c-peptide and Liver-Cirrhosis

Topics: C-Peptide; Carbohydrate Metabolism; Glucose Tolerance Test; Hepatitis, Viral, Human; Humans; Hypoglycemia; Insulin; Insulin Resistance; Liver Cirrhosis; Liver Diseases

It was observed that type II diabetes mellitus associated with chronic liver failure improved after stem cell transplantation. However, there were no adequate studies regarding this issue. The aim of this study was to evaluate the effect of stem cell transplantation on associated type II diabetes mellitus and on the liver function tests.. This pilot study included 30 patients of post-hepatitis chronic liver failure who were classified into two groups: Group I included patients with chronic liver cell failure associated with type 2 diabetes. Group II included patients without type II diabetes. Autologous CD34+ and CD133+ stem cells were percutaneously infused into the portal vein. Responders (regarding the improvement of diabetes as well as improvement of liver condition) and non-responders were determined. Patients were followed up for one, three and six months after the intervention evaluating their three-hour glucose tolerance test, C- peptide (Fasting and postprandial), Child-Pugh score and performance score one month, three months, and six months after stem cell therapy.. Both synthetic and excretory functions of the liver were improved in 10 patients (66.66 %) of group I and in 12 patients (80 %) of group II. Significant improvement in the Oral Glucose Tolerance Test in the responders of both the groups was well defined from the 3rd month and this was comparable to changes in liver function tests and Child-Pugh score.. Successful stem cell therapy in chronic liver cell failure patients can improve but not cure the associating type 2 diabetes by improving insulin resistance.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Egypt; End Stage Liver Disease; Fasting; Female; Follow-Up Studies; Glucose Tolerance Test; Hepatitis C; Humans; Insulin; Insulin Resistance; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Pilot Projects; Stem Cell Transplantation; Treatment Outcome

Cirrhosis of the liver is characterised by insulin resistance and low levels of insulin-like growth factor I (IGF-I). Lack of IGF-I may contribute to this insulin resistance, as IGF-I increases insulin sensitivity. This study aimed to determine the effects of normalisation of IGF-I on insulin action in cirrhosis.. This article is a randomised sequence-crossover placebo controlled study. Eight patients with cirrhosis and eight controls were studied following treatment with IGF-I (50 μg/kg twice daily) or saline. Insulin action, glucose utilisation and endogenous glucose production were measured during the euglycaemic hyperinsulinaemic clamp.. The patients with cirrhosis had normal fasting glucose level, but increased levels of insulin (P < 0.05) and C-peptide (P < 0.05). Insulin resistance resulted from a defect in glycogen synthesis, whereas insulin-mediated suppression of glucose production was unaltered. In cirrhosis, IGF-I treatment normalised free (from 0.07 ± 0.01 to 0.26 ± 0.05 μg/L) and total IGF-I (from 73 ± 6 to 250 ± 39 μg/L), whereas in controls, the IGF-I level increased into the upper physiological range (free IGF-I from 0.23 ± 0.02 to 0.61 ± 0.06 μg/L; total IGF-I from 200 ± 19 to 500 ± 50 μg/L) (all P-values < 0.05). In cirrhosis, IGF-I treatment did not change fasting glucose, insulin or C-peptide levels (P > 0.05). In the controls, insulin and C-peptide levels decreased (P < 0.05). IGF-I treatment did not improve insulin sensitivity in cirrhosis.. Because normalisation of IGF-I levels did not affect insulin sensitivity lack of IGF-I is unlikely to result in insulin resistance in cirrhosis. IGF-I supplementation is therefore unlikely to improve insulin action in patients with cirrhosis.

Topics: Blood Glucose; C-Peptide; Cross-Over Studies; Fatty Acids, Nonesterified; Fluoroimmunoassay; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Liver Cirrhosis; Male; Middle Aged; Radioimmunoassay; Statistics, Nonparametric

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.

Topics: Adult; Amino Acids; Amino Acids, Aromatic; Amino Acids, Branched-Chain; C-Peptide; Circadian Rhythm; Dietary Carbohydrates; Dietary Proteins; Female; Humans; Insulin; Insulin, Long-Acting; Liver Cirrhosis; Male; Middle Aged

Insulin resistance is present in nearly all patients with liver cirrhosis, but its etiology remains unclear. Recent studies have shown that tumor necrosis factor-alpha (TNF-alpha) system is involved in the insulin resistance of human obesity. Serum concentrations of TNF-alpha, and 2 soluble TNF receptors (sTNF-RI and sTNF-RII) are increased in cirrhotic patients. This study explored whether TNF-alpha system activity was associated with insulin resistance in liver cirrhosis. A total of 26 male nondiabetic patients with liver cirrhosis (mean age, 59 +/- 3 years; body mass index, 23.7 +/- 0.4 kg/m2) and 25 male control subjects (age, 65 +/- 2 years; body mass index, 24.4 +/- 0.5 kg/m2) were studied. Serum insulin, c-peptide, TNF-alpha, sTNF-RI, and sTNF-RII concentrations were determined by immunoassay. The insulin resistance was estimated by homeostasis assessment model (HOMA IR). In cirrhotic patients, serum levels of TNF-alpha, sTNF-RI, and sTNF-RII were all higher than those in the controls, and correlated with disease severity. Also, the serum c-peptide, insulin concentrations, and the HOMA IR were higher in liver cirrhosis with comparable blood glucose to control subjects, indicating a degree of insulin insensitivity. In the whole population, there was a moderate, but statistically significant, correlation between serum sTNF-RI or sTNF-RII, and HOMA IR. Also, body mass index was associated with HOMA IR, but not related to serum TNF-alpha, and sTNF-Rs levels. In multiple regression analysis, both sTNF-RII and body mass index jointly contributed to 30% variance of HOMA IR. Our study demonstrated that elevated sTNF-RII levels were associated with insulin resistance in liver cirrhosis. The data indicated that TNF-alpha system might play a role in modulating insulin action in patients with liver cirrhosis.

Topics: Aged; Aging; Body Mass Index; C-Peptide; Cytokines; Homeostasis; Humans; Immunoassay; Insulin; Insulin Resistance; Interleukin-6; Liver Cirrhosis; Male; Middle Aged; Receptors, Tumor Necrosis Factor; Regression Analysis

Dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers plasma lactic acid concentration. Three potential mechanisms could underlie the hypolactatemic action of DCA, but the dominant mechanism in vivo remains unclear. This study tested whether DCA-induced hypolactatemia occurs via decreased lactate production, increased lactate clearance, or decreased rate of glycolysis in healthy humans and in patients with end-stage cirrhosis. Cirrhosis is associated with decreased hepatic pyruvate dehydrogenase (PDH) content. Six healthy volunteers and 7 cirrhotic patients received a primed, constant infusion of 1-13C-pyruvate and 15N-alanine for 5 hours. DCA (35 mg/kg intravenously) was administered at 2 hours. Plasma isotopic enrichment was measured by gas chromatography/mass spectrometry (GC/MS), and exhaled CO2 enrichment by isotope ratio mass spectrometry. Pyruvate and alanine production rates (Ra) were determined by isotope dilution, and pyruvate oxidation calculated as 13CO2 production from 13C-pyruvate. Ra lactate was calculated as the difference between Ra pyruvate and its disposal by oxidation to CO2 and conversion to alanine. Baseline plasma lactate kinetics in cirrhotic patients did not differ from controls. DCA decreased lactate concentration in both groups by approximately 53%. DCA decreased glycolysis (Ra pyruvate) by 24%, increased the fraction of pyruvate oxidized to CO2 by 26%, and decreased pyruvate transamination to alanine by 25%. DCA also inhibited lactate production by 85%, but decreased plasma lactate clearance by 60% in both groups. DCA reduces plasma lactic acid concentration by inhibiting production, via stimulating pyruvate oxidation and inhibiting glycolysis, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.

Topics: Adult; Alanine; C-Peptide; Dichloroacetic Acid; Female; Gas Chromatography-Mass Spectrometry; Glucagon; Humans; Insulin; Kinetics; Lactates; Liver; Liver Cirrhosis; Male; Oxidation-Reduction; Pyruvic Acid

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Dietary Carbohydrates; Dietary Fiber; Glucose Intolerance; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Pilot Projects; Postprandial Period

Hyperinsulinaemia and reduced insulin sensitivity are common features in patients with cirrhosis. Octreotide, a long-acting somatostatin analogue, is used in cirrhotic patients in the treatment of bleeding oesophageal varices. Octreotide has potent effects on the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis in healthy subjects. but the effects on the GH/IGF-I axis in patients with cirrhosis have been described only briefly. The effects of a 12 h infusion of octreotide (bolus 0.75 microg/kg followed by 0.75 microg/kg/h) in 25 subjects (normals n=9, compensated cirrhotics n=8, decompensated cirrhotics n=8) were compared with those in placebo-treated controls (n=19) during fasting conditions. IGF-I, free IGF-I, IGF binding proteins (IGFBPs), insulin, C-peptide, GH and glucose were measured. Insulin resistance was calculated using the HOMA method. Octreotide reduced levels of total IGF-I in patients with compensated cirrhosis (p=0.03) and free IGF-I in decompensated cirrhosis (p<0.01). Insulin resistance was significantly reduced in normal subjects. whereas the reduction in insulin resistance did not reach statistical significance in patients with cirrhosis. In normal subjects, octreotide increased the IGFBP-1 area under curve threefold (p<0.01) and decreased IGFBP-3 levels (p<0.01), but these effects were blunted in the cirrhotic patients. Similarly, the reduction of insulin and C-peptide was blunted in the cirrhotic patients, whereas a significant reduction in GH was demonstrated in all groups. The effects of octreotide on the GH/IGF-I axis are mitigated in patients with cirrhosis and this may be a reflection of relative hyperinsulinaemia during octreotide treatment in these patients.

Topics: Adult; Blotting, Western; C-Peptide; Female; Fluorescent Antibody Technique; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Liver Cirrhosis; Male; Middle Aged; Octreotide; Placebos; Reproducibility of Results

Non-insulin-dependent diabetes mellitus (type 2 diabetes) not responding to dietary treatment alone in patients with non-alcoholic liver cirrhosis is characterized by high postprandial hyperglycaemia. The control of postprandial hyperglycaemia in such patients, is generally achieved by the means of progressively higher doses of insulin, with an increasing risk of hypoglycaemia in the late postprandial period. The aim of this study was to evaluate the use of acarbose for the control of postprandial hyperglycaemia in 100 patients with well-compensated liver cirrhosis and type 2 diabetes treated with insulin.. The study was double blind with randomization of treatments into acarbose (52 patients) vs. placebo (48 patients) with parallel branches over a period of 28 weeks.. All patients tolerated the treatments well and no significant variations in liver function tests were observed (< 5% vs. pretreatment). A significant reduction of several parameters was observed only after acarbose treatment: fasting glycaemia (173 +/- 28 vs. 146 +/- 19 mg/dl; p < 0.01), postprandial glycaemia (230 +/- 24 vs. 148 +/- 20 mg/dl; p < 0.01), mean glycaemia (206 +/- 20 vs. 136 +/- 13 mg/dl; p < 0.01), mean variation (180 +/- 14 vs. 51 +/- 10 mg/dl; p < 0.01), HbA1c (8.9 +/- 0.8 vs. 7.2 +/- 0.5; p < 0.05), C-peptide 2 h after a standard meal (4.5 +/- 1.9 vs. 2.8 +/- 1.7 ng/ml; p < 0.05), whereas the parameters did not change significantly after the placebo. After acarbose treatment a significant increase of intestinal voiding/week (+116% vs. +10%; p < 0.01) and a parallel reduction of blood ammonia levels (-52 +/- 9% vs. -9 +/- 5%; P < 0.01) were observed.. The results clearly document the good tolerability and the absence of toxic effects of acarbose on liver, due to the lack of both intestinal absorption and hepatic metabolism of the drug at doses in the therapeutic range. In fact, acarbose increases the peristalsis movements of the gut, stimulates the proliferation of the saccarolytic bacteria and simultaneously reduces the proliferation of proteolytic bacteria, thus resulting active in the reduction of blood ammonia levels. These effects of acarbose may be advantageously exploited in the treatment of type 2 diabetic patients with well-compensated non-alcholic liver cirrhosis.

Topics: Acarbose; Ammonia; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Food; Glycated Hemoglobin; Humans; Insulin; Liver Cirrhosis; Male; Placebos

In spite of the high prevalence of diabetes mellitus (DM) in patients with liver cirrhosis (LC) few studies have focused on the clinical implications of this association. We investigated the clinical and pancreatic-endocrine features of 34 patients who developed DM after LC (Group I). Results were compared with 34 carefully matched patients with only Type II DM (Group II). A standard meal test was performed in 26 patients with normal renal function from each group to assess beta-cell function. Group I patients, less frequently had retinopathy (14.7% vs. 45.5%, P < 0.05) and a family history of diabetes (23.5% vs. 58.8%, P < 0.01). Group I patients also showed signs of enhanced insulin resistance, reflected by higher insulin dose requirements in insulin-treated patients (0.87 +/- 0.10 vs. 0.62 +/- 0.05 IU/kg/day, P < 0.01) and increased basal C-peptide values (0.88 +/- 0.06 vs. 0.68 +/- 0.07 pmol/l, P < 0.05, respectively) than those in Group II. These results suggest that several clinical features, probably related to the hepatopathy, define DM occurring in patients with LC.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Islets of Langerhans; Liver Cirrhosis; Male; Middle Aged; Prevalence

Ecballium elaterium (EE), widely used plant in Mediterranean medicine, showed anticancer activity. This study aimed to investigate EE effects on liver fibrosis in an animal model of thioacetamide (TAA). Intraperitoneal administration of TAA was performed twice weekly for four weeks in C57BL6J mice. Livers were extracted and serum were evaluated for inflammatory markers (H&E staining, ALT, AST, ALP), pro-inflammatory cytokines, fibrosis (Sirius red staining, Masson's trichrome, α-smooth muscle actin and collagen III), and metabolic (cholesterol, triglyceride, C-peptide, and fasting-blood-sugar) profiles. Glutathione, glutathione peroxidase, and catalase liver antioxidant markers were assessed. Tissue-resident NK cells from mice livers were functionally assessed for activating receptors and cytotoxicity. Compared to vehicle-treated mice, the TAA-induced liver injury showed attenuation in the histopathology outcome following EE treatment. In addition, EE-treated mice resulted in decreased serum levels of ALT, AST, and ALP, associated with a decrease in IL-20, TGF-β, IL-17, IL-22 and MCP-1 concentrations. Moreover, EE-treated mice exhibited improved lipid profile of cholesterol, triglycerides, C-peptide, and FBS. EE treatment maintained GSH, GPX, and CAT liver antioxidant activity and led to elevated counts of tissue-resident NK (trNK) cells in the TAA-mice. Consequently, trNK demonstrated an increase in CD107a and IFN-γ with improved potentials to kill activated hepatic-stellate cells in an in vitro assay. EE exhibited antifibrotic and antioxidative effects, increased the number of trNK cells, and improved metabolic outcomes. This plant extract could be a targeted therapy for patients with advanced liver injury.

