Insulin resistance following nocturnal hypoglycaemia in insulin-dependent diabetes mellitus

Glucose metabolism was studied by a somatostatin-insulin-glucose infusion test (SIGIT) for 8 h in 7 male patients with insulin-dependent diabetes mellitus. They were investigated on two occasions in random order, with and without preceding hypoglycaemia induced between 3.00 and 4.00 h. SIGIT was started at 7.00 h when blood glucose was restored to normal and the counterregulatory hormones had returned to basal values. As expected, hypoglycaemia evoked an enhancement of the plasma levels of GH (43.7 +/- 10.1 vs 4.4 +/- 1.8 micrograms/l), cortisol (690 +/- 59 vs 140 +/- 32 nmol/l), glucagon (225 +/- 35 vs 143 +/- 25 ng/l), and epinephrine (3.80 +/- 1.00 vs 0.10 +/- 0.03 nmol/l). During the SIGIT, the levels of circulating free insulin and counterregulatory hormones were similar in the two tests notwithstanding that excessive hyperglycaemia appeared when SIGIT was preceded by hypoglycaemia. The present study thus demonstrates that nocturnal hypoglycaemia induces insulin resistance in insulin-dependent diabetic patients not deprived of insulin.     

Influence of acute alcohol ingestion on the hormonal responses to modest hypoglycaemia in patients with Type 1 diabetes.

AIMS: To determine whether mild alcohol intoxication (45-50 mg/dl) influences counterregulatory hormone responses to moderate hypoglycaemia (2.8 mmol/l)in patients with Type 1 diabetes. METHODS: Seventeen subjects (14 male, age range 21-46 years) with Type 1 diabetes underwent four hyperinsulinaemic glucose clamps: euglycaemia with placebo; euglycaemia with alcohol (0.4 g/kg); hypoglycaemia (2.8 mmol/l for 65 min)with placebo; and hypoglycaemia (2.8 mmol/l for 65 min) with alcohol (0.4 g/kg).Arterialized venous blood samples were taken for measurement of insulin and counterregulatory hormones. RESULTS: During hypoglycaemia, peak growth hormone concentrations were significantly lower after alcohol compared with placebo (14.3 +/- 2.9 vs.25.9 +/- 3.4 microg/l,P< 0.001) associated with reduced insulin sensitivity in both hypoglycaemia and euglycaemia studies. CONCLUSIONS: We found an attenuated growth hormone response to hypoglycaemia associated with mild alcohol intoxication. Although this may potentially contribute to impaired recovery of glucose after hypoglycaemia in patients with Type 1 diabetes, it appears to be offset by a reduction in insulin action.     

Acute cortisol excess results in unimpaired insulin action on lipolysis and branched chain amino acids, but not on glucose kinetics and C-peptide concentrations in man

To assess whether acute cortisol excess impairs insulin action on lipolysis, plasma amino acids, endogenous insulin secretion, and glucose kinetics, nine normal subjects were studied after acute cortisol excess (80 mg hydrocortisone by mouth) and after placebo. Insulin sensitivity was assessed 6 hours after hydrocortisone using the glucose clamp technique (insulin infusion of 20 mU/m2 X minute for 120 minutes, plasma insulin levels of approximately equal to 50 mU/L). Hyperinsulinemia suppressed plasma free fatty acids (FFA) similarly by 75 and 76%, respectively. Most plasma amino acid concentrations were increased after hydrocortisone; however, the insulin-induced decrease of branched chain amino acids, serine, threonine, and tyrosine was unimpaired after hydrocortisone. Plasma C-peptide concentrations were less suppressed during hyperinsulinemia after hydrocortisone than after placebo (by 0.15 +/- 0.03 v 0.25 +/- 0.02 nmol/L, P less than 0.01), suggesting diminished insulin-induced suppression of insulin secretion. The glucose infusion rates required to maintain euglycemia were 35% lower (P less than 0.01) after hydrocortisone due to decreased insulin effects on metabolic clearance rate of glucose and diminished suppression of hepatic glucose production (0.4 +/- 0.1 v -0.1 +/- 0.1 mg/kg X minute, p less than 0.05, 3-3H-glucose infusion method). The data demonstrate that acute elevation of plasma cortisol to levels near those observed in severe stress results in insulin resistance of peripheral and hepatic glucose metabolism but in unimpaired insulin effects on plasma FFA and branched chain amino acids, suggesting that cortisol's lipolytic and proteolytic effects are antagonized by elevated plasma insulin levels.     

Symptomatic and hormonal hypoglycaemic responses to human and porcine insulin in patients with type I diabetes mellitus.

