Impaired Counter Regulation of Hypoglycemia in a Group of Insulin-dependent Diabetics with Recurrent Episodes of Severe Hypoglycemia

Abstract The counterregulatory response to insulin-induced hypoglycemia was investigated in 22 insulin-dependent diabetics (IDD) with recurrent hypoglycemia and in 6 healthy volunteers. Hypoglycemia was induced by a constant rate infusion of insulin (2.4 U/h) up to four hours. Conventional insulin therapy was changed to an i.v. infusion of regular insulin 24 hours prior to the experiment. The presence of diabetic autonomic neuropathy was evaluated by respiratory sinus arrhythmia and Valsalva maneuver. In healthy subjects, blood glucose was decreased to 2.5 mmol, here reaching steady state level and giving rise to marked glucagon and growth hormone (GH) responses. The majority of IDD (group A) reached a slightly lower steady state glucose level and exhibited similar glucagon and GH responses while the epinephrine response was augmented. Six IDD (group B) showed a continuous decrease in blood glucose to 1.2+0.1 mmol/l at which level the infusion of insulin was discontinued due to neuroglucopenic symptoms. These subjects had no glucagon and epinephrine responses while their GH and cortisol responses were normal. A comparison of the diabetic groups revealed a longer duration of diabetes and a more impaired autonomic nervous function in group B while glycosylated hemoglobin was similar. It is concluded that most IDD have normal hormonal responses (epinephrine, glucagon, GH, cortisol) and normal counterregulartory capacity to hypoglycemia induced by a prolonged infusion of a moderate dose of insulin. Some patients with long-term diabetes and impaired capacity to counteract hypoglycemia exhibit deficient glucagon and epinephrine responses to hypoglycemia.     

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.     

Metabolic response to egg white and cottage cheese protein in normal subjects

In type II diabetic subjects, we previously demonstrated differences in the serum insulin, C-peptide, and glucagon response to ingestion of seven different protein sources when administered with 50 g of glucose. The response was smallest with egg white and greatest with cottage cheese protein. In the present study, we compared the responses to 50 g of the above two proteins ingested without glucose in normal male subjects. We also determined the proportion of each ingested protein converted to urea nitrogen. The incremental area response integrated over 8 hours for serum insulin, C-peptide, glucagon, alpha-amino-nitrogen (AAN), and urea nitrogen were all approximately 50% less following egg white. This was associated with a 50% smaller conversion of protein to urea. Overall, 70% of the cottage cheese but only 47% of the egg white protein could be accounted for by urea formation. Most likely the smaller hormonal response to egg white is due to poor digestibility of this protein.     

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.     

Effects of meal size and composition on incretin, α-cell, and β-cell responses

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate postprandial insulin release from the β-cells. We investigated the effects of 3 standardized meals with different caloric and nutritional content in terms of postprandial glucose, insulin, glucagon, and incretin responses. In a randomized crossover study, 18 subjects with type 2 diabetes mellitus and 6 healthy volunteers underwent three 4-hour meal tolerance tests (small carbohydrate [CH]-rich meal, large CH-rich meal, and fat-rich meal). Non-model-based and model-based estimates of β-cell function and incremental areas under the curve of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP were calculated. Mixed models and Friedman tests were used to test for differences in meal responses. The large CH-rich meal and fat-rich meal resulted in a slightly larger insulin response as compared with the small CH-rich meal and led to a slightly shorter period of hyperglycemia, but only in healthy subjects. Model-based insulin secretion estimates did not show pronounced differences between meals. Both in healthy individuals and in those with diabetes, more CH resulted in higher GLP-1 release. In contrast with the other meals, GIP release was still rising 2 hours after the fat-rich meal. The initial glucagon response was stimulated by the large CH-rich meal, whereas the fat-rich meal induced a late glucagon response. Fat preferentially stimulates GIP secretion, whereas CH stimulates GLP-1 secretion. Differences in meal size and composition led to differences in insulin and incretin responses but not to differences in postprandial glucose levels of the well-controlled patients with diabetes.     