Topics: Animals; Antioxidants; C-Peptide; Disease Models, Animal; Glutathione; Humans; Killer Cells, Natural; Liver; Liver Cirrhosis; Mice; Oxidative Stress; Thioacetamide

Objective The correlation between the insulin secretion levels and the risk of hepatocarcinogenesis is clinically important. The aim of the present study was to determine the effects of various clinical parameters on C-peptide (CPR) levels in patients with non-alcoholic fatty liver disease (NAFLD). Methods In this retrospective cohort study, the effects of clinical parameters on insulin resistance (HOMA-IR) and insulin secretion levels (HOMA-β and fasting CPR) were investigated. Patients A total of 244 Japanese patients with histopathologically confirmed NAFLD were evaluated. Of these, 77 underwent the meal tolerance test (MTT) to evaluate the association of various clinical parameters with the CPR levels at 120 minutes. Results A multivariate analysis identified fasting plasma glucose (FPG) (≥110 mg/dL), aspartate aminotransferase (≥1.0×ULN IU/L), and a large waist circumference as independent predictors of insulin resistance (HOMA-IR ≥2.5) or high fasting CPR levels. Significant parameters for a low insulin secretion capacity (HOMA-β <30%) were not detected, except for the parameters mentioned in the diagnostic criteria of diabetes mellitus. Regarding the MTT, the CPR levels at 120 minutes were significantly higher in patients with fibrosis stage 3-4 than in those with stage 0-2. Body composition and genetic variation did not affect the CPR levels at 120 minutes. A multivariate analysis identified fibrosis stage (3-4), hyperuricemia, FPG (≥110 mg/dL), and procollagen III peptide (>1.0 U/mL) as independent predictors of high CPR levels at 120 minutes. Conclusion The present study showed that high plasma glucose levels and severe liver fibrosis stage influence insulin secretion levels in Japanese patients with NAFLD. Conservation of delayed insulin secretion levels was confirmed in patients with severe liver fibrosis.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Blood Glucose; C-Peptide; Female; Humans; Insulin; Insulin Resistance; Insulin Secretion; Japan; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Predictive Value of Tests; Retrospective Studies; Risk Factors; Young Adult

A higher prevalence of nonalcoholic steatohepatitis (NASH) and advanced stages of fibrosis was observed in type 2 diabetes. We aim to investigate whether C-peptide is associated with nonalcoholic fatty liver disease (NAFLD) progression in type 2 diabetic adults.. A total of 4937 diabetic participants were enrolled from China in 2018. Liver steatosis was detected by ultrasound. Subjects with NAFLD were categorized into simple NAFLD and probable NASH by the concurrent presence of metabolic syndrome. NAFLD fibrosis score was used to identify patients with probable advanced fibrosis.. Individuals with a longer history of type 2 diabetes had a lower C-peptide level and a lower prevalence of probable NASH but a higher prevalence of advanced fibrosis. C-peptide was positively associated with simple NAFLD and probable NASH, with odds ratios (ORs) of 4.55 [95% confidence interval (CI) 3.16, 6.55] and 5.28 (95% CI 3.94, 7.09), respectively, comparing quartile 4 with quartile 1 (both p for trend <0.001). However, C-peptide quartiles were negatively associated with the probable presence of advanced fibrosis (Q4 vs. Q1, OR 0.59, 95% CI 0.36, 0.97, p for trend <0.05). A 1-SD increment of ln(C-peptide) was also significantly associated with inflammatory and fibrotic progression (OR 1.34, 95% CI 1.27, 1.41; OR 0.88, 95% CI 0.79, 0.98, respectively).. Significant but opposite associations between C-peptide and inflammatory and fibrotic progression of NAFLD were observed. Understanding islet hormone changes during type 2 diabetes and differentiating the stage of NAFLD may help to personalize treatment strategies for NAFLD patients with type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Disease Progression; Female; Follow-Up Studies; Humans; Inflammation; Liver Cirrhosis; Male; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease; Prognosis; Severity of Illness Index; Young Adult

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which becomes a rapidly growing health problem in the Western countries. The development of the disease is most often connected to obesity. NAFLD is also considered as the hepatic manifestation of metabolic syndrome. Transforming growth factor b1 (TGF-b1) plays an important role in the pathogenesis of liver fibrosis, being involved in activation of hepatic stellate cells, stimulation of collagen gene transcription, and suppression of matrix metalloproteinase expression. The objective of the study was to evaluate by immunohistochemistry the expression of TGF-b1 in the liver tissue of NAFLD patients and correlate it with anthropometric, biochemical and routine histological parameters.. The study group consisted of 48 patients with diagnosed NAFLD. Liver steatosis, NAFLD Activity Score (NAS) and METAVIR score of fibrosis were evaluated in liver biopsies. The immunoreactivity of TGF-b1 was evaluated semi-quantitatively separately in portal, septal, lobular hepatocytic and lobular sinu-soidal liver compartments. The results were analyzed in regard to patients' clinical and biochemical parameters.. Neither steatosis nor NAS correlated with TGF-b1 expression in any liver compartment, whereas METAVIR score of fibrosis was associated with increased immunoreactivity of TGF-b1 in most of the studied liver compartments. TGF-b1 immunoreactivity showed positive correlation with patients' age and its expression in septal compartment disclosed positive correlation with body mass index, and waist and hip circumference. Hyaluronic acid serum level was positively and iron concentration was negatively associated with TGF-b1 ex-pression in the selected consecutive liver compartments.. The immunohistochemical expression of TGF-b1 may be complementary to routine methods of liver fibrosis evaluation.

Topics: Adult; C-Peptide; Fatty Liver; Female; Glycated Hemoglobin; Haptoglobins; Humans; Hyaluronic Acid; Immunohistochemistry; Iron; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Transforming Growth Factor beta1

In patients with type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and liver fibrosis is frequent and presumably associated with increased cardiovascular disease risk and mortality. The objective was to investigate risk factors associated with hepatic fibrosis in patients with type 2 diabetes and NAFLD to provide a basis for the prevention and treatment.. Liver stiffness measurements (LSM) expressed in kilopascals (kPa) and controlled attenuation parameter (CAP) expressed in dB/m were diagnosed by transient elastography. Hepatic steatosis and significant fibrosis were defined as having a CAP score ≥ 260 dB/m and an LSM score ≥ 8 kPa, respectively. Associations between fibrosis categories with anthropometric and metabolic variables were determined; then, variables with statistical significance in the univariate analysis were included in multivariate model.. A total of 108 participant with type 2 diabetes and NAFLD (mean age: 44.69 ± 5.57 years; mean duration of diabetes 4.68 ± 4.24 years) were recruited. In these patients, body mass index, obesity, fat mass, waist circumferences, resting energy expenditure, CAP score, fasting insulin, C-peptide, HbA1C, hs-CRP as well as liver enzymes and systolic blood pressure and diastolic blood pressure were positively associated with fibrosis (all p < 0.05). Using multivariate logistic regression, serum aspartate aminotransferase (OR 1.12; 95% CI 1.06-1.19), waist circumferences (odds ratio [OR] 1.15; 95% CI 1.05-1.25) and C-peptide (OR 3.81; 95% CI 1.5-9.7) remained as independently associated with liver fibrosis.. For participants with type 2 diabetes with coexisting NAFLD, stratification by independent risk factors for fibrosis could have important prognostic value.

Topics: Adult; Aspartate Aminotransferases; Blood Pressure; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Waist Circumference

The relationship between hepatitis B virus (HBV) infection, leptin and insulin resistance remains unclear. We hypothesised links between serum leptin and insulin resistance in non-diabetic patients with chronic viral hepatitis B infection and their relation to liver fibrosis.. We recruited 190 untreated patients with chronic HBV infection and 72 healthy controls. Serum leptin, fasting glucose, insulin, liver function tests (LFTs), C-peptide and Homeostasis model assessment-IR (HOMA-IR) were measured/calculated by ELISA and standard techniques.. Serum leptin, C-peptide (both P < 0.001), HOMA-IR (P = 0.021) and several LFTs were increased in patients with chronic HBV-infection. In multivariate regression analysis, both HOMA-IR (P = 0.003) and leptin (P = 0.002) were significant independent predictors of HBV infection. There were significant positive correlations (P < 0.01) between leptin and HOMA-IR (r = 0.81), between serum leptin and METAVIR activity (r = 0.95), and between HOMA-IR and BMI (r = 0.75), fasting glucose (r = 0.005), and fasting insulin (r = 0.81). Several LFTs, glucose and insulin correlated modestly (r = 0.61-0.69, P < 0.05) with leptin.. Serum leptin may be related to the rate of fibrosis progression in nondiabetic patients with chronic HBV infection. Follow-up by serial measurement of serum leptin and HOMA-IR in non diabetic HBV-infected patients may be used as a non-invasive marker of early liver fibrosis.

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Fasting; Female; Hepatitis B virus; Hepatitis B, Chronic; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged

To investigate the situations of abnormal glucose metabolism and dysfunction of pancreatic islet beta cells in subjects of chronic hepatitis B (CHB) with cirrhosis.. 106 hepatitis B virus (HBV) positive subjects with liver cirrhosis as well as with different grade of Child-Pugh and 37 healthy subjects were included in this study. The oral glucose tolerance test (OGTT), C-peptide and insulin release test were detected. Plasma glucose and insulin levels were analyzed periodically for 2 h after oral glucose loading.. There was no significant difference in the level of fasting plasma glucose and C-peptide between cirrhosis group and control group (P>0.05). The levels of OGTT 2 h glucose, insulin and C peptide were significantly higher in cirrhosis group than control group (P<0.01). Peak plasma glucose levels were obtained at 60 min in normal group and cirrhosis group. The peak insulin and C-peptide response occurred at 60 min in normal group, whereas it was delayed to 120 min in cirrhosis group. There was a significant difference between two groups in the pattern of plasma glucose levels at corresponding time points (P<0.05). The OGTT 2 h glucose and insulin levels were positively correlated with Child-Pugh Score (r1 = 0.389, r2 = 0.508, P<0.01).. These findings implied that there was a certain degree of insulin resistance and abnormal glucose metabolism in the patients with liver cirrhosis.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Female; Glucose; Glucose Tolerance Test; Hepatitis B, Chronic; Humans; Insulin; Insulin Resistance; Insulin Secretion; Liver Cirrhosis; Male; Middle Aged; Pancreas

The aim of investigation was to study the impact of insulin resistance in patients with HCV infection. 130 patients were investigated: 20 with acute hepatitis C; 38 with chronic hepatitis C; 72 with cirrhosis. The study demonstrated, that the serum level of C-peptide and Insulin in patients with liver cirrhosis is higher, than in patients with acute and chronic HCV infection. This is necessary the monitoring of patients with insulin resistance, which will contribute to the prevention of complications and can improve patients' quality of life.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Female; Hepatitis C, Chronic; Humans; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged

Insertion of a transjugular intrahepatic porto-systemic shunt (TIPS) increases body cell mass (BCM) in patients with liver cirrhosis. The responsible mechanism is unidentified, but may involve changes in insulin sensitivity and glucose metabolism. Eleven patients with liver cirrhosis were examined before and 6 mo after a TIPS procedure with bioimpedance analyses, 2-h oral glucose tolerance tests, and two-step hyperinsulinemic euglycemic clamp with tracer-determined endogenous glucose production. After TIPS, BCM increased by 4.8 kg [confidence interval (CI): 2.7-7.3]. Fasting (f)-insulin increased from 123 +/- 81 to 193 +/- 124 pmol/l (P = 0.03), whereas f-glucose was unchanged (6.0 +/- 0.8 vs. 6.2 +/- 1.0 mmol/l). Glucose and insulin oral glucose tolerance test area under the curve increased by 14% (CI: 7-22%) and 53% (CI: 14-90%), respectively, P < 0.05. The C-peptide-to-insulin ratio decreased by 21% (CI: 8-35%, P = 0.01). Insulin sensitivity based on glucose infusion rate (4.69 +/- 1.82 vs. 4.85 +/- 2.37 mg.kg(-1).min(-1)) and glucose tracer-based rate of disappearance were unchanged (5.01 +/- 1.61 vs. 4.97 +/- 2.13 mg.kg(-1).min(-1)). Despite a further increase in peripheral hyperinsulinemia, f-endogenous glucose production did not change between study days (2.01 +/- 0.42 vs. 2.42 +/- 0.58 mg.kg(-1).min(-1)) and was suppressed equally by insulin (1.1 +/- 0.1 vs. 1.0 +/- 0.1 mg.kg(-1).min(-1)). Insulin clearance, growth hormone, cortisol, and glucagon levels were unchanged. BCM improvement did not correlate with the measured variables. After TIPS, BCM rose, despite enhanced hyperinsulinemia and aggravated glucose intolerance, but unchanged peripheral and hepatic insulin sensitivity. This apparent discrepancy may be ascribed to shunt-related decreased insulin exposure to the liver cells. However, the anabolic effect of TIPS seems not to be related to improvements in insulin sensitivity and remains mechanistically unexplained.

Topics: Body Composition; C-Peptide; Diabetes Mellitus; Energy Metabolism; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Liver; Liver Cirrhosis; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic; Predictive Value of Tests; Rest

We report about our experience with combined en-bloc liver-pancreas transplantation in 14 patients with liver cirrhosis and insulin dependent type 2 diabetes mellitus. Exocrine drainage was achieved by duodeno-duodenostomy. Median posttransplant follow-up is currently 92.5 months. All patients were rendered independent from insulin therapy shortly after transplantation. Levels of glycosylated hemoglobin normalized in all recipients. Mean fasting C-peptide values increased from pretransplant 7.0+/-1.7 ng/mL to 10.5+/-2.9 ng/mL 3 months posttransplantation (P<0.001). One recipient (7.1%) developed recurrent exogenous insulin dependence 7 years after transplantation. Pancreas allograft rejection was confirmed by endoscopic biopsy of donor duodenum mucosa in two patients (14.3%). Calculated 5- and 7-year survival is currently at 64.3% and 64.3%, respectively. Our results indicate that combined en-bloc liver-pancreas transplantation using duodeno-duodenostomy is technically feasible and leads to excellent long-term control of glucose metabolism in patients with liver cirrhosis and insulin-dependent type 2 diabetes.