In recent years there has been great concern that human insulin (HI) may induce fewer hypoglycaemic warning symptoms than porcine insulin (PI). We addressed this issue in eight patients aged 25.6 +/- 3.3 (SEM) years with Type I (insulin-dependent) diabetes mellitus of 15.1 +/- 3.7 years duration who complained that hypoglycaemia unawareness had appeared after transferring from PI to HI. Acute induction of hypoglycaemia was induced on two occasions with semisynthetic HI and purified PI under double-blind conditions. Blood glucose was first clamped for 2 h at 4.4-6.7 mmol l-1 with an intravenous infusion of HI or PI at 50 mU kg-1 h-1 and 20% glucose at a variable rate. Thereafter, insulin infusion alone was maintained for 100 minutes. Heart rate, arterial pressure, reflex times, autonomic and neuroglycopenic signs and symptoms were assessed every 10 min. Arterialized venous blood samples were taken to measure blood glucose every 10 min and catecholamines, insulin, glucagon, growth hormone, and cortisol every 20 min. Autonomic symptoms first appeared at a plasma glucose level of 2.92 +/- 0.21 mmol l-1 with HI vs 2.92 +/- 0.48 mmol l-1 with PI (NS). There were no significant differences between the two studies concerning any of the above mentioned clinical parameters or the counterregulatory hormone responses. A differential effect of insulin species on the ability to perceive hypoglycaemia in patients who ascribed diminished perception of hypoglycaemia to the use of HI was thus not observed.     

Rate of fall of blood glucose and physiological responses of counterregulatory hormones,clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

AIMS/HYPOTHESIS: The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. METHODS: We studied 11 subjects with Type I (insulin-dependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1+/-0.003 mmol x min(-1) x l(-1) (fast fall), on the other at the rate of 0.03+/-0.001 mmol x min(-1) x l(-1) (slow fall). Subjects underwent a control euglycaemic clamp study as well. RESULTS: In response to fast-fall as compared to slow-fall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: Trail-Making B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8+/-0.5 vs 3.5+/-0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5+/-1.0 vs 5.2+/-0.4 pmol x min(-1) x 100 ml(-1), p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. CONCLUSION/INTERPRETATION: In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia.     

Combination of continuous subcutaneous infusion of insulin and octreotide in Type 1 diabetic patients

The effect of 7 day continuous subcutaneous infusion of octreotide (200 microg day(-1)) was evaluated in seven insulin-pump treated Type 1 diabetic patients (age 43+/-1.5 year; BMI 25.1+/-0.7 kg m(-2); HbA(1c) 7.4+/-0.3%). A 24-h metabolic and hormonal profile, and a euglycaemic hyperinsulinaemic clamp (0.25, 0.5, 1.0 mg kg(-1) min(-1)), with [3H]glucose infusion and indirect calorimetry, were performed before and after a 7-day octreotide infusion. Mean 24-h plasma glucose was similar before and after octreotide (9.7+/-0.8 vs. 9.1+/-1.0 mmol l(-1)) but insulin requirement dropped by 45% (49+/-4 vs. 27+/-2 U day(-1); P<0.01). Both 24-h plasma hGH and glucagon were suppressed by octreotide (1.85+/-0.35 vs. 0.52+/-0.04 microg l(-1), and 117+/-23 vs. 102+/-14 ng l(-1), respectively). Glucose utilisation increased after octreotide (insulin 0.5 mU kg(-1) min(-1) clamp 3.09+/-0.23 vs. 4.19+/-0.19 mg kg(-1) min(-1); 1 mU kg(-1) min(-1) clamp 5.64+/-0.61 vs. 7.93+/-0.57 mg kg(-1) min(-1); both P<0.05) and endogenous glucose production was similarly suppressed. Glucose oxidation was not affected by octreotide, while the improvement in glucose storage (insulin 1.0 mU kg(-1) min(-1) clamp 3.89+/-0.60 vs. 5.64+/-0.67 mg kg(-1) min(-1), P<0.05) entirely accounted for the increase in glucose disposal. Endogenous glucose production was more effectively suppressed at the two lower insulin infusion rates (P>0.05). Energy expenditure declined after octreotide. Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose metabolism by enhancing glucose storage, and reduces energy expenditure. These results support a role for counterregulatory hormones in the genesis of insulin resistance and the catabolic state of Type 1 diabetes.     

Effect of physiological hyperinsulinemia on counterregulatory hormone responses during hypoglycemia in humans.

