How does glucose regulate the human pancreatic A cell in vivo?

Summary To investigate the mechanism whereby changes in plasma glucose level alter human pancreatic A-cell activity in vivo, A-cell activity was determined during manipulation of plasma glucose and pancreatic B-cell activity by insulin and glucose infusions. A-cell activity (the acute immunoreactive glucagon response to intravenous arginine, 0–10 min) rose from 482±125 to 968±191 pg · ml^-1 · 10 min^-1 (mean±SEM) when the plasma C-peptide level (a measure of B-cell activity) was suppressed from 2164±365 to 872±162 pg/ml by an insulin infusion at euglycaemia (employing the glucose clamp technique) in six normal subjects. Raising plasma glucose to 6.7 mmol/l during the same insulin infusion returned mean C-peptide (2688±581 pg/ml) and the acute glucagon response to arginine (447±146 pg · ml^-1 · 10 min^-1) close to basal levels. Individual changes in the acute glucagon response to arginine followed the C-peptide changes. The mean change in the acute glucagon response to arginine per unit change in plasma glucose (-191±36) was similar to that seen when plasma glucose was raised to twice basal levels in six different subjects without an insulin infusion (-159±45). This suggests that, when plasma glucose is raised to about twice basal level in vivo, the major factor in suppressing A-cell activity is the concurrent change in B-cell activity rather than direct effects of glucose or circulating insulin on the A cell.     

Effect of the enteroinsular axis on both the A- and B-cell response to arginine after oral glucose in man

Summary Studies were made on the effect of the enteroinsular axis on amino acid-induced insulin and glucagon secretion during hyperglycaemia in man. The responses of plasma immunoreactive insulin, C-peptide, and immunoreactive glucagon to arginine infusion were investigated in nine healthy subjects after induction of hyperglycaemia by an oral glucose load and by intravenous glucose infusion to produce similar glucose concentrations in the arterialised blood. The plasma immunoreactive insulin and C-peptide levels increased to higher levels after an oral glucose load than after an intravenous infusion of glucose. The incremental areas under the immunoreactive insulin and C-peptide curves during arginine infusion were significantly greater (p<0.01) after oral than after intravenous glucose administration. The plasma immunoreactive glucagon level was suppressed equally after oral and intravenous glucose loads. However, during subsequent arginine infusion, the plasma immunoreactive glucagon level rose more in the presence of hyperglycaemia induced by oral than intravenous glucose. The incremental area under the plasma immunoreactive glucagon curve during arginine infusion was 1.6-fold greater after glucose ingestion than after intravenous glucose infusion. These results suggest that the enteroinsular axis has a stimulatory effect on the responses of pancreatic A and B cells to arginine after oral glucose administration.     

Failure of indomethacin to affect arginine-induced C-peptide and glucagon release in insulin-treated diabetics

Summary Fourteen insulin-treated diabetics were submitted to an arginine infusion test performed with either 11.7 or 5.85mg kg^-1 min^-1 arginine monohydrochloride infused during 40 min with or without previous oral administration of a low (75+50 mg) or a high (75 mg + 3 mg/kg) dose of indomethacin. Blood glucose, plasma non-esterified fatty acids, insulin, C-peptide and glucagon were determined at regular intervals before, during and after the arginine infusion. These parameters were totally unaffected by the two doses of indomethacin both in the basal state and during the arginine infusions at the two loads tested. Eight subjects had a basal C-peptide level above 0.07 pmol/ml and a mean (± SEM) maximal rise of 0.21±0.04 pmol/ml during the arginine infusion, whereas the remaining six patients had virtually zero values throughout the tests. The arginine-induced plasma glucagon rise was similar for the two rates of arginine infusion; the sum of the increments in plasma glucagon averaged 877±120 and 647±92 pg/ml (p>0.1) for the high and low rates of arginine infusion, respectively. The magnitude of the blood glucose rise appeared independent of the amount of arginine infused. Confirming previous reports, we found that the blood glucose rise after arginine was three to four times higher in subjects without C-peptide than in subjects with C-peptide. The mean glucagon response did not differ significantly between subjects with or without C-peptide. Thus, residual B cell function determines the magnitude of the blood glucose rise but not the glucagon response after intravenous arginine.     