Topics: Adult; Aged; Anastomosis, Surgical; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Duodenum; Female; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Insulin; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Pancreas Transplantation

As acylation stimulating protein (ASP) acts on adipocytes mainly as a paracrine factor to increase triglyceride synthesis and storage; hypothetically, it may play a similar role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).. Forty-six male patients with NAFLD (group A), age-matched 30 male patients with chronic viral hepatitis (group B) and 30 age-matched and body mass index (BMI)-matched healthy male subjects were enrolled in the study.. Among the NAFLD patients, 10 patients (24.4%) had simple steatosis and 36 patients (69.6%) had nonalcoholic steatohepatitis (NASH). The mean levels of ASP, complement 3, insulin, C-peptide, HOMA-IR, triglyceride, and very low-density lipoprotein (VLDL) were significantly higher in group A patients than both controls and group B. ASP levels correlated significantly in a positive manner with BMI, insulin, and HOMA-IR.. Dysregulation of the ASP pathway may have important metabolic consequences in NASH and is associated with insulin resistance.

Topics: Adipocytes; Adult; Biopsy, Needle; C-Peptide; Complement C3; Complement C3a; Fatty Liver; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Insulin Resistance; Lipoproteins, VLDL; Liver; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Reference Values; Statistics as Topic; Triglycerides

Chronic hepatitis B (CHB) and C (CHC) are commonly associated with hepatic steatosis. The aims of this study were to investigate predictors of hepatic steatosis, and their impact on inflammation and fibrosis in CHB and CHC.. Consecutive patients with either CHB or CHC who underwent a liver biopsy at The Alfred Hospital between April and September 2002 were included. Histological analysis of liver biopsies was performed by two hepatopathologists blinded to the clinical data.. Ninety-one patients were analysed including 17 patients with CHB and 74 with CHC. CHC genotype 3, C-peptide, glucose and waist circumference were independent predictors of extent of Brunt steatosis grade, while CHC genotype 3, C-peptide and waist circumference were independent predictors of microvesicular steatosis grade. Alcohol intake and age were predictors of hepatic fibrosis. There was a trend toward a correlation between both Brunt steatosis and microvesicular steatosis grades and fibrosis progression rate in CHC genotype non-3.. Hepatic steatosis is common in chronic hepatitis B and C, and is associated with waist circumference, glucose, C-peptide and chronic hepatitis C genotype 3. Steatosis grade appears to relate to hepatic fibrosis progression rate in chronic hepatitis C genotype non-3.

Topics: Adult; Aging; Alcohol Drinking; Anthropometry; Blood Glucose; C-Peptide; Disease Progression; Fatty Liver; Female; Genotype; Hepacivirus; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged

Hyperglucagonemia has been described to be associated with insulin resistance in patients with liver cirrhosis. Portosystemic shunts may be involved in the etiology of hyperglucagonemia. To test this hypothesis we investigated fasting peripheral plasma glucagon levels before and after portal decompression by transjugular intrahepatic portosystemic shunting (TIPS).. Glucagon, insulin, plasma glucose, HbA1c, and C-peptide were determined in peripheral venous samples from 21 non-diabetic (ND)- and 15 diabetic patients (D; 3 treated with insulin, 3 with sulfonylurea, 9 with diet alone) with liver cirrhosis, showing comparable clinical features (gender, age, BMI, creatinine, Child-Pugh-score, complications, and etiology of liver cirrhosis) before, 3 and 9 months after elective TIPS implantation. Insulin resistance was calculated as R (HOMA) according to the homeostasis model assessment (HOMA).. Glucagon levels before TIPS were elevated in patients with diabetes compared to patients without diabetes (D: 145.4 +/- 52.1 pg/ml vs. ND: 97.3 +/- 49.8 pg/ml; p = 0.057). 3 and 9 months after TIPS implantation glucagon levels increased significantly in ND (188.9 +/- 80.3 pg/ml and 187.2 +/- 87.6 pg/ml) but not in D (169.6 +/- 62.4 pg/ml and 171.9 +/- 58.4 pg/ml). While plasma glucose, HbA1c, and C-peptide were significantly higher in D than in ND, they did not change significantly 3 and 9 months after TIPS implantation. Insulin was increased in D before TIPS (D: 31.6 +/- 15.9 mU/l vs. ND: 14.8 +/- 7.1 mU/l; p = 0.0001). 3 and 9 months after TIPS insulin significantly increased in ND (26.6 +/- 14.7 mU/l and 23.2 +/- 10.9 mU/l vs. 14.8 +/- 7.1 mU/l before TIPS) but not in D. In ND R (HOMA) also increased from 3.5 +/- 2 mU x mmol/l(2) to 5.7 +/- 3.3 mU x mmol/l(2) after 3 and 5.4 +/- 2.6 mU x mmol/l(2) after 9 months. BMI, liver and kidney function did not change with time.. In non-diabetic cirrhotic patients TIPS implantation is followed by an increase of glucagon. However, this does not result in a worsening of glycemic control, probably because of a simultaneous increase of insulin.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Complications; Female; Glucagon; Glycated Hemoglobin; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic

We evaluate the prognostic significance of chronic liver diseases followed by diabetes mellitus in 40 patients by Child class, immunoreactive insulinemia (IRI), C peptide (CP) and pancreolaury-test (PLT) at 5 years. Death and hepatic insufficiency prevalence were significantly higher in cirrhotic diabetics, and in those diabetics with a lower insulin secretion (IRI, CP). Insulin hyposecretion (lower IRI, CP) was found in cirrhotic with abnormal PLT (below 20%). The onset of diabetes mellitus in liver cirrhosis has a bad prognosis when it is caused by decreased insulin secretion produced by chronic pancreatitis or pancreatic insufficiency.

Topics: C-Peptide; Diabetes Mellitus; Humans; Insulin; Insulin Secretion; Liver Cirrhosis; Longitudinal Studies; Predictive Value of Tests; Prognosis

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.

Topics: Adult; C-Peptide; Female; Glucose Intolerance; Glucose Tolerance Test; Hepatitis C, Chronic; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver Cirrhosis; Male; Middle Aged; Prevalence

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic steatosis, inflammation, and fibrosis. Leptin is an adipocyte-derived antiobesity hormone that in rodents prevents "lipotoxicity" by limiting triglyceride accumulation and also regulates matrix deposition (fibrosis) during wound healing. We therefore determined serum leptin levels in patients with NASH to determine whether relationships existed between leptin levels and severity of hepatic steatosis or fibrosis. We used a radioimmunoassay to determine serum [total] leptin concentrations in 27 men and 20 women with NASH and 47 controls matched for gender and body mass index (BMI; and partly for age). Serum leptin values were correlated with hepatic steatosis, fibrosis, and inflammation (each categorized semiquantitatively on liver histology), and with anthropometric indices, serum lipids, glucose, insulin, c-peptide, and alanine aminotransferase (ALT) levels. Compared with the controls, mean serum leptin levels were raised in both men and women with NASH (men 14 +/- 11 ng/mL vs. 7.2 +/- 4.1 ng/mL, P =.003; women 35 +/- 16 ng/mL vs. 15 +/- 8.2 ng/mL, P <.001). Leptin values correlated with serum c-peptide levels but not with BMI. In a multivariate analysis, serum leptin (P =.027), serum c-peptide (P =.001), and age (P =.027) were selected as independent predictors of the severity of hepatic steatosis. However, serum leptin was not an independent predictor of hepatic inflammation or fibrotic severity. In conclusion, hyperleptinemia occurs in NASH and is not explained simply by gender, obesity, or the presence of type 2 diabetes. Furthermore, leptin levels correlate directly with the severity of hepatic steatosis but not with inflammation or fibrosis. We propose that the relationship between leptin and steatosis reflects a pathogenic role of leptin in hepatic insulin resistance and/or a failure of the antisteatotic actions of leptin ("peripheral leptin resistance").

Topics: Adult; Aged; C-Peptide; Fatty Liver; Female; Hepatitis; Humans; Insulin; Insulin Resistance; Leptin; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Severity of Illness Index; Sex Factors; Triglycerides

Human liver cirrhosis is commonly associated with increased fasting and glucose induced insulin concentrations. However, whether the hyperinsulinaemia is a consequence of increased pancreatic insulin secretion, decreased hepatic insulin removal, or impaired feedback regulation of insulin secretion is still doubtful. To investigate these issues, insulin secretion-during 24 hours of standardised living conditions-insulin sensitivity, and hepatic insulin extraction were assessed in cirrhotic patients compared with matched healthy subjects.. Nine Child's disease grade B cirrhotic patients and seven healthy volunteers, participated in the study. The subjects were studied on two separate days, one for the assessment of insulin secretion during a standardised 24 hour life period (calorimetric chamber), and one for the determination of insulin sensitivity.. Insulin secretion rates were reconstructed from plasma C peptide concentrations by deconvolution, and indices of beta cell function were derived using a mathematical model describing the functional dependence of insulin secretion on plasma glucose concentrations. Insulin sensitivity was determined using the euglycaemic hyperinsulinaemic clamp technique.. Cirrhotic patients showed a marked hypersecretory response, both in absolute terms (mean (SEM) 295 (53) versus 138 (11) nmol/m(2), p<0.02), and in relation to glucose (175 (26) versus 57 (5) pmol/min/m(2), p<0.02). In particular, the beta cell dose-response function was shifted upward compared with controls. The sensitivity of insulin secretion to the rate of glucose change was also increased. Insulin sensitivity, markedly reduced in cirrhosis (157 (10) versus 296 (30) ml/min/m(2), p<0.002), was strongly inversely correlated (r=0.89, p<0.002) in these patients with insulin secretion at 5 mM glucose. Insulin clearance and hepatic insulin extraction were not reduced. A frank hypermetabolism with increased lipid oxidation was found in this series.. This study suggests that hyperinsulinaemia, at least in Child's disease grade B cirrhotic patients, is the consequence of increased beta cell sensitivity to glucose, while hepatic insulin extraction does not seem to play a significant part.

Topics: Biomarkers; Blood Glucose; C-Peptide; Case-Control Studies; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver; Liver Cirrhosis; Male; Middle Aged; Models, Biological; Monitoring, Physiologic; Regression Analysis; Statistics, Nonparametric

Patients with cirrhosis of the liver suffer from hyperinsulinaemia and a certain degree of insulin resistance. More frequently than in the rest of the population they have diabetes. Transjugular intrahepatic portosystemic shunts (TIPS) as a therapeutic method in complications of portal hypertension lead to rapid haemodynamic changes in the liver. The objective of the submitted work was to assess whether TIPS has an impact on insulinaemia and whether it influences insulin resistance in patients with cirrhosis of the liver.. The authors evaluated a group of 22 patients with cirrhosis of the liver (10 diabetics and 12 subjects without diabetes) indicated for TIPS. They investigated the insulin and C-peptide concentration in blood obtained by catheterization from the hepatic and portal vein before and after TIPS and in the peripheral blood before TIPS, 1 hour, 1 day, 1 week and 1 month after TIPS. The insulin resistance was examined by the method of the hyperinsulin euglycaemic clamp (HEC) before TIPS, 1 day, 1 week, and 1 month after TIPS. The levels of C-peptide and insulin were assessed by the IRMA method. The blood sugar level in HEC was measured by means of a Hemocue apparatus. The results were evaluated by the non-parametric Wilcoxon test for two dependent samples.. Both groups (diabetics and non-diabetics) were comparable as to age, sex, etiology of liver cirrhosis and indication for TIPS. After introduction of TIPS a change of insulin clearance occurred (p = 0.01) and a change of the insulin level in the hepatic vein immediately after TIPS (p = 0.02). Insulin clearance before TIPS was 37-90% (median 54%) and after TIPS it declined to 0-79% (median 38%) (p = 0.01). Already 1 hour after the operation the authors observed a rise of the insulin level in peripheral blood as compared with baseline values (p = 0.002). Statistically significant hyperinsulinaemia persisted one month after TIPS (p = 0.005). Values of C-peptide did not change significantly in time, neither in the hepatic vein nor in the peripheral blood. On examination of IR no statistically significant changes occurred after TIPS. On evaluation of different groups of diabetics and non-diabetics the IR was more marked in patients with DM (mean M = 1.7 mg/kg/min.) than in patients without DM (3.7 mg/kg/min.) (p = 0.03). The authors did not record significant changes of IR in time in different groups. Compensation of DM was not influenced by TIPS. The fasting blood sugar levels before TIPS and 1 month after TIPS were comparable.. After TIPS a rise of the insulin level in peripheral blood occurred due to the reduced insulin clearance in the liver. Despite hyperinsulinaemia which persisted for one month after the operation, the insulin resistance did not deteriorate. Compensation of diabetes was not affected by TIPS.

Topics: Adult; Aged; C-Peptide; Diabetes Complications; Diabetes Mellitus; Female; Humans; Hypertension, Portal; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic

To investigate the relationship between the expression of insulin receptor (IR) and the content of tyrosine protein kinase (TPK) in patients with hepatic cirrhosis.. Glucose tolerance test (GTT), insulin, c-peptide, insulin antibodies in serum, the expression of IR and TPK were quantitively analysed in patients with hepatic cirrhosis. The amount of IR and TPK was evaluated by immunohistochemical quantitative analysis using image analyzer in 12 patients with positive HBV marks and cirrhosis. Insulin and c-peptide in serum were determined by immunoenzymemetric assay (IEMA) and insulin antibodies in serum determined by RIA.. IR amount in normal and abnormal GTT patients with hepatic cirrhosis was signifficantly less than that in control group (P<0.01). TPK amount in liver of patitents with abnormal GTT was less than that of normal GTT (P<0.01).. IR decreases in cirrhotic patients. Abnormal GTT has relation to reducing TPK activity.

Topics: Antibodies; C-Peptide; Glucose Tolerance Test; Humans; Immunohistochemistry; Insulin; Liver Cirrhosis; Protein-Tyrosine Kinases; Receptor, Insulin

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.

