Effects of the infusion of glucagon on the blood levels of thyroid hormones

We have attempted to determine if mild hyperglucagonemia induced by exogenous glucagon infusion induces changes of serum thyroid hormone levels. Eleven healthy subjects, overnight fasting, received glucagon infusion (2 mg/90 min i.v.), whereas 5 healthy subjects (control group) received normal saline infusion. In the subjects infused with exogenous glucagon plasma glucagon concentrations increased from 130 +/- 24 pg/ml to 550 +/- 68 pg/ml at the end of infusion. At the same time no significant changes in serum T3, rT3 and T4 levels were found. A significant increase in serum rT3 levels was found 270 min after glucagon infusion withdrawal, whereas serum T4 levels remained unaltered during the whole period. Normal saline infusion failed to induce any variation in control group, however a late (at 6th hour) mild increase of serum rT3 in these subjects resulted comparable to the same increase of glucagon infused subjects. The results from this study suggest that mild increase in plasma glucagonemia, as found in patients with severe illness, does not induce a short-time significant lowering of serum T3 and a simultaneous rise of serum rT3 in normal subjects.     

Effect of somatostatin on lower esophageal sphincter (les) pressure and serum gastrin in normal and achalasic subjects

Serum gastrin and lower esophageal sphincter (LES) responses to somatostatin infusion were evaluated in ten normal subjects and in nine achalasic patients in order to determine evidence of hormonal (presumably gastrin)control of LES pressure. After somatostatin infusion, a significant decrease of serum gastrin was observed in normal subjects at 30 min (81.6 +/- 3.2 versus 40.0 +/- 4.7 pg/ml; p less than 0.01) and a rapid increase of LES pressure was also observed (26.0 +/- 1.3 versus 34.1 +/- 1.6 mmHg; p less than 0.01). In achalasia no change was observed in serum gastrin concentration after somatostatin infusion. LES pressure at 20 min however significantly decreased (45.8 +/- 7.6 versus 31.6 +/- 2.3 mmHg; p less than 0.05). Endogenous gastrin is not a major control factor for LES pressure in either normal or achalasic subjects.     

Multiple hormone secretion by a human pancreatic glucagonoma in culture

A patient presenting clinically with the glucagonoma syndrome had high plasma glucagon levels (1920 ng/l) and at laparotomy, a pancreatic islet cell tumour was removed. The tumour was dispersed and placed in culture where it remained viable for 63 days. The tumour cells secreted immunoreactive (IR) glucagon at levels up to 2400 ng/l as detected by a C-terminal glucagon specific antibody and 85 400 ngequiv./l as measured by an N-terminal glucagon specific antibody. The difference between these two levels was attributed to the presence of different molecular forms of glucagon measured with the N-terminal specific antibody. IR insulin (up to 302 mU/l) and IR somatostatin (up to 2500 ng/l) were also detected. There was no direct or inverse correlation between different hormone levels. Small but significant levels of N-terminal and C-terminal vasoactive intestinal peptide (VIP) were detected in some cultures but there was no evidence of gastrin or ACTH. Glucagon and somatostatin secretion persisted for the duration of the culture (63 days) but insulin concentrations declined. Incubation of cultures with somatostatin (1 ng/ml) caused a 75% decrease in glucagon levels, while insulin (1000 mU/l) produced a 70% inhibition of somatostatin.     

Prostate-specific antigen levels among cirrhotic patients

PURPOSE: The aim of this study was to determine serum prostate-specific antigen (PSA) levels in patients with liver cirrhosis. PATIENTS AND METHODS: Between January 1995 and August 2001, 216 men with cirrhosis were evaluated. The extent of their liver disease was classified according to the Child-Pugh classification. Serum PSA levels were measured with the Hybritech Tandem-R RIA method and matched with age-related reference PSA levels. Digital rectal examination (DRE) was performed in all patients. Patients with elevated PSA levels and/or abnormal DRE were recommended to undergo further assessment including transrectal ultrasonography (TRUS) and biopsy performed by an urologist. RESULTS: Two hundred and sixteen men (mean age 54.09 +/- 9.09 years, range 25-76) with cirrhosis were examined. Their mean PSA value was 0.57 +/- 0.84 ng/mL and tended to be lower than in the normal population. The degree of PSA decrease was found to parallel the severity of the liver disease (p=0.002). The mean serum PSA level increased with each age decade in a statistically significant manner (p<0.001). Four patients (three with elevated PSA values) underwent prostate biopsy. Three biopsies were positive for prostate cancer, the other showed evidence of benign prostatic hyperplasia (BPH). CONCLUSION: Serum PSA is influenced by the severity of liver disease and its levels tend to be lower in cirrhotic patients than in the normal population. However, serum PSA can still be considered a reliable marker in the clinical management of prostatic disease in patients with cirrhosis.     