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.     

Pancreatic alpha-cell function in diabetic hemochromatotic subjects.

To clarify further the etiology of the carbohydrate intolerance in idiopathic hemochromatosis, we investigated the glucose, insulin, C-peptide, and glucagon responses to arginine (0.5 g/kg) infused during 30 min in lean normal subjects; in insulin-requiring subjects with hemochromatosis, genetic diabetes, and total pancreatectomy; and in nondiabetic cirrhotic subjects without portosystemic shunting. Serum insulin, C-peptide, and glucagon responses (30K antibody) were determined by RIA, and glucose level was determined by a glucose oxidase technique. Hemochromatotic and genetic diabetic subjects had similar basal glucose (157 +/- 25 vs. 168 +/- 40 mg/dl) and C-peptide (0.73 +/- 0.42 vs. 0.65 +/- 0.22 ng/ml) values, with subnormal C-peptide peak responses to stimulation (1.05 +/- 0.38 and 1.40 +/- 0.83 vs. 3.95 +/- 0.4 ng/ml in normals; P less than 0.05). No glucagon or C-peptide response to arginine was seen in any pancreatectomized subject. Similar but excessive glucagon levels were present in hemochromatosis, diabetes, and cirrhosis under basal conditions (166 +/- 24, 232 +/- 111, and 263 +/- 116 vs. 76 +/- 15 pg/ml; P less than 0.05) and after arginine stimulation (782 +/- 80, 834 +/- 123, and 902 +/- 275 vs. 489 +/- 81 pg/ml; P less than 0.05) when compared with normals. The excessive glucagon levels found in hemochromatosis, diabetes mellitus, and cirrhosis contrast to the absent response in pancreatectomized subjects and indicate that generalized islet cell destruction is not the major factor in diabetic hemochromatotic subjects.     

Pancreatic alpha- and beta-cell function in pheochromocytoma.

Arginine infusion tests were carried out in seven patients with pheochromocytoma before and after extirpation of the tumors in order to evaluate pancreatic islet alpha- and beta-cell function during the state of endogenous catecholamine excess. Six of the patients had glucose intolerance; one did not. Preoperatively, the pancreatic glucagon response was suppressed, while the insulin response was comparable to that in normal control subjects. Plasma glucose levels decreased rapidly after the beginning of arginine infusion in all patients. Theses changes during the infusion were evident in the one patient without glucose intolerance. Postoperatively, the glucagon response and plasma glucose changes were normalized. In addition to the obvious suppression of pancreatic alpha-cell function in our patients with pheochromocytoma, it seems likely that pancreatic beta-cell function also was suppressed; there was no enhancement of the insulin response to arginine during the period of chronic hyperglycemia, a situation in which a synergistic effect between glucose and arginine might be expected.     

Abnormal glucagon response to arginine and its normalization in obese hyperinsulinaemic patients with glucose intolerance: importance of insulin action on pancreatic Alpha cells

Summary An excessive glucagon secretion to intravenous arginine infusion was found in obese hyperinsulinaemic patients with glucose intolerance. This study was designed to determine whether the glucagon hyperresponsiveness to arginine in these patients would improve by insulin infused at a high enough dose to overcome insulin resistance. By infusing high dose insulin during arginine infusion, the previously exaggerated glucagon response to arginine could be normalized. To normalize the abnormal glucagon response, insulin doses of 4.2±0.7 and 3.8±0.5 IU were required during arginine infusion in obese hyperinsulinaemic patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetes mellitus, respectively. This achieved plasma peak insulin levels 3 to 4 times higher than those observed in non-obese healthy subjects. Furthermore, we clarified whether or not the effect of normalizing insulin action and/or glycaemic excursions contributed to normalizing the exaggerated glucagon response to arginine in these patients. Blood glucose was clamped while high dose insulin was infused at the same levels as observed during the arginine infusion test with no insulin infusion. As a result, normalization of the exaggerated plasma glucagon response was achieved, whether hyperglycaemia existed or not. These results clearly demonstrate that, similar to non-obese hypoinsulinaemic Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients, the exaggerated Alpha-cell response to arginine infusion in obese hyperinsulinaemic patients with glucose intolerance is secondary to the reduction of insulin action on the pancreatic Alpha cell, and that the expression of insulin action plays an important part in normalizing these abnormalities.     

