c-peptide and Carcinoma--Hepatocellular

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

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

Topics: Adolescent; C-Peptide; Carcinoma, Hepatocellular; Female; Glucose Tolerance Test; Humans; Insulin; Islets of Langerhans Transplantation; Liver Neoplasms; Liver Transplantation; Pancreatectomy; Time Factors

Proinsulin is usually targetted to the regulated secretory pathway of beta cells, and converted to insulin in beta granules. Under certain pathological situations, a significant amount of proinsulin becomes diverted to the constitutive pathway. To study the kinetics of proinsulin conversion in the constitutive pathway, FAO (hepatoma) cells, which secrete proteins uniquely via this pathway and not the regulated pathway, were stably transfected with cDNA encoding human, rat I or rat II proinsulin. Products released to the medium of transfected cells were analysed by reversed phase HPLC and radioimmunoassay. For human proinsulin, des 31,32 split proinsulin (the conversion intermediate resulting from cleavage only at the B-chain/C-peptide junction followed by trimming of C-terminal basic residues by carboxypeptidase) was the only detectable conversion intermediate; for rat proinsulin II it was des 64,65 split proinsulin (cleaved and trimmed only at the C-peptide/A-chain junction); for rat proinsulin I, both intermediates were seen. Complete processing to insulin occurred for all three, but was most extensive for rat proinsulin I. When considered with the corresponding proinsulin sequences, these data show that a -4 basic residue (i.e. 4 residues N-terminal to the site of cleavage) facilitates proinsulin conversion in the constitutive pathway, and that arginine is preferred over lysine.

Topics: Amino Acid Sequence; Animals; C-Peptide; Carcinoma, Hepatocellular; Cell Line; DNA, Complementary; Humans; Insulin; Kinetics; Liver Neoplasms; Macromolecular Substances; Molecular Sequence Data; Proinsulin; Protein Processing, Post-Translational; Rats; Substrate Specificity; Transfection; Tumor Cells, Cultured

We previously found that patients with hypoglycemia due to chronic renal and liver disease had anomalous metabolic responses to glucose and glucagon stimulation. In this study we evaluated the use of glucagon (2 mg, iv) tests in the diagnosis of spontaneous hypoglycemia secondary to hepatocellular carcinoma (HCC) and insulinoma. Twenty-one normal subjects, 45 patients with HCC (11 with hypoglycemia), and 14 patients with insulinoma (all with hypoglycemia) were studied. The fasting blood glucose level was low in all patients with hypoglycemia. The fasting plasma insulin and C-peptide concentrations were high in patients with insulinoma and low in patients with HCC and hypoglycemia. The blood glucose responses to glucagon administration were less than normal in patients with HCC and hypoglycemia and within normal limits in patients with insulinoma. The insulinoma patients had increased plasma insulin and C-peptide responses to glucagon despite having low blood glucose levels. Compared with the HCC patients without hypoglycemia, HCC patients with hypoglycemia had impaired plasma insulin and C-peptide responses. The fasting hypoglycemia, hypoinsulinemia, and impaired insulin/C-peptide responses to glucagon in patients with hepatoma and hypoglycemia presumably reflect the production of insulin-like substances by the hepatoma. We conclude that glucagon administration results in characteristic responses in these groups of patients and can be of use in the diagnosis of spontaneous hypoglycemia secondary to hepatoma or insulinoma.

Topics: Adenoma, Islet Cell; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Carcinoma, Hepatocellular; Female; Glucagon; Humans; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms

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

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

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