Evaluation of the effects of pentagastrin, gastrin and pancreatic glucagon on cell proliferation in the rat gastrointestinal tract

The effects of six injections of a range of doses (100-1000 micrograms/kg bodyweight) of pentagrastrin and single injection of a range of doses of porcine gastrin (10-40 micrograms/kg bodyweight) and pancreatic glucagon (25-100 micrograms/kg bodyweight) on cell proliferation in the intestine of fasted rats has been investigated. The end-point employed included the measurement of 14C leucine incorporation and thymidine-derived tritium content of the body of the stomach, duodenum, jejunum, ileum and colon. The carbon 14 and tritium content per microgram of tissue in triplicate samples of fifty individually dissected crypts of glands were determined. From these data and the wet weight of the washed, blotted, intestinal segments, values for crypts/micrograms tissue and crypts/segment were calculated. The results demonstrated that pentagastrin at physiological doses decreased cell proliferation slightly in stomach, while gastrin and glucagon were without effect. In the small intestine, pentagastrin and gastrin were without significant effect with the exception that they increased the weight of the duodenum. In contrast, a high physiological dose of glucagon increased DNA and protein synthesis throughout the small bowel, but particularly in the ileum. Pharmacological doses of pentagastrin and all doses of gastrin appeared to increase cell proliferation in the colon although the possibility could not be excluded that this was due to stimulation of precursor uptake. Gastrin also increased colonic weight. Glucagon had no effects in the colon. These observations are compatible with the hypothesis that (i) the primary effects of gastrin and pentagastrin on the proximal intestine are as secretogogues and effects on cell proliferation may be secondary, (ii) gastrin and pentagastrin at physiological levels do not stimulate small intestinal cell proliferation, however glucagon does, and (iii) gastrin at physiological levels and pentagastrin at pharmacological levels may stimulate cell proliferation in the colon.     

Evaluation of the Effects of Pentagastrin, Gastrin and Pancreatic Glucagon On Cell Proliferation In the Rat Gastrointestinal Tract

ABSTRACT The effects of six injections of a range of doses (100–1000 μg/kg bodyweight) of pentagrastrin and single injection of a range of doses of porcine gastrin (10–40 μg/kg bodyweight) and pancreatic glucagon (25–100 μg/kg bodyweight) on cell proliferation in the intestine of fasted rats has been investigated. the end-point employed included the measurement of ¹⁴C leucine incorporation and thymidine-derived tritium content of the body of the stomach, duodenum, jejunum, ileum and colon. the carbon 14 and tritium content per μg of tissue in triplicate samples of fifty individually dissected crypts of glands were determined. From these data and the wet weight of the washed, blotted, intestinal segments, values for crypts/μg tissue and crypts/segment were calculated. the results demonstrated that pentagastrin at physiological doses decreased cell proliferation slightly in stomach, while gastrin and glucagon were without effect. In the small intestine, pentagastrin and gastrin were without significant effect with the exception that they increased the weight of the duodenum. In contrast, a high physiological dose of glucagon increased DNA and protein synthesis throughout the small bowel, but particularly in the ileum. Pharmacological doses of pentagastrin and all doses of gastrin appeared to increase cell proliferation in the colon although the possibility could not be excluded that this was due to stimulation of precursor uptake. Gastrin also increased colonic weight. Glucagon had no effects in the colon. These observations are compatible with the hypothesis that (i) the primary effects of gastrin and pentagastrin on the proximal intestine are as secretogogues and effects on cell proliferation may be secondary, (ii) gastrin and pentagastrin at physiological levels do not stimulate small intestinal cell proliferation, however glucagon does, and (iii) gastrin at physiological levels and pentagastrin at pharmacological levels may stimulate cell proliferation in the colon.     