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.     

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.     

C-peptide and glucagon profiles in minority children with type 2 diabetes mellitus

The present study was conducted to determine the extent of insulin deficiency and glucagon excess in the hyperglycemia of type 2 diabetes in children. The incidence of type 2 diabetes mellitus in children and adolescents has increased substantially over the past several years. Because insulin and glucagon action both regulate blood glucose concentration, we studied their responses to mixed meals in children with type 2 diabetes. Subjects were 24 patients with type 2 diabetes compared with 24 controls, aged 9--20 yr (predominantly African-Americans), matched for body mass index and sexual maturation. All of those with diabetes were negative for antibodies to glutamic acid decarboxylase. Plasma glucose, glucagon, and serum C-peptide concentrations were measured at 0, 30, 60, 90, and 120 min after a mixed liquid meal (Sustacal) ingestion (7 mL/kg body weight; maximum, 360 mL). The area under the curve (AUC) was calculated by trapezoidal estimation. The incremental C-peptide (Delta CP) in response to the mixed meal was calculated (peak -- fasting C-peptide). The plasma glucose AUC was significantly greater in patients than in controls (mean +/- SEM, 1231 +/- 138 vs. 591 +/- 13 mmol/L x min; P < 0.001). The Delta CP was significantly lower in those with diabetes than in controls (1168 +/- 162 vs. 1814 +/- 222 pmol/L; P < 0.02). Glucagon responses did not differ between the two groups. Hyperglycemia is known to inhibit glucagon secretion. Therefore, our patients with substantial hyperglycemia would be expected to have decreased glucagon responses compared with controls and are thus relatively hyperglucagonemic. Patients were divided into poorly and well controlled subgroups (glycosylated hemoglobin A(1c), > or =7.2% and <7.2%, respectively). There were no significant differences in the Delta CP and glucagon responses between these two subgroups. We next analyzed the data in terms of duration of diabetes (long term, > or =1 yr; short term, <1 yr). The CP was significantly lower in long- vs. short-term patients (768 +/- 232 vs. 1407 +/- 199 pmol/L; P < 0.05). The plasma glucagon AUC was significantly higher in the long- vs. short-term patients (9029 +/- 976 vs. 6074 +/- 291 ng/L x min; P < 0.001). Hemoglobin A(1c) did not differ between long- vs. short-term patients. Our results indicate that relative hypoinsulinemia and hyperglucagonemia represent the pancreatic beta- and alpha-cell dysfunctions in children with type 2 diabetes. The severity of both beta- and alpha-cell dysfunctions appears to be determined by the duration of diabetes.     

Effects of C-peptide on insulin-induced hypoglycaemia and its counterregulatory responses in IDDM patients

Recent studies indicate that C-peptide, when given to patients with insulin-dependent (Type 1) diabetes mellitus (IDDM), exerts significant effects on microvascular and neuronal functions. Adjuvant therapy with C-peptide has been advocated in the treatment of IDDM patients. Since endogenous insulin secretion is believed to be of importance for the alpha-cell function, we addressed the issue whether C-peptide given acutely interferes with the responses to hypoglycaemia. Seven IDDM patients were randomly exposed to hypoglycaemia with and without exogenous C-peptide. Insulin and and C-peptide were given intravenously in equimolar amounts for 3 hours. The decrease of blood glucose was faster and more pronounced during C-peptide infusion, yielding a significantly lower AUC 0–180 min of blood glucose (38.5 ± 1.6 vs 44.4 ± 2.2 mmol l⁻¹ h⁻¹ ; p = 0.032). No difference between the two experiments was found concerning glucagon when the AUC, Δ-values or levels at separate points of time were calculated. In conclusion, the main finding of this study was that exogenous C-peptide, given acutely, gave rise to a more rapid onset of hypoglycaemia yielding no detectable differences with respect to the response of glucagon and other counterregulatory hormones. © 1997 by John Wiley & Sons, Ltd.     