Topics: Blood Glucose; Body Mass Index; C-Peptide; Carcinoma, Hepatocellular; Diabetes Complications; Diabetes Mellitus; Follow-Up Studies; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Middle Aged

Alterations in carbohydrate metabolism associated with liver cirrhosis are characterized by a high serum insulin level and prolonged hyperglycemia on oral glucose tolerance test (OGTT). We measured plasma glucose, immunoreactive insulin (IRI), and C-peptide immunoreactivity (CPR) levels during a 75-g OGTT before and after varices obliteration in 10 cirrhotic patients with gastric varices. After obliteration, the indocyanine green retention rate was decreased and the portal flow velocity was increased. A significant decline in plasma glucose and IRI levels was also noted on OGTT. Moreover, the plasma glucose and IRI levels declined at 90 and 120 min in OGTT while they increased progressively by 120 min before obliteration. The levels of CPR were similar before and after treatment. These results indicate that decreased portal flow due to extrahepatic shunt and consequent impairment of insulin metabolism play a role in glucose intolerance observed in cirrhotic patients and that shunt occlusion improves glucose metabolism.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Collateral Circulation; Esophageal and Gastric Varices; Glucose Intolerance; Glucose Tolerance Test; Humans; Infant; Insulin; Liver Cirrhosis; Male; Middle Aged; Portal System

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.

Topics: Ascites; Blood Glucose; C-Peptide; Female; Fructosamine; Hemorrhage; Humans; Hyperinsulinism; Insulin; Liver Cirrhosis; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic; Proinsulin; Reference Values

Zinc deficiency is common in cirrhosis, and was proved to affect nitrogen metabolism. In experimental animals, zinc status may also affect glucose disposal, and acute zinc supplementation improves glucose tolerance in healthy subjects. This study was aimed at measuring the effects of long-term oral zinc supplements on glucose tolerance in cirrhosis. The time courses of glucose, insulin, and C-peptide in response to an intravenous (i.v.) glucose load were analyzed by the minimal-model technique before and after long-term oral zinc supplements (200 mg three times per day for 60 days) in 10 subjects with advanced cirrhosis and impaired glucose tolerance or diabetes. The test was performed using a simplified procedure, based on 20 blood samples collected within 4 hours from the glucose load. Normal values were obtained in 25 age-matched healthy subjects. Zinc levels were low to normal or reduced before treatment, and were normalized by oral zinc. Glucose disappearance improved by greater than 30% in response to treatment. There were no changes in pancreatic insulin secretion and systemic delivery, or in the hepatic extraction of insulin. Insulin sensitivity (SI), which was reduced by 80% before treatment, did not change. Glucose effectiveness (SG) was nearly halved in cirrhosis before treatment (0.013 [SD 0.007] min(-1) v. 0.028 [SD 0.009] in controls; P < .001), and increased to 0.017 (SD 0.009) after zinc (P < .05 v. baseline). The return to normal of plasma zinc levels after long-term zinc treatment in advanced cirrhosis improves glucose tolerance via an increase of the effects of glucose per se on glucose metabolism. Poor zinc status may contribute to the impaired glucose tolerance and diabetes of cirrhosis.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Liver Cirrhosis; Male; Middle Aged; Zinc; Zinc Sulfate

To determine insulin action and insulin secretory function in patients with hemochromatosis, and to find evidence for or against hypothesized pathogenetic mechanisms for the abnormal glucose metabolism associated with hemochromatosis. These mechanisms include decreased beta-cell secretion of insulin due to iron overload, insulin resistance and genetic factors.. Prospective in vivo study.. Seventeen subjects with hemochromatosis, of whom 4 had cirrhosis but not diabetes mellitus, 6 had diabetes mellitus and 7 had neither; 10 controls.. Insulin sensitivity and insulin secretion were determined during an intravenous glucose tolerance test. Insulin secretion was measured as the acute insulin response to glucose (AIRg). Insulin sensitivity (Si) was quantified with the minimal-model method. Of the patients with hemochromatosis, 14 agreed to undergo a second metabolic study after treatment with venous phlebotomy.. All subjects with hereditary hemochromatosis had impaired glucose tolerance as measured by K(g) (rate of glucose disappearance). Subjects who were free of both diabetes mellitus and liver cirrhosis had a normal S1 and a decreased AIRg. In these subjects, phlebotomy treatment normalized serum ferritin levels, increased AIRg by 35% and normalized glucose tolerance (K(g)). Subjects with hemochromatosis and cirrhosis had a reduced Si and maintained a normal insulin secretion. Phlebotomy treatment did not change these parameters. Subjects with hemochromatosis and diabetes mellitus had both a reduced Si and AIRg, and these parameters were unaffected by phlebotomy treatment.. These results suggest that iron overload can impair insulin secretion and glucose tolerance early in hereditary hemochromatosis, before cirrhosis occurs. Phlebotomy treatment can reverse these defects. Impaired glucose tolerance resulting from insulin resistance in subjects with cirrhosis or diabetes mellitus is not affected by phlebotomy treatment.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Diabetes Mellitus; Ferritins; Glucose Tolerance Test; Glycated Hemoglobin; Hemochromatosis; Humans; Insulin; Insulin Secretion; Iron; Liver; Liver Cirrhosis; Middle Aged; Phlebotomy; Prospective Studies

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Hepatitis C; Humans; Immunosuppression Therapy; Islets of Langerhans Transplantation; Liver Cirrhosis; Liver Transplantation; Time Factors

Topics: Adolescent; Adult; C-Peptide; Child; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Histocompatibility Testing; Humans; Insulin Resistance; Islets of Langerhans Transplantation; Liver Cirrhosis; Liver Transplantation; Middle Aged; Pilot Projects

Following a hyperosmolar diabetic coma in a cirrhotic patient with hepatocellular carcinoma undergoing transcatheter arterial chemo-embolization, we assessed the prevalence, severity, causes and prognostic impact of impaired glucose metabolism following transcatheter arterial chemo-embolization.. Plasma glucose, pancreatic and thyroid hormones, cortisol, growth hormone, ACTH and TSH concentrations were determined before and after transcatheter arterial chemo-embolization in 98 patients (70 with a normal fasting glucose, 7 with mild fasting hyperglycaemia and 21 diabetics) undergoing 226 transcatheter arterial chemo-embolization procedures. Child status, body temperature, serum ALT and amylase levels, tumour size, gelfoam embolization and disease aetiology were recorded. Liver function was assessed before and after transcatheter arterial chemo-embolization by measuring monoethylglycinexylidide formation after i.v. lidocaine.. A significant rise in glucose levels (p < 0.0001) was observed in 30/98 patients. Hyperglycaemia was more frequent in diabetics (67%) and patients with mild fasting hyperglycaemia (71%). Glucose concentrations doubled in 12 patients; 4 required long-term insulin. Fever, a previously altered carbohydrate metabolism and raised ALT levels were prognostic factors for hyperglycaemia (p < 0.01). Plasma C-peptide, glucose/insulin and glucose/C-peptide ratios, were increased after transcatheter arterial chemo-embolization (p < 0.05). Transcatheter arterial chemo-embolization was followed by a reduction in the monoethylglycinexylidide formation capacity (p < 0.05), particularly in hyperglycaemia patients (p < 0.02).. Transcatheter arterial chemo-embolization is frequently followed by a derangement in glucose metabolism which is potentially severe, associated with preceding glucose imbalance, fever and a transient deterioration in liver function.

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fasting; Female; Hormones; Humans; Hyperglycemia; Insulin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

A blunted initial insulin secretory response may contribute to oral glucose intolerance in cirrhosis. Oral glucose is a better stimulant to insulin secretion than intravenous (IV) glucose in part because of release of gut peptides, notably glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1 [7-36 amide]). Because impaired release of or resistance to these gut peptides could explain impaired insulin secretion after oral glucose, we measured insulin secretion, plasma GIP, and GLP-1 [7-36 amide] levels, basally and after 75 g oral glucose, in 10 cirrhotics and 10 controls. Insulin secretion was calculated from a two-compartment analysis of serum C-peptide levels using kinetic parameters derived from IV injection of recombinant human C-peptide. C-peptide metabolic clearance rate, and the fractional rate constants for C-peptide (using the two-compartment model) were not significantly different, but the volume of the central compartment was 15% greater in cirrhotics (P < .01). Fasting blood glucose levels were similar (cirrhotics, 4.9 +/- 0.2; controls, 4.6 +/- 0.1 mmol/L) but serum insulin was six times higher in cirrhotics (P < .001). Cirrhotics had higher fasting GIP (215 +/- 72 vs. 42 +/- 18 pmol/L) and GLP-1 [7-36 amide] levels (25 +/- 3 vs. 16 +/- 1 pmol/L) (both P < .05). After oral glucose, blood glucose levels were significantly higher in cirrhotics. The timing of the gut peptide response to oral glucose was similar in the two groups, but peak levels of both peptides were approximately x2 higher in the cirrhotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Insulin; Insulin Secretion; Liver Cirrhosis; Male; Middle Aged; Peptide Fragments

Glucose intolerance and diabetes mellitus are both prevalent in cirrhosis, yet the pathogenesis of impaired glucose metabolism remains unknown. Therefore insulin secretion (hyperglycemic clamp, +125 mg/dl), insulin sensitivity (euglycemic hyperinsulinemic insulin clamp, +10 microU/ml and +50 microU/ml), whole-body glucose oxidation (indirect calorimetry) and glucose turnover ([6,6-2H2]glucose isotope dilution) were evaluated in a homogenous group of cirrhotic patients with glucose intolerance (n = 7) or frank diabetes mellitus (n = 6). The results were compared with those obtained in control subjects (n = 8). In glucose-intolerant patients, whole-body glucose uptake (mainly reflecting glucose utilization by muscle) was significantly impaired in patients during both insulin infusions as a result of decreased stimulation of the two major intracellular pathways of glucose disposal--nonoxidative glucose disposal (i.e., glycogen synthesis) and glucose oxidation. Hepatic glucose production was normal in the basal state and was normally suppressed during stepwise insulin infusion (by 65% and 85%, respectively, p = NS vs. controls). Hyperglycemia-induced increases of plasma C-peptide concentrations were comparable to those in controls (p = NS). In diabetic patients, insulin-mediated glucose uptake was significantly reduced, mainly because of impaired non-oxidative glucose disposal. Glucose oxidation appeared to be reduced, too. Hepatic glucose production was significantly increased in the basal state (3.03 +/- 0.24 vs. 2.34 +/- 0.10 mg/kg min, p < 0.02) and during insulin infusion (+50 microU/ml: 0.67 +/- 0.17 vs. 0.13 +/- 0.08 mg/kg min, p < 0.05) compared with that in controls. Both the first and second phases of beta-cell secretion were significantly reduced in response to steady-state hyperglycemia (both p < 0.01 vs. control values). In conclusion, glucose intolerance in cirrhosis results from two abnormalities that occur simultaneously: (a) insulin resistance of muscle and (b) an inadequate response (even when comparable to that of controls) of the beta-cells to appropriately secrete insulin to overcome the defect in insulin action. Diabetes mellitus in insulin-resistant cirrhotic patients develops as the result of progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hyperglycemia and a diabetic glucose tolerance profile.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Female; Glucose; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperglycemia; Insulin; Lactates; Lactic Acid; Liver Cirrhosis; Male; Middle Aged; Reference Values

The ability of glucagon to stimulate hepatic glucose production (HGP) was studied in clinically stable cirrhotic patients (n = 8) who had, based on long-term follow-up evaluation, relatively good liver function (Child-Pugh A) and whose dietary intake and physical characteristics were comparable to those of healthy control subjects (n = 8). Plasma glucagon concentration was slightly but not significantly increased in cirrhotic patients versus control subjects in the basal state (190 +/- 41 v 126 +/- 24 pg/mL, P = NS) and during a continuous 180-minute glucagon infusion at 3 ng/kg/min (349 +/- 56 v 243 +/- 37, P = NS). The increment in plasma glucagon level (+164 +/- 57 v +127 +/- 35, P = NS) also was slightly greater in the cirrhotic group. HGP (measured with [6-3H]-glucose) in the basal state was similar in cirrhotic and control subjects (1.79 +/- 0.09 v 1.94 +/- 0.15 mg/kg/min, P = NS). In cirrhotic patients, stimulation of HGP by glucagon was blunted during the first 15 to 30 minutes of the infusion period (representing glucagon's predominant effect on glycogenolysis; 0.23 +/- 0.20 v 1.06 +/- 0.19 mg/kg/min, P < .05), but it was not different from that in control subjects during the remaining course of the experiment (30 to 180 minutes). Basal plasma insulin and C-peptide concentrations did not change from baseline during the glucagon infusion in cirrhotics, whereas they increased slightly but not significantly in controls. These data demonstrate that even in the early stages of cirrhosis, the liver is resistant to the stimulatory effect of glucagon on hepatic glycogenolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Amino Acids; Blood Glucose; C-Peptide; Female; Glucagon; Glucose; Glycogen; Humans; Insulin; Liver; Liver Cirrhosis; Male; Middle Aged; Molecular Weight; Time Factors

Insulin resistance is a characteristic feature of glucose-intolerant and diabetic cirrhotic patients. The pathogenic factors, however, that are responsible for the development of impaired glucose tolerance in cirrhosis, remain unclear. To examine whether the ability of hyperglycemia per se to enhance glucose uptake (by means of mass-action effect) is impaired in cirrhosis, we measured (insulin-independent) whole-body glucose disposal during hyperglycemia (hyperglycemic clamp studies, +125 mg/dl, in combination with an infusion of somatostatin (500 micrograms/hr), insulin (0.1 mU/kg min) and glucagon (0.5 ng/kg min) to "clamp" hormone levels at baseline), whole-body glucose oxidation (indirect calorimetry) and glucose turnover (prime-continuous infusion of [6,6-2H2-]glucose in a clinically homogeneous group of cirrhotic patients with glucose intolerance (n = 7) or frank diabetes mellitus (n = 7) and in control individuals (n = 7). Fasting plasma glucose concentrations were normal in glucose-intolerant patients but were significantly increased in diabetic patients (158 +/- 19 vs. 87 +/- 2 mg/dl in controls; p < 0.01). Plasma glucose concentrations were clamped at 214 +/- 4 mg/dl in controls, at 212 +/- 4 mg/dl in glucose-intolerant patients and at 287 +/- 19 mg/dl in diabetic patients; plasma insulin and glucagon concentrations were maintained at baseline levels. In the basal state, total-body glucose disposal (which equals basal hepatic glucose output) was normal in glucose-intolerant patients (2.25 +/- 0.11 mg/kg min) but was increased in diabetic patients compared with controls (3.32 +/- 0.26 mg/dl vs. 2.45 +/- 0.10 mg/dl; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Complications; Diabetes Mellitus; Drug Resistance; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Humans; Insulin; Lactates; Lactic Acid; Liver; Liver Cirrhosis; Male; Middle Aged; Osmolar Concentration; Oxidation-Reduction

Forearm glucose uptake during a hyperglycaemic (10 mmol/l) glucose clamp was diminished to 33% of the normal value (p = 0.012) in six cirrhotic patients compared with matched control subjects. Fasting insulin concentrations were significantly elevated in the cirrhotic patients confirming insulin resistance which may have been induced by chronic hyperinsulinaemia. The cirrhotic patients received one week of treatment with 50 micrograms octreotide subcutaneously three times daily which reduced pre-dose fasting insulin levels from 26.2 +/- 7.9 to 18.1 +/- 6.2 mU/l p < 0.005, and post dose levels to 7.0 +/- 3.5 mU/l p < 0.005. However when the glucose clamp was repeated 20 hours after the last dose of octreotide no change was detected in clamp glucose requirements, forearm glucose uptake, or stimulated insulin secretion. It was concluded that one week of lowering insulin levels does not reverse the insulin resistance of cirrhosis.