Metabolic response to cottage cheese or egg white protein, with or without glucose, in type II diabetic subjects.

Test meals with 25 g protein in the form of cottage cheese or egg white were given with or without 50 g glucose to male subjects with mild to moderately severe, untreated, type II diabetes. Water was given as a control meal. The glucose, insulin, C-peptide, alpha amino nitrogen (AAN), glucagon, plasma urea nitrogen (PUN), nonesterified fatty acid (NEFA), and triglyceride area responses were determined using the water meal as a baseline. The glucose area responses following ingestion of cottage cheese or egg white were very small compared with those of the glucose meal, and were not significantly different from one another. The serum insulin area response was 3.6-fold greater following ingestion of cottage cheese compared with egg white (309 v 86 pmol/L.h). The simultaneous ingestion of glucose with cottage cheese or egg white protein decreased the glucose area response to glucose by 11% and 20%, respectively. When either protein was ingested with glucose, the insulin area response was greater than the sum of the individual responses, indicating a synergistic effect (glucose alone, 732 pmol/L.h; glucose with cottage cheese, 1,637 pmol/L.h; glucose with egg white, 1,213 pmol/L.h). The C-peptide area response was similar to the insulin area response. The AAN area response was approximately twofold greater following ingestion of cottage cheese compared with egg white. Following ingestion of glucose, it was negative. When protein was ingested with glucose, the AAN area responses were additive. The glucagon area response was similar following ingestion of cottage cheese or egg white protein. Following glucose ingestion, the glucagon area response was negative.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intestinal nutrient influence on the enteroinsular axis.

The gastrointestinal contribution to carbohydrate metabolism includes carbohydrate absorption and the release of gastrointestinal hormones that interact with the endocrine pancreas. To learn the contributions to the enteroinsular axis from different levels of the gastrointestinal tract and different nutrients in chyme, we determined serum concentrations of glucose, gastric inhibitory peptide (GIP), insulin, and glucagon postprandially in six normal subjects who underwent diversion of chyme just proximal to an occlusive balloon at the ligament of Treitz and jejunal infusion of saline or chyme carbohydrate, protein, and lipid, separately or in combination. Postprandial elevations of serum glucose, GIP, and insulin and decrease of serum glucagon were elicited predominantly from the bowel and its contents distal to the ligament of Treitz. In this segment, each chyme nutrient (but especially carbohydrate) significantly stimulated factors affecting carbohydrate metabolism. Protein and lipid were able to block carbohydrate-induced glucagon inhibition. The gastroduodenal segment, although containing several proposed insulinotropic hormones (gastrin, secretin, and cholecystokinin), had no effect on serum glucose of glucagon and stimulated only small insulin and GIP responses.     

Metabolic responses in a model of insulin resistance: comparison between oral glucose and meal tolerance tests

The purpose of this investigation was to compare the benefits of a meal tolerance test (MTT) against those of an oral glucose tolerance test (OGTT) in one of the most commonly used models of insulin resistance, the Zucker fatty rat. Comparison of these two oral challenges will facilitate determination of the most effective means of inducing both glucose and insulin responses in this particular model and allow for possible therapeutic benefits to be examined more effectively. Eight-week-old Zucker fatty rats (n = 7 or 8) were used to perform either an OGTT or a MTT following an overnight fast. The OGTT contained a final amount of carbohydrate (CHO) of 1.2 g/kg body weight (BW). The MTT (commercially available liquid meal), in addition to having fat and protein, included a final amount of available CHO and volume to match the OGTT. A saline-treated group served as control. A greater glucose excursion was observed following the OGTT compared to the MTT. The maximal change in glucose from baseline was 140 +/- 10 mg/dL (a 2.1-fold rise) for the OGTT compared to 86.3 +/- 6.1 mg/dL (a 1.7-fold rise) for the MTT (P <.05). The MTT induced a greater change from baseline in insulin response compared to the OGTT (7.5 +/- 1.1 v 3.9 +/- 0.5 ng/mL, MTT v OGTT, respectively; P <.05). The saline challenge induced only minimal glucose and insulin responses in comparison to the other treatments. These results suggest that, in a model of insulin resistance, the MTT is a more potent insulin stimulator than glucose alone. A mixed meal, such as a MTT, provides a complete nutrient challenge (CHO, fat, and protein) that will induce both glucose and insulin responses, enabling a better capacity to detect differences in one of the most often used models of insulin resistance, the Zucker fatty rat.     

