The effect of oral synthetic protease inhibitor (FOY 305) on endocrine pancreas and carbohydrate and lipid metabolism in normal and streptozotocin-induced diabetic rats

The effect of long-term oral synthetic protease inhibitor (FOY 305) administration on fasting blood sugar (FBS), body weight, glucose tolerance, plasma insulin and glucagon levels, pancreatic insulin and glucagon contents, hepatic enzyme activities, and plasma lipids in normal and streptozotocin (STZ)-induced diabetic rats was studied. Normal rats treated with oral FOY 305 for 9 weeks were found to have pancreatic hypertrophy and decreased body weight gain as compared with the untreated normal controls. FBS, glucose tolerance, plasma insulin and glucagon levels, pancreatic insulin and glucagon contents, and plasma lipids were uninfluenced in FOY 305 treated normal rats. STZ-induced diabetic rats treated with oral FOY 305 were found to have decreased FBS for 5 weeks after the beginning of FOY 305 administration as compared with the untreated diabetic controls, whereas at the 7th and 9th week after treatment there was no difference in FBS between FOY 305 treated and untreated diabetic rats. In the metabolic balance observed at the 4th week after treatment, a slight improvement of the diabetic state was found in FOY 305 treated diabetic rats. There was no apparent difference in the blood sugar curve and insulin response following oral glucose load between diabetic rats treated for 7 weeks and untreated diabetic rats. All the rats were sacrificed after 9 weeks of treatment. Diabetic rats treated with oral FOY 305 for 9 weeks showed pancreatic hypertrophy and decreased plasma glucagon level and decreased pancreatic glucagon content as compared with the untreated diabetic controls, whereas there was no difference in body weight, plasma insulin level and pancreatic insulin content between FOY 305 treated and untreated diabetic rats. Furthermore, oral FOY 305 treatment improved hyperlipidemia in STZ-induced diabetic rats and also significantly improved the hepatic pyruvate kinase and phosphoenlpyruvate carboxykinase activities of diabetic rats. These improvements might partly be due to a decreased pancreatic content and secretion of glucagon and/or a direct action of the synthetic PI, FOY 305 to tissues.     

Counterregulation of insulin-induced hypoglycaemia in primary hypothyroidism

Hypothyroidism has been alleged to modulate insulin action and influence the secretion of growth hormone and catecholamines. We recently investigated the influence of hypothyroidism on glucose counter-regulatory capacity and the hormonal responses to insulin-induced hypoglycaemia in 6 patients with primary hypothyroidism (age 32-52 years, TSH-values 66-200 mU/l). Hypoglycaemia was induced in the hypothyroid state and again when the subjects were euthyroid. After an overnight fast a constant rate infusion of insulin (2.4 U/h) was given for 4 h. Glucose was measured every 15 min and insulin. C-peptide, glucagon, epinephrine, norepinephrine, growth hormone and cortisol every 30 min for 5 h. During insulin infusion somewhat higher concentrations of the hormone were obtained in the hypothyroid state and simultaneously glucose levels were 0.5 mmol/l lower. As expected, basal norepinephrine levels were higher in hypothyroidism. However, no increase in circulating norepinephrine during hypoglycaemia was registered in the two experiments. The responses of counterregulatory hormones showed an enhanced response of cortisol, similar responses of growth hormone and epinephrine while the glucagon response was paradoxically impaired. Our findings suggest that hypothyroidism alters insulin metabolism, and that the glucagon response to hypoglycaemia is impaired in this condition.     

Leptin-A regulator of islet function?: Its plasma levels correlate with glucagon and insulin secretion in healthy women

It has previously been demonstrated that plasma leptin correlates to body fat content. It has also been demonstrated that in subjects with normal glucose tolerance, circulating leptin correlates to circulating insulin and to insulin secretion and that these relations are independent of body fat. However, whether leptin also covaries with other islet hormones is not known. We therefore studied the relation between plasma levels of leptin and glucagon secretion and circulating pancreatic polypeptide (PP) in healthy humans. Arginine was injected intravenously (5 g) at fasting and at 14 and 28 mmol/L glucose in 71 postmenopausal women with normal glucose tolerance. In a multivariate analysis controlling for the influence of the body mass index, we found that circulating leptin correlated significantly to fasting insulin (r = .38, P = .002), and to circulating insulin at 14 mmol/L glucose (r = .29, P = .0019) and 28 mmol/L glucose (r = .32, P = .009), as well as to the insulin response to arginine at all three glucose levels (r> .30, P < .013). Circulating leptin, independently of the body mass index, also correlated to fasting glucagon (r = .31, P = .012) and to the glucagon response to arginine at all three glucose levels (r> .28, P < .038). In contrast, circulating leptin did not correlate to plasma glucagon at 14 or 28 mmol/L glucose or to plasma levels of PP. We conclude that circulating leptin correlates to the secretory capacity of both glucagon and insulin but not to the reduction of plasma glucagon during hyperglycemia or to PP in a large group of postmenopausal women. This suggests that islet function is related to circulating leptin in humans.     