We evaluated the effect of continuous physiological hyperinsulinemia on counterregulatory hormone responses in seven healthy subjects, each studied on two occasions. Hormone responses were measured during identical 2-h periods of hypoglycemia (plasma glucose target 3.5 mmol/L) at insulin levels of 350 pmol/L or 640 pmol/L. During hypoglycemia, there were significant (50-1400%) increases in glucagon, epinephrine, norepinephrine, GH, and cortisol which were comparable in the two groups. We further evaluated the influence of the duration of mild hyperinsulinemia on the responses in an additional group of normal subjects (n = 7). Brief (30 min) exposure to insulin was compared to a prolonged (3.5 h) insulin infusion, each followed by identical hypoglycemia. Plasma insulin (approximately 350 pmol/L) and plasma glucose (target 3.3 mmol/L) were similar in both groups. The increases in epinephrine, norepinephrine, GH, and cortisol during hypoglycemia were virtually identical in the two groups. However, the secretion of glucagon was blunted following prolonged hyperinsulinemia, increasing to levels of 249 +/- 17 ng/L in the brief studies and to only 185 +/- 20 ng/L in the prolonged studies (P < 0.005). The insulin-induced decrement in plasma amino acids were similar in the two studies and could not account for the impaired glucagon secretory response. Conclusions: 1) Brief exposure to even high physiological levels of insulin do not alter the magnitude of counterregulatory hormone secretion during hypoglycemia; 2) prolonged hyperinsulinemia results in a selective blunting of the plasma glucagon response to hypoglycemia, perhaps due to a direct suppressive effect of insulin on alpha-cell secretion.     

Counterregulatory hormones in insulin-treated diabetic patients admitted to an accident and emergency department with hypoglycaemia

The aim of the study was (1) to describe hormone responses in insulin-induced hypoglycaemia and (2) to investigate if a combined treatment with intravenous glucose and intramuscular glucagon (group A) would improve glucose recovery as compared to treatment with intravenous glucose alone (group B). Eighteen adult patients with insulin-treated diabetes mellitus admitted to the Accident and Emergency Department with hypoglycaemia (plasma glucose 1.23 ± 0.15 mmol l⁻¹ on admission) were randomized to one of the above treatments and plasma glucose and counterregulatory hormones were measured before and 30–120 min after treatment. Pre-treatment counterregulatory hormone concentrations were significantly lower than hormone concentrations during induced hypoglycaemia in healthy control subjects but significantly higher than healthy fasting concentrations for plasma adrenaline (p = 0.020), glucagon (p = 0.008), growth hormone (p = 0.011), and cortisol (p<0.00001). Thus, although glucagon and adrenaline responses may be absent when studying Type 1 diabetic patients in the experimental setting, both hormones increase to a significant extent in ‘real-life’ hypoglycaemia in this patient group, although to a lesser degree than might be expected. Plasma glucose did not differ significantly between the two treatments at any time point. Despite access to food, one of four patients in group B and one of five patients in group A had plasma glucose below 4.0 mmol l⁻¹ after 120 min. In conclusion, low yet significantly elevated concentrations of adrenaline and glucagon were found in diabetic patients admitted with severe hypoglycaemia to an Accident and Emergency Department. © 1998 John Wiley & Sons, Ltd.     

Adrenergic influence on glucocounterregulation in man

Summary To investigate the adrenergic role in glucocounterregulatory mechanisms, single-blind randomised studies were performed in 7 normal males during severe insulin-induced hypoglycaemia with or without adrenergic blockade. Intravenous phentolamine administration (5 mg stat and 0.5 mg/ min) did not interfere with the restoration of euglycaemia from hypoglycaemia. However, recovery of blood glucose in the presence of propranolol (3 mg/ 3 min and 0.8 mg/min) was retarded when compared with control studies (mean plasma glucose levels ±SEM, 50±6 mg/dl versus 66±4 mg/dl at 120 min after insulin administration) despite appropriate glucagon, epinephrine, cortisol, and growth hormone responses. Plasma norepinephrine response was unaffected by propranolol but augmented threefold by phentolamine. Increases in plasma lactate, pyruvate and non-esterified fatty acids were blunted with propranolol while rebound non-esterified fatty acid was observed with phentolamine infusion. These data suggest that complete recovery of blood glucose from severe hypoglycaemia requires full sympathetic nervous system activity despite the integrity of other counterregulatory mechanisms.     

Insulin counterregulatory hormones are ineffective in neonatal hyperinsulinemic hypoglycemia.