Liquid carbohydrate/essential amino acid ingestion during a short-term bout of resistance exercise suppresses myofibrillar protein degradation

A number of physiological events including the level of contractile activity, nutrient status, and hormonal action influence the magnitude of exercise-induced skeletal muscle growth. However, it is not the independent action of a single mechanism, but the complex interaction between events that enhance the long-term adaptations to resistance training. The purpose of the present investigation was to examine the influence of liquid carbohydrate (CHO) and essential amino acid (EAA) ingestion during resistance exercise and modification of the immediate hormonal response on myofibrillar protein degradation as assessed by 3-methylhistidine (3-MH) excretion. After a 4-hour fast, 32 untrained young men (18-29 years) performed a single bout of resistance exercise (complete body; 3 setsx10 repetitions at 75% of 1-repetition maximum; 1-minute rest between sets), during which they consumed a 6% CHO (n=8) solution, a 6-g EAA (n=8) mixture, a combined CHO+EAA (n=8) supplement, or placebo (PLA; n=8) beverage. Resistance exercise performed in conjunction with CHO and CHO+EAA ingestion resulted in significantly elevated (P<.001) glucose and insulin concentrations above baseline, whereas EAA ingestion only increased the postexercise insulin response (P<.05). Time matched at 60 minutes, the PLA group exhibited a peak cortisol increase of 105% (P<.001) with no significant change in glucose or insulin concentrations. Conversely, the CHO and CHO+EAA groups displayed a decrease in cortisol levels of 11% and 7%, respectively. Coinciding with these hormonal response patterns were significant differences in myofibrillar protein degradation. Ingestion of the EAA and CHO treatments attenuated 3-MH excretion 48 hours after the exercise bout. Moreover, this response was synergistically potentiated when the 2 treatments were combined, with CHO+EAA ingestion resulting in a 27% reduction (P<.01) in 3-MH excretion. In contrast, the PLA group displayed a 56% increase (P<.01) in 3-MH excretion. These data demonstrate that not only does CHO and EAA ingestion during the exercise bout suppress exercise-induced cortisol release; the stimulatory effect of resistance exercise on myofibrillar protein degradation can be attenuated, most dramatically when the treatments are combined (CHO+EAA). Through an "anticatabolic effect," this altered balance may better favor the conservation of myofibrillar protein.     

Glucose metabolism in patients receiving chronic calcitonin treatment

The effect of long term (two months) administration of synthetic salmon calcitonin (100 MRC Units per day) on plasma glucose, insulin, C-peptide, glucagon and growth hormone responses to iv glucose and arginine were investigated in patients with either Paget's disease of bone (n = 6) or significant osteoporosis (n = 9). Glucose tolerance did not deteriorate after treatment, despite a reduction in the early insulin response to glucose, resetting of the C-peptide response at a lower level and a reduction in glucose-mediated glucagon suppression. The rise in plasma glucose triggered by arginine was reduced after treatment despite similar hormonal environment. This seems to suggest a positive influence of calcitonin on glucose disposal. The diabetogenic action of acute calcitonin administration is not observed after prolonged administration of the hormone. However, the possibility that calcitonin may produce a diabetic state in subjects with decreased insulin reserve cannot be totally exclused.     