Fasting- and meal-stimulated peptide hormone concentrations before and after gastric surgery for morbid obesity

The influence of morbid obesity and of gastric surgery operation in circulating peptide hormone concentrations was studied in 26 patients. Plasma hormone levels were determined in the fasting state and after a standardized test meal before and six to nine months after gastric surgery. Before surgery fasting and postprandial blood glucose and hormone levels did not significantly differ in morbidly obese subjects from those in obese or normal subjects, except that in morbidly obese subjects, postprandial gastrin concentration remained at peak levels and did not return to fasting levels 120 minutes after the test meal. An average weight loss of 92 lb following the gastric surgery operation was accompanied by a decrease of fasting glucose and insulin levels and a decreased postprandial insulin response. There were no significant differences in plasma levels of pancreatic glucagon, of pancreatic polypeptide in the basal state, or of pancreatic glucagon after the test meal between the preoperative and postoperative groups. As compared to preoperative values, fasting gastrin levels decreased after surgery, the postprandial release of gastrin was virtually absent, and that of pancreatic polypeptide reduced. The significance of altered postprandial pancreatic polypeptide response and of the reversal of prolonged postprandial hypergastrinemia to a state of low circulating gastrin levels following gastric surgery on gastrointestinal secretion and mucosa remain to be determined.     

Comparative insulinogenic effects of glucose,arginine and glucagon in patients with diabetes mellitus,endocrine disorders and liver disease

Summary In order to compare the insulinogenic effects of glucose, arginine and glucagon, plasma immunoreactive insulin levels following oral glucose loading (50 g), intravenous arginine infusion (30 g for 45 min) and intravenous glucagon injection (1 mg) were determined in patients with diabetes mellitus, various endocrine diseases and chronic hepatitis. In patients with Cushing’s syndrome, plasma insulin responses to all three stimuli were exaggerated, whereas they were low in patients with pheochromocytoma. In other diseases, certain disparities were observed in plasma insulin responses. In patients with mild diabetes mellitus, insulin secretion elicited by glucose seems to be selectively impaired, because arginine and glucagon caused a rise in plasma insulin not significantly different from that in normal subjects. In patients with hyperthyroidism, plasma insulin responses to arginine and glucagon were either absent or limited, although rather a exaggerated response was noted following oral glucose loading. On the contrary, exaggerated responses to arginine and glucagon, and limited response to glucose were observed in hypothyroidism. In patients with chronic hepatitis, the responses of plasma insulin to glucose and arginine were both exaggerated, whereas the response to glucagon was comparable to that in normal subjects. These disparate responses suggest that glucose, arginine and glucagon act on the B-cell via different mechanisms.     

Fasting hyperglycemia impairs glucose- but not insulin-mediated suppression of glucagon secretion

AIM: Our aim was to assess the effect of chronic hyperglycemia on glucose- and insulin-mediated suppression of glucagon secretion by the alpha-cell. METHODS: Thirty subjects with normal glucose tolerance, 27 with impaired fasting glucose and/or impaired glucose tolerance, and 32 type 2 diabetic subjects were studied with oral glucose tolerance test (OGTT) and euglycemic hyperinsulinemic clamp. Fasting plasma glucagon concentration and plasma glucagon concentration during the OGTT and insulin clamp were measured. RESULTS: During the OGTT, the decrement in the plasma glucagon concentration (area under the curve) was correlated inversely with the fasting plasma glucose concentration (r = -0.35; P < 0.001). As the fasting glucose level increased, the suppression of plasma glucagon progressively diminished. In contrast, during the euglycemic insulin clamp, the suppression of plasma glucagon was not correlated with the fasting plasma glucose concentration and was similar in subjects with normal glucose tolerance, subjects with impaired fasting glucose/impaired glucose tolerance, and diabetic subjects: 18, 23, and 18%, respectively. CONCLUSION: Insulin-mediated suppression of glucagon secretion is unrelated to the fasting plasma glucose concentration and is not impaired by chronic hyperglycemia. Thus, the defect in plasma glucagon suppression during the OGTT most likely results from impaired glucose-mediated glucagon suppression. The close correlation between fasting plasma glucose concentration and reduced glucagon suppression suggests a glucotoxic effect on alpha-cell function.     