Metabolic effects of long-term arterialization of portal blood

In nine splenectomized male dogs a splenic artery, -splenic vein shunt was made. Before splenectomy and 3, 6 and 18 months after arterialization of portal blood, different metabolic and endocrine parameters were estimated. Long-term arterialization of portal blood was followed by only insignificant increase of portal vein pressure but a significant drop of pCO2 and increase of pO2 in portal blood was recorded. Simultaneously, a significant decrease of the erythrocyte count, hematocrit value, serum cholesterol and uric acid levels, and a shortening of the T1/2 of insulin and glucagon were found. In contrast, long-term arterialization of portal blood was followed by a significant increase of serum triglycerides, alpha2-globulins, plasma renin activity, cortisol, gastrin and 25-hydroxyvitamin D, and by slight carbohydrate intolerance. No morphological abnormalities in the liver and kidney tissue were found. Data presented in this paper suggest usefulness of a splenic artery-splenic vein shunt in the treatment of some metabolic disorders and of the failing hepatocytes.     

Changes of serum copper and zinc levels in patients with nasopharyngeal carcinoma by radiotherapy

Serum copper levels (SCL) and serum zinc levels (SZJ) were evaluated in 128 patients with nasopharyngeal carcinoma (NPC) of varying stages before, during, and after radiotherapy, and then compared with normal age-matched subjects. Among these patients, there were 119 undifferentiated squamous cell carcinoma, 5 differentiated squamous cell carcinoma, and 4 moderately differentiated squamous cell carcinoma, respectively. Before radiotherapy, SCLs were significantly higher in NPC patients than in normal subjects, but the difference of SZLs was not significant. The ratio of Cu/Zn also showed a significant difference between normal subjects and NPC patients preradiotherapy. Moreover, except stage II, patients with more advanced stages of the disease had more elevated Cu/Zn ratios. During and after the period of radiotherapy, the SCL decreased as compared with the level of preradiotherapy. The Cu/Zn ratio also decreased after radiotherapy but not significant. However, Cu/Zn ratio of expired patients at least 2 yr after radiotherapy did not show the significant decrease in contrast to the alive ones.     

Decreases in the serum VLDL-TG/non-VLDL-TG ratio from early stages of chronic hepatitis C: alterations in TG-rich lipoprotein levels

Background

The liver secretes very-low-density lipoproteins (VLDLs) and plays a key role in lipid metabolism. Plasma total triglyceride (TG) level variations have been studied in patients with hepatitis C virus (HCV)-related chronic hepatitis (CH-C). However, the results of these studies are variable. A homogenous assay protocol was recently proposed to directly measure the TG content in VLDL (VLDL-TG) and VLDL remnants.

Methodology/Principal Findings

Using the assay protocol, we determined serum VLDL-TG levels in 69 fasting patients with biopsy-proven HCV-related chronic liver disease and 50 healthy subjects. Patients were classified into stages F0–F4 using the 5-point Desmet scale. Serum total TG levels in patients with non-cirrhotic (F1–F3) CH-C did not demonstrate significant differences compared with healthy subjects, but serum VLDL-TG levels did demonstrate significant differences. Mean serum VLDL-TG levels tended to decrease with disease progression from F1 to F4 (cirrhosis). Compared with healthy subjects, serum non-VLDL-TG levels significantly increased in patients with stages F2 and F3 CH-C; however, we observed no significant difference in patients with liver cirrhosis. Furthermore, the serum VLDL-TG/non-VLDL-TG ratio, when taken, demonstrated a significant decrease in patients with CH-C from the mildest stage F1 onward.

Conclusions/Significance

The decrease in serum VLDL-TG levels was attenuated by increase in non-VLDL-TG levels in patients with non-cirrhotic CH-C, resulting in comparable total TG levels. Results of previous studies though variable, were confirmed to have a logical basis. The decrease in the serum VLDL-TG/non-VLDL-TG ratio as early as stage F1 demonstrated TG metabolic alterations in early stages of CH-C for the first time. The involvement of TG metabolism in CH-C pathogenesis has been established in experimental animals, while conventional TG measurements are generally considered as poor indicators of CH-C progression in clinical practice. The serum VLDL-TG/non-VLDL-TG ratio, which focuses on TG metabolic alterations, may be an early indicator of CH-C.     