Insulin counterregulatory hormones play a major role in the maintenance of glucose homeostasis. To evaluate the hypothesis that the reported imprecise control of glucose production by insulin is mirrored by a corresponding lack of response to the various insulin counterregulatory hormones, 30 spontaneously delivered mixed-breed term lambs weighing 4.9 +/- 0.5 kg (mean +/- SD) were studied at 5.0 +/- 0.7 days after birth following administration of 100 microCi D-[6-(3)H2]glucose in 0.9% NaCl by the primed-constant infusion technique to measure glucose kinetics. Infusion of 2.0 mU kg(-1) x min(-1) insulin produced hyperinsulinemic hypoglycemia and was combined with 1.0 mg x kg(-1) x min(-1) somatostatin (SRIF) to block insulin, glucagon, and growth hormone release. Infusion of 2 ng x mg(-1) x min(-1) glucagon or 10 microg x kg(-1) x h(-1) growth hormone with SRIF and insulin isolated the glucagon or growth hormone effect, respectively. The addition of metyrapone blocked cortisol release. Controls received only the isotope. In toto, the data can be interpreted to suggest that insulin has a greater effect on glucose uptake than on glucose production, and that neither glucagon, growth hormone, nor cortisol appreciably influenced the endogenous glucose production rate (Rp) during hyperinsulinemic hypoglycemia. The imprecise effect of these insulin counterregulatory hormones on neonatal glucose production mirrors the previously documented imprecise control by insulin.     

Glucose and amino acid metabolism in aging man: differential effects of insulin

Insulin is a major regulator of glucose and body protein homeostasis, both of which demonstrate age-related changes. To clarify insulin's role in these age-related changes and to compare age-related glucose and protein homeostatic responses, insulin-mediated aspects of glucose and amino acid metabolism were simultaneously examined in healthy postabsorptive young (n = 5, mean age, 25 years) and elderly (n = 5, mean age, 76 years) men. Primed constant infusions of L-[1-13C]leucine and L-[15N]alanine were administered during a basal period (0 to 180 minutes) and during four separate single rate euglycemic insulin infusions (180 to 360 minutes). Steady state insulin concentrations were 16 +/- 1, 29 +/- 3, 75 +/- 5, and 2407 +/- 56 microU/mL in the young and 23 +/- 4, 37 +/- 8, 96 +/- 11 and 3,357 +/- 249 microU/mL in the elderly at the different insulin infusion rates of 6, 10, 30, and 400 mU mU.m-2.min-1, respectively. For the 6 and 10 mU insulin infusion rates, a primed, constant infusion of [6,6 - 2H2]glucose permitted quantitation of hepatic glucose production. Glucose disposal rates adjusted for lean body mass (LBM) were lower in the elderly than in the young at the 6, 10, and 30 mU insulin infusion rates and similar in the two age groups in the 400 mU studies. Insulin dose-dependent reductions occurred in eight of ten plasma amino acids and were not influenced by age. There was an insulin dose-dependent reduction in plasma leucine flux which was similar in both age groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Alteration of the counterregulatory hormones in the conscious rat after protein-energy restriction

Summary We have recently reported that in rats submitted to protein-energy restriction early in life, an increased insulin efficiency upon the whole-body glucose utilization rate may be one reason for their chronic mild basal hypoglycaemia. However, the basis for their low plasma glucose level may also lie in the impaired activation of one or several of the counterregulatory hormones that prevent or correct hypoglycaemia. Our study was therefore designed to compare glucose counterregulatory mechanisms in restricted and control rats, both in the basal postabsorptive state and at controlled high plasma insulin level and standardized low glycaemic level (hypoglycaemic-hyperinsulinaemic glucose clamps performed in conscious rats). When tested in the basal postabsorptive state, the restricted rats exhibited prominent increases in the plasma levels of epinephrine (4.5 fold), norepinephrine (3.4 fold) and glucagon (1.7 fold). This was in the presence of significant decreases of plasma growth hormone and corticosterone levels (by 59 and 32 %, respectively). With respect to the responses to acute severe hypoglycaemia (2.5 mmol/l), the glucagon, epinephrine and norepinephrine plasma levels in the restricted rats increased to values similar to those in controls. Also, the corticosterone level increased but remained significantly lower (p < 0.001) compared to the control response. The plasma growth hormone level was not significantly affected by acute hypoglycaemia in the restricted or in the control groups. We conclude that protein-energy restriction, starting early in life in the rat, severely impairs the release of counterregulatory hormones that defend against hypoglycaemia. [Diabetologia (1997) 40: 1028–1034] Received: 5 December 1996 and in revised form: 28 April 1997     

Alcohol and glucose counterregulation during acute insulin-induced hypoglycemia in type 2 diabetic subjects