Glucose intolerance in thyrotoxicosis roles of insulin, glucagon and somatostatin

The responses in plasma glucose, insulin, C-peptide, glucagon and somatostatin to an oral glucose load were studied in 10 thyrotoxic patients and 10 matched euthyroid controls. The thyrotoxic patients had higher mean fasting plasma glucose (P less than 0.05) and responded to oral glucose with an earlier peak at 30 min which was higher than the corresponding glucose level in the controls (P less than 0.05). Impaired glucose tolerance was found in 3 patients. Fasting insulin and C-peptide levels were normal in the thyrotoxic patients when corrected for the higher glucose levels. Following glucose ingestion, there was no significant difference between the areas under the insulin or C-peptide curves in patients and controls, but Seltzer's insulinogenic index was reduced in the patients (P less than 0.01) suggesting an impaired pancreatic B-cell response to oral glucose. Mean basal glucagon was normal in the thyrotoxic patients. However, while in the controls plasma glucagon became suppressed following glucose ingestion (P less than 0.0001), no significant suppression was found in the patients. In the thyrotoxic patients, mean basal somatostatin was normal, but the area under the somatostatin curve following glucose ingestion was significantly increased (P less than 0.02). Our findings suggest that decreased glucagon suppression and impaired insulin response after glucose ingestion are involved in glucose intolerance in thyrotoxicosis. Enhanced somatostatin responses to oral glucose in thyrotoxicosis may have contributed to the observed impairment in pancreatic B-cell responsiveness.     

Effect of rioprostil,a methylprostaglandin E1 analog,on basal and stimulated plasma pancreatic hormone levels in man

The effect of rioprostil, a methylprostaglandin E₁ analog on circulating pancreatic hormones was evaluated in 13 healthy male subjects. Rioprostil administration, 300 g twice daily resulted in a significant decrease of fasting insulin, C-peptide, glucagon, and pancreatic polypeptide. No change in fasting plasma glucose or somatostatin levels was observed. An oral glucose tolerance test induced similar increments in plasma glucose concentration before and during treatment, but a delayed rise of insulin and C-peptide levels occurred during the administration of the drug. On rioprostil, the glucose load no longer inhibited peripheral glucagon or somatostatin. Treatment with rioprostil remained without effect on mixed meal-induced changes in plasma glucose levels and concomitant increases in insulin, pancreatic polypeptide, and somatostatin levels. It is concluded that in healthy individuals rioprostil influences the basal and glucose-induced levels of glucagon, insulin, and somatostatin. In healthy men this effect did not, however, result in glucose intolerance.     

Preoperative insulin secretion ability and pancreatic parenchymal thickness as useful parameters for predicting postoperative insulin secretion in patients undergoing pancreaticoduodenectomy

Periampullary malignant neoplasms have been increasing in Japan, mainly in response to an increase in the incidences of pancreatic cancer, and glucose intolerance due to deterioration of insulin secretion is an important problem. We investigated preoperative parameters to predict postoperative insulin secretion and the need for insulin therapy in patients undergoing pancreaticoduodenectomy (PD). Thirty-six patients with malignant neoplasms of periampullary lesions were enrolled. Preoperative pancreatic parenchymal thickness was evaluated by computed tomography. Insulin secretion and glucose tolerance were evaluated by a 75-g oral glucose tolerance test and an intravenous glucagon loading test. The relationships between postoperative insulin secretion and preoperative parameters and the cut-off values for predicting the need for postoperative insulin therapy for glycemic control were investigated. Pancreatic parenchymal thickness and other preoperative parameters, including the increment of serum C-peptide (Δ C-peptide), fasting plasma C-peptide (F-CPR), insulinogenic index (I.I.) and fasting plasma glucose (FPG), were significantly associated with postoperative insulin secretion. Multiple regression analyses revealed that preoperative Δ C-peptide or F-CPR was the most significant determinant of postoperative insulin secretion, followed by pancreatic parenchymal thickness. In the receiver operating characteristic curve, the best preoperative cut-off values for predicting the need for postoperative insulin therapy were a Δ C-peptide of 0.65 ng/mL, a F-CPR of 0.85 ng/mL and a pancreatic parenchymal thickness of 6.0 mm. Both preoperative insulin secretion and pancreatic parenchymal thickness effectively predict postoperative insulin secretion and identify subjects who need postoperative insulin therapy for glycemic control.     