Defective blood glucose counter-regulation in diabetics is a selective form of autonomic neuropathy.

Administration of a low-dose insulin infusion to normal subjects results in a mild drop in blood glucose concentration (1.1 mmol/1 (20 mg/100 ml)) and the resetting of the basal glucose at the lower concentration. Clinical hypoglycaemia does not develop, and there is a significant release of glucagon, growth hormone, and cortisol. A similar infusion in insulin-requiring diabetics results in hypoglycaemia accompanied by a release of growth hormone and cortisol but no significant release of glucagon. Subsequently giving arginine to these patients results in a significant release of glucagon, indicating that the alpha cell is intact and can respond to local, direct stimulation. In one patient the defect in glucagon response to impending hypoglycaemia developed after two years'' insulin treatment. This type of dissociated response'' of the alpha cell has been reported in animals after denervation of the pancreas, and insulin-requiring diabetics may develop a selective form of autonomic neuropathy affecting the vagal control of glucagon release.     

Liver autophagy contributes to the maintenance of blood glucose and amino acid levels

Both anabolism and catabolism of the amino acids released by starvation-induced autophagy are essential for cell survival, but their actual metabolic contributions in adult animals are poorly understood. Herein, we report that, in mice, liver autophagy makes a significant contribution to the maintenance of blood glucose by converting amino acids to glucose via gluconeogenesis. Under a synchronous fasting-initiation regimen, autophagy was induced concomitantly with a fall in plasma insulin in the presence of stable glucagon levels, resulting in a robust amino acid release. In liver-specific autophagy (Atg7)-deficient mice, no amino acid release occurred and blood glucose levels continued to decrease in contrast to those of wild-type mice. Administration of serine (30 mg/animal) exerted a comparable effect, raising the blood glucose levels in both control wild-type and mutant mice under starvation. Thus, the absence of the amino acids that were released by autophagic proteolysis is a major reason for a decrease in blood glucose. Autophagic amino acid release in control wild-type livers was significantly suppressed by the prior administration of glucose, which elicited a prompt increase in plasma insulin levels. This indicates that insulin plays a dominant role over glucagon in controlling liver autophagy. These results are the first to show that liver-specific autophagy plays a role in blood glucose regulation.     

Liver autophagy contributes to the maintenance of blood glucose and amino acid levels

Both anabolism and catabolism of the amino acids released by starvation-induced autophagy are essential for cell survival, but their actual metabolic contributions in adult animals are poorly understood. Herein, we report that, in mice, liver autophagy makes a significant contribution to the maintenance of blood glucose by converting amino acids to glucose via gluconeogenesis. Under a synchronous fasting-initiation regimen, autophagy was induced concomitantly with a fall in plasma insulin in the presence of stable glucagon levels, resulting in a robust amino acid release. In liver-specific autophagy (Atg7)-deficient mice, no amino acid release occurred and blood glucose levels continued to decrease in contrast to those of wild-type mice. Administration of serine (30 mg/animal) exerted a comparable effect, raising the blood glucose levels in both control wild-type and mutant mice under starvation. Thus, the absence of the amino acids that were released by autophagic proteolysis is a major reason for a decrease in blood glucose. Autophagic amino acid release in control wild-type livers was significantly suppressed by the prior administration of glucose, which elicited a prompt increase in plasma insulin levels. This indicates that insulin plays a dominant role over glucagon in controlling liver autophagy. These results are the first to show that liver-specific autophagy plays a role in blood glucose regulation.     

Suppression of serum growth hormone levels by glucagon in patients with active acromegaly.

One mg of glucagon was given subcutaneously to eight patients with active acromegaly. Seven out of eight patients had a rapid decrease in serum growth hormone (GH) levels at 30 min after the glucagon injection. In two out of seven patients a rebound increase in serum GH following the early GH reduction was observed. On the other hand, oral administration of 50 g glucose which caused a comparable increase in blood glucose to that after the glucagon injection elicited no early suppression in serum GH levels in the same patients. These data suggest that the inhibition of GH release induced by glucagon could not be related to the increase in blood glucose by glucagon.     