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Fatty Acids, Nonesterified; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Octreotide

To characterize the pulsatile liberation of pancreatic hormones, blood was taken from the portal vein of four patients (three men, one woman; aged 65-71 years) with alcoholic (n = 3) or posthepatitic (n = 1) liver cirrhosis. The concentrations of glucose, insulin, C-peptide and glucagon were measured within one minute. The concentrations of insulin, C-peptide and glucagon varied considerably in intervals of 4.1-6.5 min. The swings in insulin concentration ranged between 17 and 163.5 microU/ml. Oral glucose loading with 100 g increased the insulin and C-peptide swings, but not their periodicity. This indicates that pulsatile insulin secretion is amplitude not rate driven.

Topics: Aged; Blood Glucose; C-Peptide; Catheterization, Peripheral; Female; Glucagon; Glucose; Hepatitis; Humans; Insulin; Insulin Secretion; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Portal Vein; Pulsatile Flow; Radiography, Interventional; Time Factors

In cirrhotic patients with normal fasting glucose levels both insulin insensitivity and a blunted early insulin response to oral glucose are important determinants of the degree of intolerance to oral glucose. It is not known whether the ability of hyperglycaemia per se to enhance glucose disposal (glucose effectiveness) is also impaired. It is also unclear whether overt diabetes is due to: (1) more marked insulin insensitivity; (2) impaired insulin secretion; (3) reduced glucose effectiveness; or (4) a combination of these mechanisms. We used the "minimal model" to analyse the results of a 3-h intravenous glucose tolerance test to assess glucose effectiveness, insulin sensitivity and insulin responses in 12 non-diabetic cirrhotic patients, 8 diabetic cirrhotic patients and 10 normal control subjects. Fasting blood glucose levels were 4.8 +/- 0.2, 7.5 +/- 0.6 and 4.7 +/- 0.1 mmol/l, respectively. Fasting insulin and C-peptide levels were higher in both cirrhotic patient groups compared with control subjects. The glucose clearance between 6 and 19 min after i.v. glucose was lower in both cirrhotic groups (non-diabetic, 1.56 +/- 0.14, diabetic, 0.76 +/- 0.06, control subjects, 2.49 +/- 0.16 min-1%, both p < 0.001 vs control subjects). Serum insulin peaked at 3 and 23 min in the non-diabetic cirrhotic patients and control subjects; both peaks were higher in the non-diabetic cirrhotic patients and showed a delayed return to basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Diabetes Mellitus; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Injections, Intravenous; Insulin; Insulin Resistance; Liver Cirrhosis; Middle Aged; Tolbutamide

Topics: Abdominal Neoplasms; Adolescent; Adult; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Pancreatectomy; Transplantation, Autologous; Transplantation, Heterotopic

To characterize the mechanisms of insulin resistance in liver cirrhosis (LC), we estimated the peripheral tissue sensitivity and responsiveness to insulin using the euglycemic clamp technique and determined the insulin binding to erythrocytes in patients with compensated LC as well as in patients with non-insulin dependent diabetes mellitus (NIDDM). The insulin dose-response curves of the glucose metabolic clearance rates (MCR) were shifted to the right and downward both in patients with LC and NIDDM, indicating a reduced sensitivity and responsiveness to insulin. In the cirrhotics, MCR at the maximally effective insulin level, an index of insulin responsiveness, was correlated with fasting insulin levels (r = -0.57, P < 0.01) and sigma BG in 75 gOGTT (r = -0.43, P < 0.05), but no correlations were found between them and the diabetics. Although specific insulin bindings to erythrocytes were significantly lower in patients both with LC and NIDDM, Scatchard analysis revealed a significant decrease in the number of insulin receptors in the cirrhotics, and a decrease in the empty-site affinity in the diabetics. These findings suggest that insulin resistance in LC consists of a combination of binding and postbinding defects. The latter defect may be caused by basal hyperinsulinemia and contribute to the development of glucose intolerance. Although binding and postbinding abnormalities are also found in NIDDM, the mechanisms of insulin resistance in LC and NIDDM may be different.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Erythrocytes; Fatty Acids, Nonesterified; Female; Glucagon; Glucose Clamp Technique; Glucose Tolerance Test; Growth Hormone; Humans; Hydrocortisone; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; Receptor, Insulin

Insulin-induced glucose metabolism was investigated in 26 patients with biopsy-proven liver cirrhosis and 10 control subjects. Two glucose clamp protocols together with continuous indirect calorimetry were performed to examine whether reduced rates of glucose oxidation and/or nonoxidative glucose metabolism explain insulin resistance in liver cirrhosis. Using a 4-hour, two-step protocol (0-2 hours, plasma glucose 5.2 mmol/L, plasma insulin 92 mU/L to test the half-maximum response; 2-4 hours, hyperglycemia 10.0 mmol/L, plasma insulin 442 mU/L to test the maximum cellular glucose disposal) liver cirrhosis reduced glucose disposal to 45% and 60% of control values, respectively. Simultaneously, insulin-induced increases in glucose oxidation, plasma lactate levels, and lipogenesis were normal, whereas nonoxidative glucose metabolism was reduced (-82% and -47% of controls, respectively). To determine whether reduced nonoxidative glucose metabolism was caused by reduced glucose disposal, glucose disposal was "matched" to normal values in a subgroup of cirrhotic patients. Nonoxidative glucose metabolism values were normal, but plasma lactate concentrations disproportionally increased (+96%) after "matching" glucose disposal. Insulin resistance was independent of the etiology of the cirrhosis, the biochemical parameters of parenchymal cell damage and liver function, and the clinical and nutritional state of the patients. It is concluded that liver cirrhosis impairs insulin sensitivity and maximum cellular glucose disposal. Reduced glucose disposal is caused by defective glucose storage. Insulin resistance is independent of the etiology of liver cirrhosis and of the clinical and nutritional state of the patient.

Topics: Adult; C-Peptide; Energy Metabolism; Female; Glucose; Humans; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged

Topics: Adolescent; Adult; C-Peptide; Child; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Humans; Islets of Langerhans Transplantation; Liver Cirrhosis; Liver Transplantation; Middle Aged

Ten patients with non-alcoholic cirrhosis and ten control subjects were studied in basal conditions and after ingestion of a standard mixed test meal. Plasma somatostatin, blood glucose, plasma insulin, C-peptide and glucagon were determined before and 15, 30, 45, 60, 90, 120 and 180 min after the start of the meal. Basal somatostatin levels in patients (31.9 +/- 1.8 ng/l) were significantly higher (p less than 0.01) than in controls (12.5 +/- 0.9 ng/l). The time-course of the somatostatin secretory response after the meal was similar in the two groups, but the increase, evaluated as incremental area above baseline, was significantly smaller (p less than 0.01) in cirrhotics (804 +/- 134 ng/l per min) than in controls (1482 +/- 149 ng/l per min). Data indicate that elevated basal plasma somatostatin concentrations in cirrhosis may be consequent to elevated gastrointestinal and/or pancreatic secretion, whereas the blunted somatostatin response to the mixed test meal may derive from the hyperinsulinemia which occurs in the postprandial period.

Topics: Administration, Oral; Aged; Blood Glucose; C-Peptide; Fasting; Female; Food, Formulated; Glucagon; Glucose Tolerance Test; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Somatostatin; Time Factors

The in vivo dose response curve to insulin were studied, using an euglycemic insulin clamp technique, in 13 cirrhotic patients [8 with "hepatocellular" (HC) (nonalcoholics) and 5 with "cholestatic" (CHOL) cirrhosis] and 12 healthy controls (N). Subjects were studied in the basal state and during infusion of insulin at 3 different rates - 1, 3, 10 mU kg-1 min-1. Insulin responsiveness was similar in N and in HC, but it was 23% greater in CHOL (p less than 0.001). Insulin sensitivity was decreased in cirrhotics as compared with N but this difference was only significant (p less than 0.001) in HC. (ED50:62 + 5, 88 + 13 and 136 + 16 muu ml-1 in N, CHOL and HC respectively). Insulin clearance rate (ICR) was significantly (p less than 0.005) decreased in HC (1060 +/- 80, 996 +/- 95 and 776 +/- 128 ml sq m-1 ml-1 in N, CHOL and HC respectively. Basal hepatic glucose production (BHGP) was 39% lower in HC (p less than 0.005) and 24% lower in CHOL (p less than 0.05) than in N. Erythrocyte cholesterol phospholipid ratio was significantly elevated (p less than 0.001) in both groups of cirrhotic patients but was not correlated to specific metabolic changes described. In summary: i) intervariations in insulin dependent glucose metabolism were described in different cirrhotic groups; ii) basal hepatic glucose production and insulin clearance rate impaired in the different groups of cirrhotics; iii) the role of decreased cholesterol/phospholipid ratio on tissues glucose metabolism in cirrhotic patients should be further studied.

Topics: Adult; Blood Glucose; C-Peptide; Cholesterol; Erythrocytes; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Liver; Liver Cirrhosis; Liver Cirrhosis, Biliary; Male; Metabolic Clearance Rate; Middle Aged; Phospholipids

Hepatic insulin extraction is difficult to measure in humans; as a result, the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001), which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose, the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min), suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients, both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However, with oral glucose the rise in serum C-peptide concentration was relatively delayed, and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Blood Glucose; C-Peptide; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Liver Cirrhosis; Metabolic Clearance Rate

Insulin action on carbohydrate metabolism is known to be reduced in liver cirrhosis. However, little is known about the effect of insulin on free fatty acid (FFA) metabolism in these patients. To investigate this aspect we performed a two-step insulin euglycemic clamp in 11 cirrhotic patients and 6 controls. Insulin was infused at 0.25 mU/Kg min from 0 to 100 min and at 1 mU/Kg from 100 to 200 min. The FFA lowering capacity of insulin was studied during the first step; the glucose metabolizing capacity (M) was evaluated during the second step. In the cirrhotic patients, the M value was lower than in controls (3.91 +/- 0.48 vs 7.75 +/- 1.09 mg/kg/min, respectively). During the low insulin infusion, FFA and glycerol plasma levels were decreased in both groups. However, the ability of insulin to suppress plasma FFA and glycerol was lower in cirrhotics than in controls. In fact, at 100 min, FFA were 50% of basal values in cirrhotics and 20% in controls (p less than 0.01), while glycerol plasma levels decreased to 70% of basal values in patients and to 56% in controls. The slope of the linear regression obtained between Ln-FFA concentrations vs time was significantly less in cirrhotic patients than in controls (p less than 0.001). In addition, a positive correlation was found between the M value (r = 0.70; p less than 0.01) and the slope of the Ln-FFA in each patient. These findings suggest that in cirrhotic patients the effects of insulin on both FFA and glucose metabolism are reduced.

Topics: Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycerol; Humans; Insulin; Insulin Resistance; Kinetics; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Triglycerides

The authors report preliminary data on the behavior of some lipid fractions in cirrhosis of the liver and correlate them with the changes in the insulin, glucagon and C-peptide levels. Elevated FFA (Free Fatty Acids) and normal cholesterol, triglyceride and total lipid values indicate a prevalent insulin induced effect and a reduction of liver metabolism of these fractions. This hypothesis is supported by the fact that L-carnitine, which reestablishes the carnitine-dependent intracellular transport system, reduces the levels of all the lipid fractions studied. The normal C-peptide values in these patients with liver cirrhosis show that hyperinsulinemia is caused by impaired metabolism of this hormone and not by hyperincretion. This hyperinsulinemia seems to react positively to the improvement of the intracellular transport systems. A fall in the hyperglucagonemia follows the decreased hyperinsulinemia leading to a hormone balance with lower values and a consequent reduction of the hormonal stimuli on the lipid metabolism. The possibility of administering drugs, which can act on the metabolic pathways responsible for the high FFA plasma levels, which seem to play a role in the physiopathology of encephalopathies and hepatic coma is clinically interesting.

Topics: Adult; Aged; C-Peptide; Female; Glucagon; Humans; Insulin; Lipids; Liver Cirrhosis; Male; Middle Aged

Fourteen normal controls, eleven patients with non-alcoholic cirrhosis, twenty-nine with hepatocellular carcinoma (HCC) and six with HCC and hypoglycemia were studied. The tests performed include iv glucose tolerance test (25 g) and glucagon challenge test (2 mg). In cirrhosis, glucose intolerance and insulin resistance were demonstrated. The fasting hyperinsulinemia in cirrhosis is the result of decreased degradation as shown by the normal fasting C-peptide. The increased insulin responses to glucose, despite a normal C-peptide response, further supports the importance of impaired degradation in the pathogenesis of hyperinsulinemia after challenge. Despite a strong etiological association between cirrhosis and HCC, patients with HCC do not have significant hyperinsulinemia or glucose intolerance. This provides metabolic evidence to support the clinico-pathological observation that HCC occurred when cirrhosis was not advanced or in a precirrhotic stage. In HCC patients with clinically overt hypoglycemia, the fasting glucose, insulin and C-peptide were very low. The C-peptide responses to glucose and glucagon challenges were suppressed despite pharmacologic stimulation. This can be explained by the suppression of insulin secretion by a circulating substance secreted by hepatoma. The results support the pathogenetic importance of insulin-like activities recently detected in HCC patients with hypoglycemia.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carcinoma, Hepatocellular; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

The effect of glipizide on hepatic uptake of insulin was studied in five patients with liver cirrhosis and five patients with varying diseases in the biliary system and pancreas. All patients had portal catheters for diagnostic purposes. The hepatic uptake of insulin was estimated from the clearance rate for insulin obtained after a constant rate infusion into a peripheral vein and the portal vein. Each patient was examined on two consecutive mornings, the second investigation carried out one hour after oral glipizide administration. The fractional hepatic uptake was significantly lower in cirrhotic patients (17% +/- 6%) than in the other patients (52% +/- 7%; P less than .01). After glipizide, an increase in the estimated uptake of insulin occurred in cirrhotic patients (from 17% +/- 6% to 39% +/- 6%; P less than .01), whereas an insignificant decrease was observed in the other patients (from 52% +/- 7% to 43% +/- 11%).