THE METABOLIC EFFECTS OF CHRONIC HYPERGLUCAGONAEMIA

A subject with a benign glucagonoma was studied before and after complete resection of his pancreatic tumour. Studies were undertaken pre- and post-operatively to determine the effects of chronic hyperglucagonaemia on glucose tolerance and glucose kinetics both in the fasting state and during physiological insulin infusions, employing the [3H]-3-glucose technique. In addition the plasma cyclic AMP response to an acute infusion of glucagon was studied pre- and post-operatively. The basal immunoreactive glucagon levels pre- and post-operatively were 10492 +/- 1296 and 149 +/- 15 pg/ml respectively. Pre- and post-operative oral glucose tolerance tests did not differ but were abnormal. Pre-operatively basal hepatic glucose production was normal and it was suppressed rapidly by the low dose insulin infusion, despite continuing hyperglucagonaemia. The metabolic clearance rate of glucose was slightly reduced. There was no plasma cyclic AMP response to a glucagon infusion, suggesting down-regulation of the glucagon receptor by the chronic hyperglucagonaemia. Post-operatively the hepatic glucose production and clearance rate of glucose fell, whereas the plasma cyclic AMP responses to the glucagon infusion reverted to a normal pattern. It is concluded that chronic hyperglucagonaemia is not a major factor in the development of the glucose intolerance, but it may lead to down-regulation of the biological action of glucagon.     

The mechanism of glucose intolerance in patients with Graves' disease]

To investigate the mechanism of glucose intolerance in patients with Graves' disease, a 2-hour oral glucose tolerance test and euglycemic glucose clamp study using Biostator were performed in patients with Graves' disease and control subjects. 80 per cent of the patients showed impaired glucose tolerance. Insulinogenic index in the patients with borderline or diabetic glucose response was lower than that in subjects with normal glucose response. Insulinogenic index was inversely correlated with sigma PG during the test. Despite normal basal plasma glucose concentrations, basal plasma insulin levels in the patients with Graves' disease were higher than in the controls. Using the euglycemic glucose clamp technique, the glucose utilization rate (M value), the metabolic clearance rate of glucose (MCRG) and the insulin sensitivity index (M/I x 100) in the patients with Graves' disease were lower than in the controls. After treatment with antithyroid drug in 3 patients, glucose tolerance completely normalized, and there was a significant increase in the M value and the MCRG and a significant decrease in the metabolic clearance rate of insulin (MCRI) compared to the values before treatment. In the patients with Graves' disease, basal serum glucagon levels were higher than in the controls, and glucagon suppression during insulin infusion was found to be decreased. From these data, it is concluded that the decrease in glucose tolerance in patients with Graves' disease can be explained by 1) the impairment of early insulin release response to rapid intestinal glucose absorption, 2) increased insulin metabolic clearance and 3) hyperglucagonemia.     

Effects of insulin on fasting and meal-stimulated somatostatin-like immunoreactivity in noninsulin-dependent diabetes mellitus: evidence for more than one mechanism of action