The gastro-entero-pancreatic hormone response to fasting in obesity

Summary A comparison of the metabolic and gastroentero-pancreatic hormonal responses of ten obese and eight lean subjects to 12 h and 36 h fasts has been made. Each subject was given a 50 g oral glucose tolerance test at the end of both 12 h and 36 h starvation. After the 12 h fast blood glucose and 3-hydroxybutyrate were similar in each group but blood glycerol was 30% higher in the obese subjects. Plasma insulin and vaso-active intestinal polypeptide were also higher in the obese subjects after 12 h starvation. After 36 h starvation in the lean subjects blood glucose was unchanged but on refeeding with 50 g oral glucose, glucose tolerance was impaired. In the same group blood glycerol and 3-hydroxybutyrate rose after 36 h starvation. Plasma glucagon, secretin and vaso-active intestinal polypeptide rose after 36 h starvation in the lean subjects but plasma insulin was unchanged. Refeeding with oral glucose suppressed the increased plasma glucagon, secretin and vaso-active intestinal polypeptide. After the 36 h fast in the obese subjects, blood glucose was unchanged, blood glycerol fell, but blood 3-hydroxybutyrate rose although to a reduced level in comparison with the lean subjects. In the obese group there was no change in plasma glucagon, secretin or vaso-active intestinal polypeptide after 36 h starvation, although plasma insulin fell. The results show different metabolic and gastro-entero-pancreatic hormonal responses to fasting in lean and obese human subjects and suggest an important metabolic role of glucagon, secretin and vaso-active intestinal polypeptide during starvation.Now Endocrinology Fellow, University of Texas at Dallas     

The effect of ingestion of meat on hepatic extraction of insulin and glucagon and hepatic glucose output in conscious dogs

The effect of ingestion of protein on hepatic extraction of insulin and glucagon and hepatic glucose output were investigated in conscious dogs. The ingestion of meat stimulated both insulin and glucagon secretion but the glucagon response was much more rapid and greater than that of insulin. Secretion of glucagon demonstrated a biphasic pattern while insulin release was monophasic. The fractional hepatic extraction of glucagon increased gradually from the basal value of 15 +/- 3% to a peak of 36 +/- 5% at 90 min, and that of insulin increased from the basal level of 41 +/- 2% to 54 +/- 4% at 45 and 60 min. The increased hepatic extraction of glucagon and insulin after meat ingestion may be explained by neural or hormonal signals from the gut. The blood glucose and hepatic glucose output did not increase significantly despite the significant decrease of the portal vein insulin to glucagon molar ratio as well as the significant decrease of the molar ratio of the hepatic uptake of these hormones. The absence of greater hepatic glucose production despite the augmented glucagon secretion and decreased portal vein insulin to glucagon molar ratio could reflect down regulation by glucagon.     

Role of the liver in endotoxin-induced hyperinsulinemia and hyperglucagonemia in rats

The intravenous administration of bacterial endotoxin to fasted rats elicited basal portal and systemic venous hyperinsulinemia and hyperglucagonemia. Enhanced pancreatic secretion of insulin and glucagon was implied by the elevated portal venous hormonal levels. Elevated insulin and glucagon levels were present at 4 hr after a 33 micrograms/100 gm intravenous endotoxin dose despite no fluctuation of the plasma glucose concentration. The role of the liver in the pancreatic hormonal response to endotoxin was investigated by infusing lipopolysaccharide slowly into the portal vein or systemic inferior vena cava. At doses of 33 and 100 micrograms per 100 gm, endotoxin administered via the systemic route stimulated significantly greater insulin and glucagon responses than did portal administration. Furthermore, rats with acute liver injury induced by partial (67%) hepatectomy, which depressed Kupffer cell phagocytosis, did respond to the 33 micrograms per 100 gm intraportal endotoxin dose with significantly greater hyperinsulinemia and hyperglucagonemia. These data suggest that hepatic Kupffer cells normally function to remove lipopolysaccharide from the portal venous blood and that at least at low pharmacological doses the pancreatic hormonal response to endotoxin is mediated by an unknown systemic mechanism.     