Diabetes mellitus in Tropical Chronic Pancreatitis Is Not Just a Secondary Type of Diabetes.

AIMS: In chronic calcific pancreatitis of the tropics, etiology and relationship to developing diabetes mellitus are unknown. Some consider these cases a straightforward secondary type of diabetes, while others suggest selective beta-cell impairment. Testing pancreatic function, we investigated whether selective beta-cell impairment triggers diabetes associated with tropical pancreatitis. METHODS: At a Bangladeshi research institute, 8 chronic tropical pancreatitis and no diabetes mellitus subjects, 14 fibrocalculous pancreatic diabetics and 27 matched healthy controls underwent arginine (endocrine pancreatic function) and secretin (exocrine pancreatic function assessment) stimulation tests. RESULTS: All patients with clinically-diagnosed, chronic pancreatitis demonstrated pronounced exocrine pancreatic dysfunction with beta-cell functioning differing significantly between the two groups. Compared to controls, patients having tropical pancreatitis and no diabetes showed normal plasma C-peptide values at baseline and after arginine stimulation, while fibrocalculous pancreatic diabetics demonstrated a typical diabetic pattern for plasma C-peptide levels. In contrast, pancreatic alpha-cell functioning (glucagon response to arginine) was preserved in both pancreatitis groups. CONCLUSION: A preserved pancreatic alpha-cell function in diabetics with advanced chronic pancreatitis of the tropics supports the concept of two different pathogenic mechanisms, one eliciting chronic pancreatitis and the other selective pancreatic beta-cell impairment and subsequent diabetes mellitus.     

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.     

Glucose regulation of glucagon secretion independent of B cell activity

To investigate whether glucose has an effect on the pancreatic A cell independent of intraislet or paracrine B cell mediation, we have tested the ability of changes in plasma glucose (PG) level to influence the acute glucagon response (AGR) to 5 g of intravenous arginine in 8 C-peptide negative insulin dependent diabetics (IDD). Insulin was infused (1 mU/kg/min) for a 90 min basal period during which PG levels were maintained constant by the glucose clamp technique. Basal AGR was then determined. In 4 of the diabetics, the PG level was subsequently lowered to a new steady state and, in 2 diabetics, PG level was raised. In 2 additional IDDs, two manipulations in PG level were carried out (PG ranges 51-390 mg/dl). The same insulin infusion was continued throughout. The acute glucagon response to arginine was determined at each PG level. The ability of unit changes in PG to influence (modulate) the AGR (MdIRG) was calculated as the difference in AGRs divided by the PG difference. MdIRG was consistent between diabetics (means +/- SEM = 2.1 +/- 0.2) and was independent of both direction and magnitude of the PG change. Thus, in vivo, in man, glucose has an effect on the pancreatic A cell which is independent of intraislet B cell influences.     

Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes

In Type II, non-insulin-dependent diabetes, insulin secretion is often reduced to the point where oral hypoglycaemic agents fail to control the plasma glucose level. We studied 12 patients (age 41-66 years; 4 lean, 8 obese) with Type II diabetes mellitus for 1-25 years who were uncontrolled despite maximal dose glibenclamide and metformin. After withdrawal of medication, blood glucose control was determined by measuring glucose before and 2 h after each meal for 48 h, and beta-cell function by insulin or C-peptide response to glucagon and to iv glucose. Following these tests, intensive insulin treatment (CSII) was initiated, and near-euglycaemia (mean of 7 daily glucose determinations less than 7.7 mmol/l) was maintained for 16.6 +/- 1.5 days, at which time the tests were repeated. Mean daily insulin requirement was 61 +/- 9 IU (0.81 +/- 0.09 IU/kg). Glucose control was improved after cessation of CSII (mean glucose 12.7 +/- 0.6 mmol/l after vs 20 +/- 1.5 mmol/l before, P less than 0.005). Maximum incremental C-peptide response improved both to glucagon (214 +/- 32 after vs 134 +/- 48 pmol/l before, P = 0.05) and to glucose iv bolus injection (284 +/- 53 vs 113 +/- 32 pmol/l, P less than 0.05). Peak insulin response, measured after iv glucose infusion, also tended to be higher in the post-CSII test (42 +/- 18 vs 22 +/- 5.6 mU/l). Basal and stimulated proinsulin concentrations were high relative to C-peptide levels during the pre-treatment period, but returned to normal after CSII.(ABSTRACT TRUNCATED AT 250 WORDS)     

Meal-stimulated glucagon release is associated with postprandial blood glucose level and does not interfere with glycemic control in children and adolescents with new-onset type 1 diabetes

CONTEXT: The role of glucagon in hyperglycemia in type 1 diabetes is unresolved, and in vitro studies suggest that increasing blood glucose might stimulate glucagon secretion. OBJECTIVE: Our objective was to investigate the relationship between postprandial glucose and glucagon level during the first 12 months after diagnosis of childhood type 1 diabetes. DESIGN: We conducted a prospective, noninterventional, 12-month follow-up study conducted in 22 centers in 18 countries. PATIENTS: Patients included 257 children and adolescents less than 16 yr old with newly diagnosed type 1 diabetes; 204 completed the 12-month follow-up. SETTING: The study was conducted at pediatric outpatient clinics. MAIN OUTCOME MEASURES: We assessed residual beta-cell function (C-peptide), glycosylated hemoglobin (HbA(1c)), blood glucose, glucagon, and glucagon-like peptide-1 (GLP-1) release in response to a 90-min meal stimulation (Boost) at 1, 6, and 12 months after diagnosis. RESULTS: Compound symmetric repeated-measurements models including all three visits showed that postprandial glucagon increased by 17% during follow-up (P = 0.001). Glucagon levels were highly associated with postprandial blood glucose levels because a 10 mmol/liter increase in blood glucose corresponded to a 20% increase in glucagon release (P = 0.0003). Glucagon levels were also associated with GLP-1 release because a 10% increase in GLP-1 corresponded to a 2% increase in glucagon release (P = 0.0003). Glucagon levels were not associated (coefficient -0.21, P = 0.07) with HbA(1c), adjusted for insulin dose. Immunohistochemical staining confirmed the presence of Kir6.2/SUR1 in human alpha-cells. CONCLUSION: Our study supports the recent in vitro data showing a stimulation of glucagon secretion by high glucose levels. Postprandial glucagon levels were not associated with HbA(1c), adjusted for insulin dose, during the first year after onset of childhood type 1 diabetes.     

Diminished A-cell secretion in the early phase of type I diabetes mellitus

The A-cell function in "true pre-type I diabetes" or in early phase of type I diabetes has not been reported. We studied A-cell reserve in response to intravenous arginine infusion in six individuals characterized by type I diabetes-associated immunologic defects and absent first-phase insulin secretory response to intravenous glucose prior to development of diabetes. The peak glucagon response in these patients was markedly impaired (153 +/- 39 pg/mL, mean +/- SEM) compared to a group of 23 normal, healthy controls (301 +/- 18; P less than 0.01) and a group of 11 healthy, discordant monozygotic twins of type I diabetic patients (250 +/- 25, P less than 0.05). The glucagon concentrations in response to oral glucose were completely suppressed to undetectable levels in three of the patients studied. In view of the well-known observations of insulitis in the prediabetic phase in man and in experimental models of type I diabetes and anti-islet cytoplasmic antibodies directed against all islet cells, our observations suggest an impairment of A-cells during the evolution of type I diabetes.     