We assessed the effects of insulin and normalization of blood glucose on plasma levels of somatostatin-like immunoreactivity (SLI) in patients with noninsulin-dependent diabetes mellitus (NIDDM). In one series of experiments, normalization of blood glucose was achieved by Biostator-controlled feedback infusion of insulin. This procedure reduced plasma SLI levels by 34% [from 17.1 +/- 2.1 (+/- SEM) to 11.3 +/- 1.9 pg/ml; P less than 0.05], concomitant with a significant reduction in plasma glucagon and C-peptide and an evanescent decrease in plasma gastric inhibitory peptide (GIP) levels. An ensuing mixed meal elicited a rise in SLI that reached the same levels during infusion of insulin as during uncontrolled hyperglycemia; the incremental increase was, however, 45% higher (P less than 0.005) during insulin infusion. Furthermore feedback insulin infusion enhanced GIP and decreased C-peptide responses, but did not affect the glucagon response to the meal. To further evaluate the influence of insulin of SLI levels, we compared the effects of normo- and hyperglycemia during constant hyperinsulinemia by varying the rate of glucose infusion (glucose clamping). Basal SLI levels decreased significantly only during the normoglycemic clamp. The SLI response to a meal was more pronounced during the normoglycemic than the hyperglycemic clamp. The patterns of glucagon and GIP were similar during the two clamp conditions, while both basal and stimulated C-peptide levels were lower during the normoglycemic clamp. To investigate the temporal relationship between changes in blood glucose and SLI levels, patients were studied during a prolonged (270-min) period of normoglycemic clamp and fasting. After attaining normoglycemia, SLI levels continued to decline for 150 min, whereas glucagon and GIP levels did not change. We conclude that in patients with NIDDM, insulin significantly lowers basal SLI levels if normoglycemia is concomitantly attained; this action of insulin was partially dissociated from its hypoglycemic action; hyperglycemia per se inhibits a meal-induced SLI response, and insulin effects on SLI are not secondary to changes in glucagon or GIP levels.     

Plasma glucagon suppressibility after oral glucose in obese subjects with normal and impaired glucose tolerance

Blood glucose, plasma insulin, and glucagon responses after a 75 g oral glucose-tolerance test were assessed in 9 normal controls, 5 obese nondiabetics (ON), 5 obese nondiabetics with fasting hyperinsulinemia (obese “resistant” nondiabetics—OR), 9 obese with impaired glucose tolerance (O-IGT), and 9 nonobese insulin-dependent diabetics (IDD). Fasting plasma glucagon concentrations were significantly higher in all groups of patients in comparison to the normal controls. Insulin secretion, evaluated in all but the IDD, was similar to normal in the ON and increased in the OR and O-IGT. Normal glucagon suppression was observed in the lean controls and ON but not in OR, O-IGT, and IDD. We suggested that the resistance to glucagon suppression after glucose load in the OR and O-IGT in the presence of increased insulin response could be an indication that the A cell participates in the relative insulin insensitivity of these subjects.     

Effect of contraceptive steroids on arginine-stimulated glucagon and insulin secretion in women. III. Medroxyprogesterone acetate

The effect of medroxyprogesterone acetate (MPA) on basal circulating lipids, arginine-stimulated glucagon and insulin secretion, and glucose tolerance was studied in normal women. After 5 days of oral MPA treatment (10 mg/day), there was a small but significant decline in basal circulating triglycerides. No changes were observed in fasting plasma concentrations of cholesterol, free fatty acids, glucagon, insulin, or glucose; in the plasma glucagon, insulin, or glucose responses during L-arginine infusion; or in the plasma insulin or glucose responses during oral glucose tolerance tests. There was no correlation of any of these parameters with the observed decline in fasting plasma triglyceride concentrations. These results confirm previous reports of no consistent changes in lipid or glucose homeostasis in women using derivatives of 17α-acetoxyprogesterone derivatives for contraceptive purposes, and suggest that MPA may be a suitable alternative for those women who develop hyperlipemia or glucose intolerance when they use contraceptive agents which contain derivatives of ethinyl estradiol and nortestosterone.     

Basal and glucose- and arginine-stimulated serum concentrations of insulin, C-peptide, and glucagon in hyperthyroid patients

The effect of oral glucose and arginine infusion on plasma glucose, glucagon, serum insulin, and C-peptide concentrations was evaluated in 16 patients with hyperthyroid Graves' disease and in ten euthyroid age- and sex-matched normal subjects. Basal plasma glucose concentrations were significantly higher in the hyperthyroid patients, but the plasma glucose response following glucose and arginine administration was similar in the two groups. The insulin response was similar in the hyperthyroid and normal subjects after glucose administration and significantly lower during arginine infusion in the hyperthyroid patients. The serum C-peptide response to both glucose and arginine administration was markedly blunted in the hyperthyroid patients, and the plasma glucagon response to arginine infusion was decreased. These results suggest that pancreatic beta and alpha cell secretory function is impaired in hyperthyroidism as assessed by C-peptide and glucagon secretion following oral glucose administration and arginine infusion. The apparent discrepancy between C-peptide and insulin secretion in the hyperthyroid patients following glucose administration might be due to diminished hepatic extraction of insulin or enhanced metabolism of C-peptide.     