Topics: Adult; Aged; Blood Glucose; C-Peptide; Female; Glipizide; Humans; Insulin; Liver; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; Sulfonylurea Compounds

Extrarenal mechanisms are important in the defense against hyperkalemia. During a potassium load, cellular uptake is essential to avoid severe hyperkalemia. Liver and muscles represent the major buffering system, partially mediated by insulin, in the distribution of potassium between intracellular and extracellular fluids. To study the potential role of the liver, we administered an oral load of potassium (0.75 mEq/kg) to nine male patients with compensated cirrhosis and ten normal subjects of similar age, sex, and weight. Despite identical renal excretion, cirrhotic patients had higher potassium levels two and three hours after oral administration. Moreover, only cirrhotic patients presented a clear-cut increase in serum C-peptide concentration after the potassium load without any change in glucose level. It is likely that, in cirrhosis, liver failure contributes to the decrease in hepatic cellular potassium uptake despite insulin hypersecretion.

Topics: Administration, Oral; Adult; C-Peptide; Homeostasis; Humans; Insulin; Liver; Liver Cirrhosis; Male; Middle Aged; Muscles; Potassium

The purpose of the present study was to elucidate the interrelationship between pancreatic polypeptide (PP) and other pancreatic endocrine hormones. For this purpose, a radioimmunoassay (RIA) system of plasma PP was established and the changes in plasma PP, plasma immunoreactive insulin (IRI), plasma C-peptide reactivity (CPR) and plasma immunoreactive glucagon (IRG) following oral administration of glucose were examined in ten normal subjects and twenty-five patients with liver cirrhosis. Patients with liver cirrhosis were classified into a normal glucose tolerance group (NGT), an impaired glucose tolerance group (IGT), and a diabetes mellitus group (DM) on the basis of the glucose tolerance curves obtained after the oral administration of glucose. In the IGT and DM groups, fasting plasma PP levels were significantly elevated when compared with those in the control and NGT groups. Also oral administration of 75g glucose elicited an exaggerated rise in plasma PP in the IGT and DM groups when compared with the response in the control and NGT groups. On the other hand, PP response to glucose in the NGT group was similar to that in the control group. Plasma IRI increased markedly before and after oral administration of glucose in the IGT and DM groups when compared with the control groups. In these patients, plasma levels of CPR almost paralleled those of IRI. No significant difference was noted between the NGT group and the control group with regard to plasma IRI and CPR levels before and after oral glucose loading. Accordingly, insufficient insulin action was considered to exist in the IGT and DM groups. This insufficiency in insulin action was expressed in terms of the indices of increase in plasma IRI and CPR, delta IRI/delta BS and delta CPR/delta BS, which corresponded to the elevated blood glucose levels, being significantly lower in the IGT and DM groups than in the control and NGT groups 30 minutes after oral administration of glucose. No significant difference was noticeable between the NGT group and control group with regard to these indices. In the patients with liver cirrhosis, the delta PP value, obtained by subtracting the plasma PP level during fasting from the PP level 30 minutes after oral glucose loading, was inversely correlated with the values of both delta IRI/delta BS and delta CPR/delta BS.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: C-Peptide; Diabetes Complications; Diabetes Mellitus; Glucagon; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Liver Cirrhosis; Middle Aged; Pancreatic Hormones; Pancreatic Polypeptide; Radioimmunoassay

Propranolol, a non-selective beta-blocker, is known to decrease glucagon release in normal subjects. The present study was aimed at investigating the effects of propranolol on the hyperglucagonism commonly observed in patients with cirrhosis. Eight cirrhotic patients and 6 matched healthy controls were studied. The plasma concentrations of glucagon, insulin, c-peptide and glucose were measured in basal conditions and after stimulating glucagon secretion by an i.v. infusion of arginine (0.4 g/kg/30 min). The study was repeated 24 h later after inducing beta-blockade by the i.v. infusion of propranolol (10 mg). In baseline conditions, patients with cirrhosis, despite normal levels of insulin and glucose, had a marked hyperglucagonism (654 +/- 303 pg/ml vs. 269 +/- 90 in controls, P less than 0.01). Prior to propranolol, arginine infusion caused greater glucagon release in cirrhotics (71 +/- 31 ng.h.ml-1) than in controls (33 +/- 17 ng.h.ml-1, P less than 0.02), but despite a similar insulin secretion (assessed from c-peptide), blood glucose did not increase. After propranolol, glucagon secretion decreased as expected in controls (29 +/- 12 ng.h.ml-1, P less than 0.05) but experienced a paradoxical increase in cirrhotics (113 +/- 64 ng.h.ml-1, P less than 0.05). Again, despite the marked increase in glucagon release, there was no increase in glucose production, providing further evidence of the glucagon resistance that accompanies hyperglucagonism in cirrhosis. Our results suggest that hyperglucagonism with glucagon resistance might be the initial disturbance in carbohydrate metabolism in patients with cirrhosis. Contrary to what could be expected, propranolol does not correct but further accentuates this disturbance.

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Drug Resistance; Female; Glucagon; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Propranolol

To clarify the pathogenesis of impaired glucose tolerance in patients with cirrhosis, several factors possibly affecting carbohydrate metabolism were studied in 12 cirrhotic patients with different blood glucose responses to an oral glucose tolerance test. Glucose levels, 120 min after the load, were inversely and significantly related to insulin sensitivity, measured by means of the euglycemic "glucose clamp" technique (r = -0.746). Basal and glucose-induced insulin secretion (insulin and C-peptide levels) only slightly correlated with glucose tolerance, which was not related to functional liver cell mass (galactose elimination), portal-systemic shunting (degree of varices at endoscopy), or maximal glucose-independent insulin secretion (peak C-peptide levels after a glucagon test). Multiple regression analysis identified insulin sensitivity and liver cell mass as the independent variables able to explain most of the variance of 120-min blood glucose (about 84%), and both of them contributed considerably to the regression. While reduced insulin sensitivity is probably the main cause of impaired glucose tolerance, the reduced hepatocellular mass only appears to modulate the degree, and therefore the clinical relevance, of this defect.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Female; Galactose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Liver; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Regression Analysis

A radioimmunoassay using a proinsulin-specific antiserum that does not react preferentially with the split forms of proinsulin has been used to compare the response of circulating proinsulin to low (25 g) and high (75 g) oral glucose loads in healthy subjects and in patients with liver cirrhosis. The patients were divided into two groups: Group A (n = 7) with normal glucose tolerance and Group B with diabetic (n = 5) and impaired (n = 1) glucose tolerance. There was no apparent correlation between glucose tolerance and the results of quantitative liver function tests. In the fasted state, the concentrations of serum proinsulin did not differ significantly in patients of Group A (0.022 +/- 0.002 nmol/l) or Group B (0.026 +/- 0.004 nmol/l) from those in healthy subjects (0.021 +/- 0.002 nmol/l). After 75 g glucose, the rise in serum proinsulin to a maximum concentration of 0.082 +/- 0.012 nmol/l in patients of Group A and to 0.070 +/- 0.019 nmol/l in Group B was not significantly different at any time point up to 180 min from the rise in healthy subjects (to 0.063 +/- 0.005 nmol/l). After 25 g glucose, the response of serum proinsulin in Group B patients (maximum concentration 0.035 +/- 0.003 nmol/l) was not significantly different from that in healthy subjects (maximum concentration 0.032 +/- 0.003 nmol/l) but a slightly enhanced release was observed in the Group A patients (maximum concentration 0.049 +/- 0.003 nmol/l) that was significantly greater (P less than 0.05) at 60 min post-glucose. In contrast, the concentrations of serum immunoreactive insulin and immunoreactive C-peptide in all patients with cirrhosis were significantly elevated compared with healthy subjects both in the fasted state and at several time points following high and low oral glucose. In the fasted state, the serum proinsulin/C-peptide molar ratio, an index of the relative state of secretion of proinsulin and insulin, was significantly lower (P less than 0.05) in both groups of cirrhotic patients than in healthy subjects. After high and low glucose, this ratio fell in all patients and in the healthy subjects. We conclude that cirrhosis of the liver is associated with a hypersecretion of insulin but hyperproinsulinaemia does not contribute appreciably to the elevated concentration of immunoreactive insulin in the peripheral circulation.

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Fasting; Female; Glucose; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Proinsulin

Hyperinsulinemia in human cirrhosis is generally considered an expression of reduced hepatic insulin degradation. To determine whether hyperinsulinemia may also depend on an altered feedback inhibition of insulin secretion, we performed euglycemic hyperinsulinemic clamp studies, infusing 40, 372, or 1280 mU/m2 X min biosynthetic human insulin in 30 compensated cirrhotic patients with portal hypertension and impaired glucose tolerance and 25 normal subjects, matched for age, sex, and weight. Mean fasting plasma insulin was significantly higher in cirrhotic patients [26.1 +/- 2.3 vs. 12.4 +/- 0.6 (+/- SE) microU/ml; P less than 0.001], while fasting plasma glucose levels were similar in the 2 groups. The mean plasma C-peptide level was significantly higher in cirrhotic patients, both basally (2.7 +/- 0.1 vs. 1.7 +/- 0.1 ng/ml; P less than 0.001) and during the clamp studies. Suppression of C-peptide at 120 min of the clamp was significantly less in cirrhotic patients (37 +/- 7% vs. 79 +/- 4%, 52 +/- 9% vs. approximately 100%, and 54 +/- 4% vs. approximately 100% during the 40, 372, and 1280 mU/m2 X min insulin infusions, respectively). The fasting C-peptide to insulin molar ratio was significantly lower in cirrhotic patients (5.4 +/- 0.3 vs. 6.4 +/- 0.3; P less than 0.005). The MCR of insulin at the three steady states was not significantly different between the 2 groups, whereas the basal systemic delivery rate of insulin was significantly higher in cirrhotic patients (14.7 +/- 1.7 vs. 6.5 +/- 0.4 mU/m2 X min; P less than 0.001). These results suggest that reduced feedback inhibition of insulin secretion may contribute to the hyperinsulinemia associated with cirrhosis.

Topics: Adult; Blood Glucose; C-Peptide; Feedback; Female; Humans; Insulin; Insulin Infusion Systems; Insulin Secretion; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged

Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinaemia. It is considered an insulin resistant state with both a receptor and a post-receptor defect of insulin activity. It would appear that reduced hepatic degradation rather than increased B-cell production is responsible for hyperinsulinaemia. The effect of surgical portosystemic shunt on insulin resistance was studied in 18 cirrhotics with impaired glucose tolerance (12 males, 6 females; mean age 46.9 +/- 0.7 years) by measuring: glucose production (3H-glucose infusion), glucose utilisation (euglycaemic clamp at approximately 100, approximately 1000 and approximately 10,000 microU/1), plasma insulin and C-peptide levels, and liver function indices (serum bilirubin, albumin, ALT, GGT) before and 2 months after surgery. Liver sorbitol clearance was also employed to measure variations in the functional liver plasma flow induced by the shunt. No significant changes were noted in: glucose production (1.94 +/- 0.17 SEM vs 1.96 +/- 0.17 mg/kg/min), glucose utilisation (metabolic clearance rate: 3.32 +/- 0.48 vs 3.42 +/- 0.43 at approximately microU/ml; 9.70 +/- 1.0 vs 9.16 +/- 0.9 at approximately 1000 microU/ml; 10.92 +/- 1.1 vs 11.07 +/- 0.8 ml/kg/min at approximately 10 000 microU/ml), fasting plasma insulin, C-peptide and C-peptide/insulin molar ratio (4.66 +/- 0.47 vs 5.50 +/- 0.54), and the liver function indices. By contrast, there was a significant decrease in functional liver plasma flow (813 +/- 34 vs 604 +/- 34 ml/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Portacaval Shunt, Surgical; Sorbitol

The liver plays a key role in glucose homeostasis and insulin metabolism. Altered glucose and insulin levels in peripheral blood are common findings in chronic liver disease. The aim of the present study was to investigate the effect of surgical portosystemic shunt on plasma glucose and insulin responses to glucose administration in a group of cirrhotic patients. For this purpose 10 cirrhotic subjects (8 males and 2 females) aged 42 to 65 years underwent an oral glucose tolerance test (OGTT, 75 g), and an intravenous glucose tolerance test (IVGTT, 0.33 g/kg) before and after undergoing a side-to side portocaval anastomosis (PCS). 6 noncirrhotic, nondiabetic patients matched for sex, age and body weight who underwent abdominal vascular surgery served as controls. In cirrhotic subjects, the PCS resulted in: increased plasma glucose and insulin levels during OGTT; decreased C-peptide level during OGTT; unmodified plasma glucose and insulin concentrations during IVGTT. In control subjects the abdominal surgery did not affect plasma glucose and insulin responses to oral or intravenous glucose loads. These results suggest that in cirrhotic subjects surgical portocaval shunt results in: deterioration of oral but not intravenous glucose tolerance, due to an escape of ingested glucose from the liver; increased peripheral insulin response to oral glucose administration as a consequence of reduction in hepatic removal of the hormone; and decreased pancreatic response to oral glucose due possibly to a greater feed back inhibition of beta-cell. These events seem to be a consequence of the shunt per se and not of a deterioration of hepatocellular function.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Insulin; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Male; Middle Aged; Portacaval Shunt, Surgical

The content of insulin and C-peptide-like immunoreactivity (CPR) were determined in the tail of pancreas from 35 autopsied diabetic and 21 non-diabetic subjects. In the 28 diabetics who had been followed for more than 6 months, the relation between the amount of insulin or CPR in the pancreas and the stability of fasting serum glucose during diabetic life before death was analyzed together with the relation between the serum CPR response to the breakfast tolerance test before death and insulin content at autopsy. As an index of the instability of the blood sugar level, the standard deviation of the mean of 15 successive determinations of fasting serum glucose was used. Both insulin and CPR content in the pancreas were significantly decreased in diabetics as compared with non-diabetics. SD of the mean fasting serum glucose and insulin or CPR content in the tail of pancreas showed a significant inverse correlation on a logarithmic scale (P less than 0.01, r = -0.704 and P less than 0.01, gamma = -0.757, respectively). Serum CPR value during the breakfast tolerance test correlated significantly with the insulin content in the pancreas of diabetic subjects. These findings suggest that one of the causes of the instability of fasting serum glucose levels is the devastation of pancreatic beta-cells and that the pancreatic insulin content is logarithmically and inversely related to fluctuations in fasting serum glucose.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fasting; Female; Food; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Pancreas

Levels of plasma cyclic AMP, serum immunoreactive insulin (IRI), serum c-peptide immunoreactivity (CPR) and blood sugar (BS) were determined 0, 15, 30, 45 and 60 min after a glucagon injection (0.01 mg per kg body weight) in normal controls, patients with acute hepatitis and liver cirrhosis. Plasma cyclic AMP responses to glucagon in liver disease patients varied widely in peak value, and only in patients with fulminant hepatitis and decompensated liver cirrhosis with poor prognosis was the response suppressed. The peak response of BS was found significantly later in liver cirrhosis patients than in normal controls. IRI and CPR responses to glucagon were lower in acute hepatitis patients than in normal controls and liver cirrhosis patients. IRI levels and their sum were also lower in acute hepatitis patients, although CPR levels were not significantly different. Thus, the ratio of the sum of CPR from 0 to 60 min to that of IRI was significantly higher in acute hepatitis, indicating impaired pancreatic secretion of insulin to glucagon stimulation as well as increased uptake of insulin by the liver in acute hepatitis.