Decreased serum osteocalcin levels in patients with liver cirrhosis

Serum levels of osteocalcin (OC) have been found to be a specific biochemical parameter of bone formation. We measured serum levels of osteocalcin, parathyroid hormone (PTH) and 25-hydroxyvitamin D (25(OH)D) in 49 patients with liver cirrhosis, who are known to have an increased prevalence of metabolic bone disease, and a matched control group (n = 35). Serum levels of OC were significantly decreased in the patients with liver cirrhosis when compared to control subjects (P < 0.001). Serum levels of 25(OH)D were decreased (P < 0.001), whereas no statistical difference was found between the serum levels of PTH in the patients with liver cirrhosis and those of the controls. In a subgroup of 23 patients with cirrhosis of the liver and 34 control subjects, the bone mineral content (BMC) of the non-dominant forearm was determined by single photon absorptiometry. BMC was significantly lower in the patient with liver cirrhosis than the control subjects (P < 0.04). Our data demonstrate vitamin D deficiency, decreased bone formation and a decreased BMC in patients with liver cirrhosis.     

Clinical significance of serum gastrin levels in patients with colorectal cancer

AIMS: An association between elevated serum gastrin levels and the presence of human colorectal cancer has been reported, and gastrin has been shown to stimulate the growth of experimentally induced colon neoplasia. The aim of this study was to determine the preoperative and postoperative concentrations of serum gastrin in 53 patients with colorectal cancer and to assess the correlation between gastrin levels and tumor characteristics and prognosis. MATERIALS AND METHODS: A prospective study was performed over a six-year period during which 53 patients received potentially curative surgery for colorectal cancer. The prognostic variables used for the analysis included age, sex, tumor site, stage and degree of differentiation, preoperative and postoperative serum values of carcinoembryonic antigen (CEA) and gastrin, cancer-related mortality, and survival. CEA and gastrin serum values were determined using radioimmunological methods. Follow-up was carried out with clinical and radiological tests. RESULTS: The mean preoperative gastrin concentration was 51.2+/-27.4 pg/mL (range 12-146). Significantly increased serum gastrin concentrations, which returned to normal after surgery, were detected only in patients with well-differentiated cancer (74.2+/-28.3 pg/mL; moderately differentiated, 52.1+/-23.8; poorly differentiated, 29.9+/-12.3, p=0.02). The prognosis was unrelated to serum gastrin level; instead, tumor stage, preoperative CEA value, and degree of differentiation affected patient survival. CONCLUSIONS: This study showed that the serum gastrin concentration is not an appropriate clinical oncogenic factor. Although occurring only in well-differentiated tumors, serum gastrin is unrelated to the prognosis of patients with colorectal cancer.     

Glucose, insulin and somatostatin infusion for the determination of insulin resistance in liver cirrhosis

Twelve patients with liver cirrhosis and ten normal subjects were studied. Using a constant intravneous infusion of glucose, insulin and somatostatin over 2 1/2 hours we determined the stteady state plasma glucose level (SSPG) in order to measure insulin resistance. The results demonstrated that the cirrhotic patients were insulin resistant compared to normals and that plasma glucagon does not account for the insulin resistance in these patients.     

Management of individuals with chronic hepatitis B virus infection and persistent normal or mildly elevated aminotransferase levels

No consensus exists with respect to positive hepatitis B virus (HBV) DNA results and persistent normal or mildly elevated alanine aminotransferase (ALT). The aim of this study is to investigate the appropriate management and prognosis of these populations with chronic hepatitis B (CHB). A total of 235 subjects with positive HBV DNA results and persistent normal or mildly elevated ALT were enrolled in this study. Liver biopsy and liver stiffness measurements (LSM) were performed in all participants at baseline. Antiviral therapy was initiated in patients with significant hepatic inflammation (G ≥ 2) and/or fibrosis (S ≥ 2). The patients were divided into entecavir and adefovir groups based on HBV DNA load (>2000 IU/mL vs <2000 IU/mL). The liver biopsies were repeated at 72 weeks for the patients received antiviral therapy. We found that 112 subjects were hepatitis B e antigen (HBeAg) positive, and 123 subjects were negative. The corresponding median ALTs were 46 (39.5-52.5) and 48 (41.5-57.0) U/mL, respectively. G ≥ 2 and/or S ≥ 2 diseases were present in 48.8% (82/168) of the HBeAg-positive and 51.2% (86/168) of HBeAg-negative patients, respectively. In addition, 96 HBeAg-positive and 72 HBeAg-negative patients were divided into entecavir and adefovir groups. Meanwhile, liver biopsies had greater diagnostic accuracy for determining cirrhosis than LSM (0.711 vs 1.0, P < 0.0001). At the end of the study period, undetectable HBV DNA levels and normal ALT levels were observed in CHB-infected patients. Furthermore, the patients showed histologic improvement at 72 weeks compared with baseline measurements (G, 1.72 ± 1.00 vs 0.73 ± 0.88, P = 0.0002; S, 1.484 ± 0.90 vs 0.99 ± 1.13, P < 0.0001). Collectively, liver biopsy enhanced diagnostic accuracy for CHB-infected individuals with persistent normal or mildly elevated aminotransferase levels. Moreover, antiviral therapy can improve or regress the hepatic fibrosis and cirrhosis.     