Infusion of synthetic human C-peptide does not affect plasma glucose, serum insulin, or plasma glucagon in healthy subjects

We studied six healthy male subjects to determine whether a four-hour infusion of synthetic human C-peptide sufficient to achieve mean (+/- SD) peripheral plasma concentrations of 1.3 +/- 0.7 pmol/mL affected plasma glucose, serum insulin, or plasma glucagon. Subjects were studied in a fasting state and following an oral glucose load during four-hour 0.9% NaCl (control) and C-peptide (mean dose: 70 nmol) infusions. No differences were observed between saline and C-peptide infusions for mean values of fasting plasma glucose (94 +/- 6 v 87 +/- 5 mg/dL), serum insulin (3 +/- 1 v 2 +/- 1 microU/mL), or plasma glucagon (124 +/- 65 v 112 +/- 70 pg/dL). Following oral glucose ingestion no differences were detected between saline and C-peptide infusions for mean peak values of plasma glucose (168 +/- 18 v 168 +/- 31) and serum insulin (59 +/- 6 v 57 +/- 21) or mean nadir values of plasma glucagon (80 +/- 73 v 75 +/- 70). There was a slight delay in the insulin rise following oral glucose on the C-peptide infusion day, but differences between mean values for individual sampling times were not statistically significantly different.     

Glucagon and insulin secretion in potential diabetes

Summary Insulin and glucagon have been studied in 20 subjects (both of the subjects’ parents were diabetic or in case of only one diabetic parent, the other showed a first degree familiarity of diabetes): 10 showed normal glucose tolerance (‘true prediabetics’) and 10 impaired glucose tolerance (‘genetic chemical diabetes’). Mean insulin response to oral (100 g) and i.v. glucose load (200 mg/kg followed by 20 mg/kg/min for 60 min) and to arginine infusion (25 g in 30 min) was normal in the prediabetics and delayed and higher in the subjects with chemical diabetes as compared to the control group. Glucagon response to arginine was higher, but not significantly, in prediabetics and in subjects with chemical diabetes. In both of these groups glucagon suppression by glucose was not observed. The insulin/glucagon molar ratio was significantly reduced after glucose infusion in these two groups. No correlation was found between insulin and glucagon secretion after arginine or glucose. A possible alteration in the mechanism controlling glucagon secretion even in the earliest phases of diabetes is suggested. This work was supported in part by C.N.R. (Consiglio Nazionale delle Ricerche), Roma, grant # CT 76.01345.04.     

Plasma alpha-cell glucagon in primary hyperparathyroidism

Plasma glucose, insulin, and alpha-cell glucagon profiles were examined in ten adults with uncomplicated primary hyperparathyroidism before and 8–12 wk after surgical removal of a single parathyroid adenoma. Treatment restored abnormal serum calcium and phosphorus concentrations to a normal range and reduced serum parathyroid hormone levels from 47 ± 4 to 16 ± 4 μ 1 Eq/ml (normal = 0–40). Plasma glucose curves during 100-g oral glucose tolerance, 30 min intravenous glucose (1.5 g/min), or arginine infusions (1.0 g/min) did not differ before and after surgery. However, basal and peak insulin concentrations were higher before treatment during these tests (p < 0.05). Basal glucagon levels were unaffected by hyperparathyroidism (72 ± 7 versus 77 ± 7 pg/ml). Peak 30 min values after arginine provocation were also similar before and after treatment as was maximal suppression of basal glucagon during glucose infusions. Four patients also received 400 g lean beef meals. Glucose and glucagon responses over 240-min periods were nearly identical before and after surgery despite higher insulin levels before treatment.It is concluded that elevated serum parathyroid hormone and plasma insulin concentrations in primary hyperparathyroidism do not relate to abnormalities of plasma alpha-cell glucagon in the basal state or after glucose, arginine, or protein administration.