Topics: Adult; Blood Glucose; C-Peptide; Cyclic AMP; Female; Glucagon; Hepatitis, Viral, Human; Humans; Insulin; Kinetics; Liver Cirrhosis; Liver Diseases; Male; Middle Aged

To study the role of pancreatic beta-cell function in glucose intolerance and frank diabetes that sometimes develops in cirrhosis, the C-peptide response to a bolus IV injection of 1 mg of glucagon was measured in nine controls and in two groups of patients with cirrhosis. The first group comprised nine subjects with normal or high-normal fasting plasma glucose and no glycosuria; five of them had impaired glucose tolerance. The second group consisted of eight cirrhotics in whom frank diabetes had developed six to 48 months after the diagnosis of cirrhosis. They were characterized by fasting plasma glucose greater than 140 mg/dL and permanent glycosuria. No differences in the degree of liver impairment or portal-systemic shunting were observed between the two groups. Plasma glucose response to glucagon was similarly reduced in cirrhotic subjects. Basal C-peptide was high normal in patients with cirrhosis, and significantly increased in nondiabetic subjects. By contrast peak C-peptide levels and total C-peptide responses to glucagon were low normal in cirrhotics and significantly reduced in patients with cirrhosis and diabetes. In 14 patients the C-peptide response to a standard meal was also measured. It was significantly reduced in patients with cirrhosis and diabetes (six cases), as compared to cirrhotic subjects without diabetes. Peak C-peptide after IV glucagon significantly correlated with peak C-peptide after the meal (r = .927), or total C-peptide response to meal (r = .871). Impaired insulin secretion may add to insulin resistance in patients with liver cirrhosis, leading to the development of frank diabetes, characterized by fasting hyperglycemia and glycosuria.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Eating; Female; Glucagon; Humans; Insulin; Islets of Langerhans; Liver Cirrhosis; Male; Middle Aged

Topics: Blood Glucose; C-Peptide; Female; Glucagon; Glucose Tolerance Test; Growth Hormone; Humans; Insulin; Liver Cirrhosis; Male

One hundred consecutive patients with nonautoimmune chronic active hepatitis (51% HBsAg-positive), 50 patients with cirrhosis (38% HBsAg-positive), 25 patients with chronic persistent hepatitis, and 118 patients with hepatoma who were seen at this hospital were reviewed to determine the prevalence and characteristics of glucose intolerance and diabetes in these conditions. Diabetes (fasting serum glucose greater than 7.8 mmol/L, 140 mg/dl on two separate occasions) was present in 8% of patients with chronic persistent hepatitis and mild chronic active hepatitis, 44% of patients with severe chronic active hepatitis, 40% of patients with cirrhosis, and 15% of patients with hepatoma, compared with 7% of all other patients aged 35 yr or over, undergoing liver biopsy. Compared with this high prevalence of diabetes in liver disease, only 3% of diabetic patients referred to the hospital diabetic clinic had chronic hepatitis or cirrhosis. Glucose tolerance was similar in chronic active hepatitis and cirrhosis and was characterized initially by basal hyperinsulinemia, normal basal glucose levels but elevated serum glucose following glucose loading, and evidence of insulin resistance. We suggest that the high prevalence of diabetes in chronic active hepatitis and cirrhosis in Saudi Arabia is due to the insulin resistance of chronic liver disease acting over many years in a population with a high genetic predisposition to diabetes.

Topics: Adrenal Cortex Hormones; C-Peptide; Carcinoma, Hepatocellular; Diabetes Complications; Diabetes Mellitus; Female; Glucose Tolerance Test; Hepatitis, Chronic; Humans; Infant; Insulin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged

Insulin and C-peptide in venous blood were determined during oral glucose tolerance testing in 59 non-manifest diabetics with histologically established chronic liver disease (fatty degeneration, chronic aggressive hepatitis, cirrhosis). Glucose tolerance was pathologic in 60-80% of patients. When compared to a control group patients with chronic liver disease showed significantly increased values of blood glucose (after glucose intake), of insulin and of C-peptide (fasting and after glucose intake). The C-peptide/insulin ratio, a measure of hepatic insulin degradation, was significantly decreased after glucose uptake. There were no significant differences of blood sugar, insulin and C-peptide among the various liver diseases. In chronic aggressive hepatitis and in cirrhosis the C-peptide/insulin ratio was partly significantly lower than in fatty degeneration. From the increased C-peptide values increased insulin secretion in chronic liver diseases can be deducted. In addition, the decreased C-peptide/insulin ratios show an impairment of insulin degradation in liver cirrhosis and other chronic hepatic diseases. However, in fatty liver degeneration this is clearly less pronounced than in more serious liver diseases.

Topics: C-Peptide; Chronic Disease; Fatty Liver; Female; Glucose Tolerance Test; Hepatitis, Chronic; Humans; Insulin; Liver Cirrhosis; Liver Diseases; Male; Middle Aged

Proinsulin, insulin and C-peptide levels were investigated in chronic renal, hepatic and muscular disorders. The proinsulin levels in human plasma were determined by radioimmunoassay using insulin-degrading enzyme (IDE). The fasting levels of proinsulin in 29 patients with chronic renal failure (0.95 +/- 0.05) were significantly higher than those in 10 patients with liver cirrhosis (0.46 +/- 0.04), six with muscular dystrophy (0.37 +/- 0.02) and 52 normal subjects (0.24 +/- 0.02 ng/ml, mean +/- S.E.). The fasting levels of insulin and C-peptide in chronic renal failure were also the highest among these groups. The insulin levels in liver cirrhosis and muscular dystrophy were significantly greater than those in normal subjects and increased molar ratios of proinsulin to total insulin immunoreactivity in chronic renal failure were observed. These results suggest that the kidney, liver and muscle are related to circulating insulin levels and that the kidney plays a particularly important role in circulating proinsulin levels. It can be concluded that increases in these peptides are due to a hypersecretion of B-cells, a decreased degradation or excretion.

Topics: C-Peptide; Humans; Insulin; Kidney Failure, Chronic; Liver Cirrhosis; Muscular Dystrophies; Proinsulin

The possible contribution of hepatocellular damage and portal-systemic shunting to hyperinsulinism in cirrhosis was studied in 23 cirrhotics, 8 of whom had a surgical portacaval shunt, and 16 controls by measuring insulin and the connecting peptide (C-peptide) concentrations in simultaneous samples of peripheral arterial and hepatic venous blood. The fractional hepatic insulin extraction (0.48 +/- 0.06, mean +/- SE) was normal in cirrhosis. The hepatic insulin elimination rate was directly related to arterial insulin levels (r = 0.91, P less than 0.001) even at very high circulating levels. Extrahepatic insulin metabolism was measured across the kidney and lower limb. There were no significant differences between cirrhotics and control subjects in relation to renal (0.25 +/- 0.05 vs. 0.23 +/- 0.04) and lower limb insulin extraction (0.14 +/- 0.07 vs. 0.19 +/- 0.04). While in the control group hepatic venous insulin (0.143 +/- 0.018 pmol/ml) markedly exceeded the peripheral insulin concentration (0.083 +/- 0.009 pmol/ml, P less than 0.01), the contrary was found in cirrhotics with end-to-side portacaval shunt in whom all the pancreatic venous effluent is shunted to the systemic circulation (hepatic venous insulin, 0.130 +/- 0.028 pmol/ml; peripheral, 0.234 +/- 0.037 pmol/ml; P less than 0.01). Portal-hypertensive cirrhotics without a surgical portacaval shunt also had hepatic venous insulin levels (0.132 +/- 0.029 pmol/ml) below peripheral arterial insulin concentrations (0.205 +/- 0.041 pmol/ml, P less than 0.01). The study suggests that hyperinsulinism in cirrhosis is not the result of an intrinsic defect of hepatic insulin metabolism but of the spontaneous shunting of portal blood to the systemic circulation.

Topics: C-Peptide; Humans; Hyperinsulinism; Hypertension, Portal; Insulin; Kidney; Liver; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Portal System; Portasystemic Shunt, Surgical

Tissue sensitivity to insulin and insulin metabolic clearance rate were assessed by means of the euglycemic clamp technique in 11 controls and 11 patients with liver cirrhosis. The method was carried out using an artificial endocrine pancreas. The amount of glucose infused to keep euglycemia, as well as the ratio of glucose infused to steady-state insulin level, were significantly lower in cirrhotics as compared to controls (p less than 0.001). The metabolic clearance rate of insulin did not show significant differences between the two groups. Our results confirm that a marked insulin resistance is present in cirrhotics, as previously shown by means of different techniques.

Topics: Adult; Blood Glucose; C-Peptide; Female; Humans; Insulin; Insulin Infusion Systems; Insulin Resistance; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged

The mechanism for the hyperinsulinaemia in cirrhosis was investigated using two different approaches. In the first study, the metabolic clearance rate of insulin was measured at steady state in 13 cirrhotic and 13 weight-matched control subjects. With comparable insulin infusion rates (1.00 +/- 0.19 versus 1.07 +/- 0.15 mU/kg/min), steady-state plasma insulin concentrations (104 +/- 25 versus 87 +/- 12 microU/ml; P greater than 0.5) and MCRIRI (13.6 +/- 1.6 versus 15.4 +/- 2.0 ml/kg/min; P greater than 0.5) were similar. In the second study, fasting and oral glucose stimulated C-peptide/insulin ratios were compared in 16 cirrhotic and 18 weight matched control subjects. Although fasting glucose levels were significantly higher in the cirrhotic groups, all values were in the normal range (5.5 +/- 0.3 versus 4.8 +/- 0.1 mmol/l, P less than 0.02). However, fasting insulin (0.171 +/- 0.02 versus 0.068 +/- 0.004 nmol/l) and C-peptide (1.02 +/- 0.13 versus 0.42 +/- 0.02 nmol/l) were strikingly higher (P less than 0.001) in cirrhotic subjects. On the other hand, fasting C-peptide/insulin ratios were not statistically different in the two groups (6.18 +/- 0.52 versus 6.77 +/- 0.46; P greater than 0.3). This suggests that beta cell hypersecretion was the principal cause of the fasting hyperinsulinaemia, rather than decreased insulin hepatic extraction. Following the glucose load in 13 of the control and seven of the cirrhotic group, the C-peptide/insulin ratio fell in both groups but was significantly lower in the cirrhotic compared to control subjects at 30, 60 and 120 min, consistent with possible impairment of hepatic insulin extraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged

To study the interdependence of utilization of branched chain amino acids and glucose and of hyperinsulinaemia in patients with liver cirrhosis the plasma disappearance of glucose and amino acids was estimated in seven patients with cirrhosis and portocaval shunt and in seven healthy controls following infusion of glucose and essential amino acids during suppression of endogenous hormone release by somatostatin. Exogenous insulin was infused by means of an automated glucose controlled insulin infusion system. The data demonstrate that (i) insulin requirement almost doubled in patients as compared to controls to obtain similar blood glucose responses to i.v. glucose, and (ii) the plasma disappearance rates of the infused amino acids were reduced in the patients as compared to controls despite hyperinsulinaemia sufficient to achieve normal glucose assimilation. Thus, in cirrhotic patients insulin resistance may be overcome by excess insulin as far as glucose homoestasis is concerned, whereas amino-acid metabolism still remains impaired.

Topics: 3-Hydroxybutyric Acid; Adult; Amino Acids; Blood Glucose; C-Peptide; Catecholamines; Fatty Acids, Nonesterified; Female; Glucagon; Growth Hormone; Humans; Hydrocortisone; Hydroxybutyrates; Insulin; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Portacaval Shunt, Surgical; Reference Values

Topics: Adolescent; Adult; Aged; C-Peptide; Carbohydrate Metabolism; Diabetes Complications; Female; Humans; Insulin; Insulin Secretion; Liver; Liver Cirrhosis; Male; Middle Aged

The levels of proinsulin, immunoreactive insulin, true insulin (calculated from the difference, namely immunoreactive insulin-proinsulin) and C-peptide were determined in the fasting state and during a 3-h oral glucose tolerance test after administration of 100 g of glucose in 12 patients with cirrhosis with normal oral glucose tolerance test (50 g) and in 12 healthy subjects serving as controls. In the patients with cirrhosis the serum levels of proinsulin and immunoreactive insulin were significantly higher in the fasting state and after glucose loading than in the healthy subjects. The serum level of true insulin was also higher in the patients with cirrhosis, but the difference was less pronounced and only significant at a few of the time points. The serum level of C-peptide was very similar in both groups. These results emphasize that cirrhosis is a condition in which the serum proinsulin level is raised and that this hyperproinsulinaemia contributes greatly to the increased immunoreactive insulin levels observed in patients with this disease.

