and an insulin sensitivity test (IST) in each phase in 11 patients with AVH. In 8 additional patients in the acute phase (total n = 19), were compared immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR) levels with transaminase levels. In the acute phase, IRI concentrations were normal from fasting to 60 min, despite an increased CPR level. In the recovery phase, IRI and CPR levels increased significantly. Immunoreactive glucagon levels in both phases did not differ significantly from those in controls. During the IST, the insulin sensitivity index in both phases was significantly lower than that in the controls. Fasting IRI and sigma IRI showed significant negative correlations with transaminase levels. We found enhanced insulin secretion and a decrease in plasma insulin in the acute phase of AVH. The discrepancy between IRI and CPR responses in the acute phase suggests an increase in the degradation or consumption of insulin in the liver.

Abnormalities of carbohydrate metabolism, including hyperinsulinaemia and insulin resistance, are well recognised complications of cirrhosis. While diabetes mellitus can be explained in many instances on the basis of coincident pancreatic disease, in most the characteristic glucose intolerance of cirrhosis is not readily explicable. A previous clinical observation that hepatitis C virus infection and diabetes mellitus appeared to be associated was formally tested by a retrospective review of 100 consecutive adult patients with cirrhosis undergoing assessment for liver transplantation. Hepatitis C virus was diagnosed by conventional serological and histological criteria. Twenty-three patients had diabetes mellitus, of whom 18 were being treated with insulin. Of the 34 patients with hepatitis C virus-related cirrhosis, 17 (50%) had diabetes mellitus, in contrast to just six (9%) of the 66 patients with cirrhosis unrelated to hepatitis C virus (chi2 = 19.1, p < 0.0001) with an odds ratio for hepatitis C virus by diabetes mellitus status 10.0 (95% confidence interval 3.4 to 29.3). Hierarchical loglinear model analysis of those factors of potential relevance to the development of diabetes mellitus revealed that only hepatitis C virus interacted significantly with diabetes mellitus while the relation between diabetes mellitus and origin, sex, body mass index and severity of cirrhosis was conditional. By multiple logistic regression analysis of diabetes mellitus status in relation to the same variables, only hepatitis C virus status was statistically significant (p < 0.0001). Origin, sex, severity of cirrhosis, body mass index and therapy were not significantly associated.(ABSTRACT TRUNCATED AT 250 WORDS)