Plasma catecholamine and serum gastrin concentrations during sham feeding

Plasma adrenaline, plasma noradrenaline and serum gastrin concentrations were measured before and after sham feeding in eight patients with duodenal ulcer and in four normal subjects. No significant change in the concentrations was observed after sham feeding. In three patients with duodenal ulcer an insulin test resulted in a 25-fold rise in plasma adrenaline. The ulcer patients showed significantly higher levels of plasma adrenaline and plasma noradrenaline than the normal subjects both before and after sham feeding, and this difference was probably not caused only by age difference in the two groups. It is concluded that sympathetic nervous activity and serum gastrin concentrations are not influenced by sham feeding in contrast to the influence of insulin hypoglycemia.     

Insuppressibility of plasma glucagon by orally or intravenously administered glucose in diabetes mellitus

In order to study the response of pancreatic alpha cells to the change blood glucose, plasma pancreatic glucagon levels were measured after glucose loading given orally (50g) or intravenously (25g) in twenty-two normal controls and eighty untreated diabetics. Basal plasma pancreatic glucagon levels did not differ significantly in the two groups. However, oral or intravenous glucose administration caused a decrease in plasma pancreatic glucagon in normal subjects but not in diabetics. In "moderate" or "severe" diabetics, plasma pancreatic glucagon tended to increase paradoxically following oral glucose loading. To evaluate the sensitivity of pancreatic alpha cells to glucose, we calculated the index, -sigma delta IRG/sigma delta BS, after oral glucose loading. It was 1.96 +/- 0.57 in normal subjects, and significantly higher than in "mild" (0.11 +/- 0.05), "moderate" (-0.002 +/- 0.06) and "severe" (-0.09 +/- 0.07) diabetics. These results demonstrate the insensitivity of alpha cells to hyperglycemia in patients with diabetes mellitus as compared with normal subjects.     

Relationship of blood trace elements to liver damage, nutritional status, and oxidative stress in chronic nonalcoholic liver disease

Trace elements are involved in chronic liver diseases because these elements may have a direct hepatic toxicity or may be decreased as a consequence of the impaired liver function, particularly in patients with alcoholic cirrhosis and/or malnutrition. In this study, we determined plasma and erythrocytes trace elements in 50 inpatients with nonalcoholic chronic liver disease (11 with biopsy-proven chronic hepatitis, 39 with cirrhosis [16 in stage A according to Child-Pugh criteria, 23 Child B+C]), and in a control group of 10 healthy subjects by the proton induced x-ray emission method. The relationship between trace element concentration and the extent of liver damage, the nutritional status (by anthropometric evaluations), and various blood markers of oxidative stress--reduced glutathione, total lipoperoxides and malonyldialdehyde--was investigated. We found that cirrhotics had a significant decrease of Fe, Zn, Se, and GSH levels in the plasma and of GSH and Se in the erythrocytes with respect to the control and chronic hepatitis groups. GSH levels were related to the degree of liver damage; a significant direct correlation was observed among Se, Zn, and GSH plasma values and between GSH and Se in the erythrocytes. The trace element decrease was, on the contrary, independent of the degree of liver function impairment and only partially affected by the nutritional status. Data indicate that liver cirrhosis, even if not alcohol related, induces a decrease of Se and Zn and that, in these patients, an oxidative stress is present, as documented by the significant correlation between Se and GSH. The plasma Br level was higher in cirrhotics with respect to the control and chronic hepatitis groups.