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Proinsulin

In order to clarify the mechanism of insulin secretion, responses of insulin (IRI) and C-peptide (CPR) in plasma to various stimuli were investigated in normal subjects and patients with diabetes mellitus, liver cirrhosis, chronic nephritis or insulinoma. The response of plasma IRI and CPR to oral glucose load was less marked in the mild and moderate diabetes groups than in the normal controls. Neither IRI nor CPR in the severe diabetes group responded to oral glucose. The patients with liver cirrhosis revealed an exaggerated and delayed response of IRI and CPR, and a lowered CPR/IRI ratio, indicating a remarkable response of IRI to glucose. In contrast, the patients with chronic nephritis showed a prominent rise of CPR alone. In the insulinoma patients, both plasma IRI and CPR increased after glucose load. In the response to glucose, there was approximately 30-min lag time between the peaks of IRI and CPR in the normal controls and the patients with various diseases. Following arginine infusion, plasma IRI and CPR increased in the normal subjects and the patients with moderate diabetes. In the normal subjects, plasma IRI reached a peak at 6 min and 3 min in response to tolbutamide and glucagon, respectively, which elicit an abrupt and sharp rise of insulin from B-cells. However, diabetic patients showed a minimal change in plasma IRI and CPR, whereas there was an exaggerated response of plasma IRI and CPR in insulinoma patients. In analysis of responses of plasma IRI and CPR to tolbutamide or glucagon, there was a lag time longer than 10 min in the normal subjects. The present study confirms the concurrent release of C-peptide from the B-cells in the secretion of insulin. In addition, it was suggested that insulin and C-peptide are mainly handled in the liver and the kidney, respectively. Furthermore, a longer lag time between the peaks of IRI and CPR in response to tolbutamide or glucagon did not necessarily indicate a simultaneous release of insulin and C-peptide from the B-cell, but a delayed release of the latter.

Topics: Adult; Aged; Arginine; C-Peptide; Diabetes Mellitus; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Liver Cirrhosis; Male; Middle Aged; Nephritis; Pancreatic Neoplasms; Peptides; Tolbutamide

Topics: Adult; Aged; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Growth Hormone; Humans; Hydrocortisone; Insulin; Liver Cirrhosis; Male; Middle Aged; Regression Analysis; Time Factors

The responses of portal, hepatic and peripheral venous blood glucose (BG), plasma insulin (IRI) and C-peptide (IRC) levels to iv tolbutamide (200 mg) have been determined in 9 non-diabetic patients with liver cirrhosis and in 6 control subjects. The basal levels of plasma IRI and IRC were similar in patients and controls as were the portal and peripheral BG levels. In the hepatic vein, however, the BG-levels were higher in cirrhotic patients than in controls. After tolbutamide administration the BG-levels were unchanged in the cirrhotic patients but a significant fall in hepatic vein BG was observed in controls. In both groups of subjects the highest post-tolbutamide IRI-levels were found in the portal vein whereas the corresponding IRC-levels were as high in the hepatic as in the portal vein. The increments of portal venous IRI and IRC were significantly higher in controls as compared to the cirrhotic patients. Nevertheless, in the peripheral veins the increments of IRI and IRC were very similar in both groups of subjects or even less in the control subjects. The results suggest that in patient with liver cirrhosis the secretion of insulin is not increased but slightly decreased. The production of glucose by the liver also seems to be increased either due to insulin resistance or portal venous shunting of insulin.

Topics: Adult; Blood; Blood Glucose; C-Peptide; Female; Hepatic Veins; Humans; Insulin; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Male; Middle Aged; Peptides; Portal Vein; Tolbutamide; Veins

Topics: Amino Acids; Ammonia; Ammonium Chloride; C-Peptide; Female; Glucagon; Humans; Infusions, Parenteral; Insulin; Liver Cirrhosis; Male; Middle Aged

Key enzymes of gluconeogenesis in the liver, phosphoenolpyruvate carboxykinase [EC 4.1.1.32] and glucose-6-phosphatase [EC 3.1.3.9], were studied in patients with primary or metastatic hepatic cancer. Liver specimens for enzyme assay were obtained by necropsy performed within four hours after death. It was confirmed that both enzyme activities in rat liver preserved at 4 degrees C remained unchanged within nine hours after the removal of the tissue. Activities of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase decreased to below ten per cent of the control in neoplastic liver tissue of patients with hepatocellular carcinoma accompanied with liver cirrhosis. These two enzyme activities in cirrhotic tissue of patients with hepatocellular carcinoma were lower than those in patients merely with cirrhosis. In patients with metastatic hepatic cancer both two enzyme activities further decreased and were scarcely detected not only in neoplastic tissue but also in non-neoplastic tissue. These results show that hepatic gluconeogenesis markedly decreases in patients with primary or metastatic hepatic cancer. The biochemical analysis of the blood in hepatic cancer, decreased in blood glucose and release in immunoreactive glucagon, also suggested the suppression of gluconeogenesis.

Topics: Adult; Aged; Animals; Blood Glucose; C-Peptide; Carcinoma, Hepatocellular; Female; Glucagon; Gluconeogenesis; Glucose-6-Phosphatase; Humans; Insulin; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Phosphoenolpyruvate Carboxykinase (GTP); Rats

To elucidate the relative contribution of parenchymal liver damage and spontaneous portal-systemic shunting to the reduction of peripheral insulin degradation rate and the decrease in plasma concentrations of three branched chain amino acids (valine, leucine, and isoleucine), plasma insulin, C-peptide, and amino acid concentrations were measured during oral glucose tolerance tests in 17 patients with liver cirrhosis, 10 with idiopathic portal hypertension, 5 hospitalized controls, and normal subjects. None of the patients had evidence of hepatic encephalopathy. Patients with idiopathic portal hypertension had histologically minimum hepatic fibrosis in spite of the existence of extensive exophageal varices. The molar ratio between plasma concentrations of C-peptide and insulin was significantly decreased in patients with cirrhosis, but not in those with idiopathic portal hypertension. In both patients with cirrhosis and idiopathic portal hypertension, the three branched chain amino acid levels were significantly decreased and the molar ratio between the concentrations of the three branched chain amino acids and two aromatic amino acids (tyrosine and phenylalanine) were markedly reduced. These results suggest that spontaneous portal-systemic shunting does not primarily contribute to the reduced degradation of insulin, but has a close relationship with the decrease in branched chain amino acid levels and in the molar ratio of plasma amino acids. In addition, the present data indicate that decreased branched chain amino acid levels in patients with cirrhosis is not merely ascribed to hyperinsulinemia and that the decrease in the molar ratio of plasma amino acids is not specific to the presence of hepatic encephalopathy.

Topics: Adult; Aged; Amino Acids; Amino Acids, Branched-Chain; C-Peptide; Female; Glucose Tolerance Test; Humans; Hypertension, Portal; Insulin; Liver Cirrhosis; Male; Middle Aged; Phenylalanine; Portal System; Tyrosine

Plasma levels of IRI, C-peptide and glucagon were determinated in 19 patients with liver cirrhosis and 9 control subjects after an oral glucose load (OGTT). 9 of the cirrhotics showed chemical diabetes, the remaining 7 cases showed ascites and a normal OGTT. Both groups of cirrhotics showed high IRI and C-peptide values in basal conditions, peaks of these parameters, higher than those observed in the control subjects, were found during the OGTT. The C-peptide/IRI ratio, which was lower than normal both during fasting and after glucose load, presented the lowest value in patients with ascites. In the conditions adopted for this study, glucagon showed higher plasma levels in all the cirrhotics studied than those found in the controls, but the highest levels were found in patients with ascites and with a normal OGTT. It can be concluded that the high levels of insulin found in liver cirrhosis are due to a B-pancreatic hypersecretion (high C-peptide levels) but are also maintained by a decreased hepatic degradation of the hormone (C-peptide/IRI ratio below normal). Hyperglucagonemia is not the chief factor in determining the insulin-resistance observed in liver cirrhosis.

Topics: Adult; Aged; Ascites; C-Peptide; Female; Glucagon; Humans; Hyperglycemia; Hyperinsulinism; Insulin; Liver Cirrhosis; Male; Middle Aged; Peptides

Insulin degradation was measured by the C-peptide/insulin ratio in 19 patients with portal vein block with extensive spontaneous portal-systemic shunting but minimal liver cell damage: 13 patients with biopsy-proved cirrhosis and 12 controls. Blood obtained fasting and for 3 hr after oral glucose was assayed for glucose, insulin, and C-peptide. Fasting C-peptide and insulin levels in patients with portal vein block and those in controls did not differ. Eight of 13 cirrhotic patients had fasting hyperinsulinemia with a significantly reduced C-peptide/insulin ratio. After glucose administration, the C-peptide/insulin ratio in portal vein block patients with normal aspartate transaminase levels did not differ from control values. In portal vein block patients with elevated asparatate transaminase levels, the C-peptide/insulin ratio was significantly reduced only from 60 min onwards. All the cirrhotic patients showed a significantly reduced C-peptide/insulin ratio after glucose administration. It is suggested that portal-systemic shunting of blood in the presence of a normal liver does not influence hepatic insulin metabolism and that the hyperinsulinemia of cirrhosis is a feature of parenchymal liver damage. In addition, insulin degradation was abnormal in all cirrhotic patients at high insulin secretion rates, even when fasting insulin levels were normal.

Topics: Adolescent; Adult; Aged; Aspartate Aminotransferases; Blood Glucose; C-Peptide; Constriction, Pathologic; Female; Glucose Tolerance Test; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Portal Vein; Thrombosis

Cirrhosis is complicated by numerous abnormalities of carbohydrate metabolism although these are seldom of clinical importance. Carbohydrate intolerance is extremely common and is accompanied by hyperinsulinaemia, hyperglucagonaemia and elevated levels of gluconeogenic precursors. The hyperinsulinaemia results from impaired hepatic degradation of insulin while recent evidence suggests that pancreatic hypersecretion is responsible for the elevated levels of glucagon in cirrhosis. The role of hepatocellular damage and portal-systemic shunting in the pathogenesis of these abnormalities is controversial but the derangements in carbohydrate metabolism probably reflect hepatocellular damage rather than portal-systemic shunting.

Topics: C-Peptide; Carbohydrate Metabolism; Glucagon; Gluconeogenesis; Glucose; Humans; Hyperinsulinism; Insulin; Liver Cirrhosis; Pancreas

Topics: Adult; C-Peptide; Carbohydrate Metabolism; Female; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Somatostatin

To clarify the mechanism of hyperinsulinism of hepatic cirrhosis, plasma insulin and C-peptide levels before and after oral glucose loads were measured in 34 patients with cirrhosis, 15 patients with chronic hepatitis, and 25 normal subjects. While plasma immunoreactive insulin (IRI) levels during oral glucose tolerance testing (OGTT) were significantly increased in cirrhotics, plasma immunoreactive C-peptide (CPR) levels were elevated slightly. The C-peptide to insulin ratio throughout OGTT was significantly smaller in cirrhotics than in normal subjects (P less than 0.01). A decreased hepatic insulin degradation rate has been suggested to one of the main causes of hyperinsulinism in hepatic cirrhosis. The ratio of the difference between basal and 30-min CPR values and basal and 30-min OGTT blood glucose values [delta CPR: delta BS(30)'] as well as the delta IRI: delta BS(30') ratio was significantly decreased in cirrhotics (P less than 0.01). These results indicate that insulin secretion in response to a glycemic stimulus is reduced in cirrhotics. Both the ratios of the sums of six IRS and CPR values of OGTT (sigma CPR: sigma IRI) and delta CPR: delta BS(30') and sigma CPR: sigma BS(30') were found in inverse relationship with indocyanine green retention rate in cirrhotics.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Chronic Disease; Female; Glucose Tolerance Test; Hepatitis; Humans; Insulin; Kinetics; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged

Topics: Acute Disease; C-Peptide; Hepatic Encephalopathy; Hepatitis; Hepatitis, Viral, Human; Humans; Insulin; Liver; Liver Cirrhosis; Liver Diseases; Peptides

The breakdown of proinsulin in the pancreatic beta cell yields insulin and C-peptide which are secreted in equimolar amounts. Unlike insulin, C-peptide is not degraded significantly by the liver, so that its measurement should give a better assessment of insulin secretion than estimation of peripheral insulin levels alone; particularly in the presence of hepatic dysfunction. Plasma C-peptide and insulin response to an oral glucose load have therefore been assessed in 14 cirrhotic and 7 normal subjects. Cirrhotic patients were divided into hyperinsulinaemic and normoinsulinaemic groups based on fasting plasma-insulin concentrations. Fasting blood-blucose and plasma-C-peptide concentrations were the same in normal and cirrhotic subjects, suggesting that basal pancreatic insulin secretion was the same in all subjects. Thus the C-peptide/insulin ratio was significantly decreased in hyperinsulinaemic subjects (2-13 +/- 0-31, compared with 4-63 +/- 0-48 in controls). After oral glucose, the two groups of cirrhotic patients showed the same glucose intolerance. C-peptide concentrations were also the same but insulin concentrations were markedly increased in the hyperinsulinaemic group. It is suggested that pancreatic insulin secretion is not increased in cirrhosis and that the peripheral hyperinsulinism is due solely to decreased hepatic insulin degradation secondary to either spontaneous portal-systemic shunting or to parenchymal damage.

Topics: Administration, Oral; Adult; Aged; Biodegradation, Environmental; Blood Glucose; C-Peptide; Female; Glucose; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Islets of Langerhans; Liver; Liver Cirrhosis; Male; Middle Aged

Fifty grams of glucose were administered orally to twelve cirrhotics, twelve uremics and ten normal controls and the plasma insulin and C-peptide responses were measured and expressed as molar concentration. Glucose intolerance, hyperinsulinemia and elevated C-peptide levels were found in cirrhotics after glucose loading and in uremics during the later part of the glucose response. The molar ratio of C-peptide to insulin was lower in cirrhotics and higher in uremics than in controls. It is suggested that insulin is mainly degraded by the liver and C-peptide by the kidneys, and that C-peptide is not affected by the liver damage but is present in raised concentration in subjects with injured kidneys. Elevated C-peptide level in cirrhotics is consistent with hyperfunction of pancreatic B-cells.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Islets of Langerhans; Kidney; Liver; Liver Cirrhosis; Male; Middle Aged; Peptides; Uremia

Topics: Adult; Aged; C-Peptide; Female; Glucagon; Humans; Insulin; Liver Cirrhosis; Male; Middle Aged; Peptides