Continuous intraperitoneal insulin infusion partly restores the glucagon response to hypoglycaemia in type 1 diabetic patients

The glycaemic and hormonal responses to a hypoglycaemic event induced by an i.v. bolus of insulin was studied in seven type 1 diabetic patients treated first with continuous subcutaneous insulin infusion (CSII) and subsequently with continuous intraperitoneal insulin infusion (CIPII). Arterialised blood glucose and venous hormonal responses were analyzed. HbA1c was improved by CIPII. Although a regimen of a higher basal insulin infusion rate was applied during CIPII the basal peripheral venous insulin levels were lower. The i.v. bolus of insulin resulted in hypoglycaemia in both tests but was more pronounced during the CSII test expressed as a smaller area under the curve (AUC) for the first hour (13.0 +/- 2.3 vs. 13.7 +/- 1.2 mmol l(-1) h(-1), p=0.016, CSII vs. CIPII). The hypoglycaemia resulted in a significant and similar increase in the plasma levels of adrenaline, cortisol and growth hormone in both experiments. A significant increase in the glucagon level was only observed during CIPII. The incremental glucagon response was also significantly more pronounced in the CIPII test expressed as maximal responses (7.5 +/- 3.0 vs. 17.0 +/- 3.1 pg ml(-1), p =0.048, CSII vs. CIPII) as well as incremental AUC (5.1 +/- 12.0 vs. 44.4 +/- 13.2 pg ml(-1) h(-1), p =0.027, CSII vs. CIPII). It seems that CIPII in type 1 diabetic patients could improve the glucagon release to hypoglycaemia. This observation may contribute in explaining why CIPII is associated with a lower incidence of hypoglycaemia in spite of an improvement in metabolic control.     

Muscarinic cholinergic modulation of insulin response to an intravenous glucose tolerance test in normal man

The effect of pirenzepine, a specific muscarinic cholinergic receptor antagonist, on insulin and glucagon responses to an intravenous injection of glucose was investigated in eight normal adult subjects. These volunteers received two iv glucose tolerance tests (0.33 g/kg) before and after the oral administration of 125 mg of pirenzepine (three doses of 25 mg during the day before the experiment and a fourth dose of 50 mg 2 h before glucose injection). Treatment with pirenzepine neither altered basal blood glucose levels nor affected glucose tolerance after the injection of the glucose load. In addition, it did not modify basal plasma insulin and glucagon levels and the decrement of glucagon in response to glucose injection. In contrast, pirenzepine significantly decreased insulin release induced by glucose administration. In man, during the present experimental conditions, the muscarinic cholinergic system modulates insulin, but not glucagon response to an iv glucose injection.     

Physiological elevations of plasma beta-endorphin alter glucose metabolism in obese, but not normal-weight, subjects.

The present study was undertaken to evaluate the metabolic and hormonal responses to physiologic elevations of plasma beta-endorphin concentrations in both normal-weight and obese healthy subjects. The infusion of synthetic human beta-endorphin (4.5 ng/kg/min) produced the following: (1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C-peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels; (2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of beta-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pretreatment did not induce any change of the flat glucose and hormonal responses to beta-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma beta-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.     