Modifications of abdominal fat and hepatic insulin clearance during severe caloric restriction

Using computed tomography on 19 obese female subjects, we determined abdominal adipose tissue, both subcutaneous and visceral adipose tissue, before and after 2 weeks of a very low caloric diet (VLCD). The following parameters were also determined before and after 15-20 days of VLCD: plasma glucose and insulin levels, oral glucose tolerance test, basal pancreatic insulin secretion estimated by fasting C peptide (Cp), and fasting insulin hepatic clearance calculated by Cp/insulin molar ratio. After VLCD the body weight and body mass index significantly declined (p less than 0.01); whereas abdominal adipose tissue and visceral abdominal tissue (VAT) significantly decreased (p less than 0.01), modifications of subcutaneous abdominal tissue (SAT) were not significant. Fasting insulin levels and plasma glucose response to oral glucose load significantly decreased (p less than 0.05). Insulin response remained unchanged. Cp immunoreactive insulin (IRI) significantly increased (p less than 0.01). A significant positive correlation was found between delta VAT and delta Cp/IRI before and after VLCD (p less than 0.01). Our data seem to suggest that the weight loss induced by VLCD fundamentally involves a decrease in VAT. The reduction in visceral fat could be associated with an increase in hepatic insulin clearance.     

Insulin secretion and body composition in obesity

Plasma immunoreactive insulin levels were measured before and for 6 hr following a 100 g oral glucose load in ten normal volunteers and 17 grossly obese subjects. Eleven of the obese had an abnormal glucose tolerance, five of whom were overt diabetics. Twelve of the obese were restudied after significant weight reduction (thinned obese). Eight thinned obese subjects were also restudied 6–12 mo after completion of the weight reduction protocol. Body composition was measured in each subject prior to testing. Obesity was associated with hyperinsulinemia in the fasting state and in response to oral glucose. The obese diabetics demonstrated a delay and an impairment of insulin secretion in response to glucose. After weight reduction, elevated fasting plasma insulin levels fell in all. Insulin response to oral glucose was not different in the thinned obese with normal glucose tolerance from that observed in the normal volunteers. There was significant correlation between both fasting plasma insulin and total measurable insulin following the glucose load, and total body fat in the obese and thinned obese nondiabetics, but not in the obese overt diabetics. There was, however, significant correlation between fasting plasma insulin levels and total body fat in the diabetics who had a normal fasting blood sugar. These data indicate that the hyperinsulinemia of obesity is clearly related to the increase in total body fat. Carbohydrate intolerance occurs in those obese individuals with a limited pancreatic insulin secretory reserve, which fails to compensate for the increase in total body fat.     

Glucose tolerance in early pregnancy

The effect of pregnancy on oral glucose tolerance (50 g of glucose) and plasma insulin and glucagon responses to oral glucose was studied in weeks 10 and 32 of pregnancy and again 1 year post partum in 12 normal women. Already in week 10, fasting plasma glucose was decreased and the glucose-induced insulin secretion increased as compared with post partum. However, glucose tolerance was not affected at this time. In week 32, glucose tolerance had deteriorated, although the levels of both fasting and glucose-induced insulin were higher than those found in early pregnancy and post partum. At all investigations fasting plasma glucagon and the suppression of plasma glucagon after oral glucose were similar, indicating that glucagon is not implicated in the changes in glucose homeostasis seen in pregnancy. It is concluded that glucose tolerance is unaltered by pregnancy in week 10. Pregnancy has, however, at this very early stage already affected glucose homeostasis as seen by the decrease in fasting plasma glucose and the increase in the insulin response to glucose.     

Pancreatic beta-cell function in cirrhotic patients with and without overt diabetes. C-peptide response to glucagon and to meal

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.     

ABNORMALITIES OF GLUCAGON METABOLISM IN DIABETES MELLITUS

Fasting plasma glucagon has been measured by a specific radioimmunoassay in twenty-three untreated maturity onset diabetic patients and twenty-three matched normal controls. Significant fasting hyperglucagonaemia was demonstrated in the diabetic subjects in spite of their raised blood glucose and insulin concentrations. Oral glucose tolerance tests were performed on ten diabetic subjects and ten normal controls and variations in blood glucose, insulin and glucagon concentration studied. Glucagon concentration was shown to increase significantly after oral glucose in the diabetic subjects and to fall in the normal controls. The differences between the changes in glucagon concentration in the two groups could not be related to the differences in insulin response. It is proposed that these findings provide evidence of derangement of metabolism within the alpha cell in maturity onset diabetes.