Effects of insulin and glucagon on plasma glucose levels and glycogen content in organs of the freshwater teleost Pimelodus maculatus

Mammalian insulin (350 IU/kg) and glucagon (2.5 mg/kg) were injected intraperitoneally into Pimelodus maculatus, a South American teleost. Extent of carbohydrate regulation was estimated through determination of plasma glucose levels, liver-somatic index, and liver and muscle glycogen contents. The effects of insulin administration, examined 6, 12, 24, 48, and 72 hr after injection, were manifested as a depletion of liver glycogen content after 12 hr and severe decrease in plasma glucose content after 24 hr; insulin had no effect on muscle glycogen or liver-somatic index. The effects of glucagon administration, examined 5, 15, 30, 90, and 360 min after injection, were a small increase in liver glycogen content after 15 min, and hyperglycemia, apparent after 30 min. Glucagon did not affect muscle glycogen or liver-somatic index. Control animals were injected intraperitoneally with saline solution. These results suggest that insulin and glucagon regulate the carbohydrate metabolism of P. maculatus by hormonal mechanisms similar to those operating in other teleost species and in mammals.     

Dose-kinetics of pancreatic glucagon responses to arginine and glucose in subjects with normal and impaired pancreatic B cell function

Summary Pancreatic glucagon responses to different amounts of intravenous arginine and glucose were studied in 10 insulin-dependent diabetics, 14 healthy controls (high insulin responders) and 15 subjects with decreased insulin response to glucose but normal intravenous glucose tolerance (low insulin responders). The dose-kinetics of the glucagon response was studied by using four different arginine doses. The suppressive effect of glucose was evaluated by infusing three glucose doses during a submaximal stimulation with arginine. The diabetics were tested first when under fair metabolic control and then following intensive treatment with insulin to produce near-normalisation of blood glucose. Finally, five subjects underwent insulin-induced hypoglycaemia. The changes in plasma glucagon and blood -amino-nitrogen in response to the four arginine doses were significantly correlated in all groups but the slope of the dose response curve was steeper in the poorly controlled-diabetics than in the non-diabetics. These diabetics displayed higher fasting plasma glucagon values than healthy controls (high insulin responders) (224±4 versus 151±22 pg/ml, p<0.01), higher plasma glucagon responses to arginine and an absence of inhibition by glucose of the arginine-stimulated glucagon release. In strictly controlled diabetic patients, fasting plasma glucagon levels (176±16 pg/ml) were not significantly different from healthy controls, the glucagon response to arginine returned to the normal range, A cell suppressibility by glucose was restored and A cell stimulation by hypoglycaemia reappeared. In the low insulin responders, fasting plasma glucagon was not different from that of high responders (107±12 pg/ml), the slope of the dose response curve to arginine was similar in both groups and the A cells were inhibited by glucose to a similar extent. These results support the concept that islet A cell dysfunction in diabetes is not a primary phenomenon.     

Insulin sensitivity predicts glycemia after a protein load

Protein ingestion results in small but distinct changes in plasma glucose and insulin. We hypothesized that the glycemic and/or insulin response to protein might be related to the degree of insulin sensitivity. Our aim was to determine the relationships between insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp) and postprandial glucose, insulin, C-peptide, and glucagon responses to a 75-g protein meal and a 75-g glucose load. Sixteen lean healthy Caucasian subjects (mean +/- SD age, 25 +/- 6 years; body mass index [BMI], 23.1 +/- 1.7 kg/m2) participated in the study. After the protein meal, the mean plasma glucose declined gradually below fasting levels to a nadir of -0.36 +/- 0.46 mmol/L from 60 to 120 minutes, showing wide intraindividual variation. Insulin sensitivity (M value) was 1.1 to 3.9 mmol/L/m2 min in the subjects and correlated inversely with the plasma glucose response to the protein meal (r = -.58, P = .03), ie, the most insulin-sensitive subjects showed the greatest decline in plasma glucose. In contrast, there was no correlation between insulin sensitivity and the insulin or glucagon response to the protein load, or between the M value and the metabolic responses (glucose, insulin, C-peptide, and glucagon) to the glucose load. Our study suggests that the net effect of insulin and glucagon secretion on postprandial glucose levels after a protein meal might depend on the individual's degree of insulin sensitivity. Gluconeogenesis in the liver may be less susceptible to inhibition by insulin in the more highly resistant subjects, thereby counteracting a decline in plasma glucose.