To investigate the influence of alcohol on glucose counterregulation and recovery during acute insulin-induced hypoglycemia in type 2 diabetic subjects, 8 diet-treated type 2 diabetic subjects were examined twice after an overnight fast. A graded hyperinsulinemic (1 mU/kg/min, 60 to 195 minutes) euglycemic/hypoglycemic clamp was performed with concomitant infusion of 3-(3)H-glucose to assess glucose turnover. After a euglycemic baseline period (150 to 180 minutes), 200 mL of water was taken either alone or with alcohol (0.4 g/kg body weight). Hypoglycemia (plasma glucose nadir, 2.8 mmol/L) was subsequently induced, and the recovery period followed after discontinuation of insulin and the variable glucose infusion. On both study days, circulating concentrations of insulin and glucose were comparable. Alcohol intake markedly increased plasma lactate (area under the curve [AUC], recovery period) (244 +/- 30 v 12 +/- 4 mmol/L x 240 minutes; P = .00009) and suppressed plasma nonesterified fatty acids (NEFA) (AUC, recovery period) (95 +/- 13 v 161 +/- 18 mmol/L x 240 minutes; P = .0008). No differences were found in the counterregulatory response of catecholamines, cortisol, and growth hormone (GH). However, alcohol intake decreased peak glucagon significantly (155 +/- 12 v 200 +/- 17 pg/mL; P = .038). In diet-treated, mild type 2 diabetic subjects, alcohol does not modify recovery from insulin-induced hypoglycemia.     

An Analysis of the Glucagon Response to Hypoglycaemia in Patients with Type 1 Diabetes and in Healthy Subjects

The study aimed to analyse the glucagon response during hypoglycaemia in relation to gender, level of hypoglycaemia, and hyperinsulinaemia as well as its relation to other counterregulatory hormones in patients with Type 1 diabetes and in nondiabetic subjects. Mild hypoglycaemia was induced by an i.v. insulin infusion (244 pmol kg^?1h^?1) for 180 min in 43 Type 1 diabetic patients and 22 nondiabetic subjects. Venous blood glucose, plasma free insulin, glucagon, adrenaline, noradrenaline, growth hormone, and cortisol were measured every 15–30 min. The hormonal responses during hypoglycaemia were evaluated from the incremental areas under their respective curves. There was a linear correlation between the glucagon response and the decremental area of blood glucose (p < 0.005), but the slope of the regression line in the diabetic group was less steep than in the controls (p < 0.5), and, in spite of the deeper hypoglycaemia in the diabetic groups, their glucagon response was diminished (p < 0.05). Plasma, adrenaline, growth hormone and cortisol all increased during hypoglycaemia. The glucagon response correlated with the responses of growth hormone and cortisol in both groups, while it was positively correlated with the adrenaline response (p < 0.001) and inversely with the plasma insulin (p < 0.001) only in the diabetic patients. Although the insulin infusion rate was identical, the female diabetic patients had a lower metabolic clearance rate of insulin as compared with the males (p < 0.05). There was no statistical difference in the counterregulatory hormone responses between males and females in neither of the groups. In conclusion, this study suggests that the glucagon response to hypoglycaemia in Type 1 diabetic patients, may be suppressed by circulating insulin within its therapeutic range, and stimulated by the simultaneously secreted adrenaline. Furthermore, female Type 1 diabetic patients have a lower metabolic clearance rate of insulin than males, yielding a more pronounced hypoglycaemia in response to the same dose of insulin, although this study does not provide evidence of a gender difference in the responsiveness of counterregulatory hormones to hypoglycaemia.     

Plasma free fatty acid concentration during hyperglycemic glucose clamp with and without somatostatin infusion in obese subjects with normal glucose tolerance

In the present study we evaluated the regulation of plasma free fatty acid (FFA) concentration by glucose and insulin in human obesity. To this purpose we measured plasma FFA concentration in normoglycemic, normoinsulinemic obese (n = 8) and nonobese (n = 8) healthy subjects during 240 min of exogenous hyperglycemia (hyperglycemic glucose clamp) in presence of both glucose-stimulated (0-120 min and 180-240 min) and somatostatin-inhibited (120-180 min) insulin secretion. We found that plasma FFA curves were roughly parallel in the 0-120 min period and FFA values of obese subjects were constantly higher throughout the experimental period. Moreover, the difference between the two groups was significant when individual data were expressed as a percent of fasting FFA value (P less than 0.0001 from 0 to 120 min). Plasma insulin levels were similar in the two groups during the entire study. The amount of glucose metabolized during the 80-120 min period was significantly lower in obese than in nonobese subjects (172 +/- 7 v. 341 +/- 11 mg/m2.min, P less than 0.01; means +/- s.e.). During the somatostatin period (120-180 min) plasma insulin was lowered close to basal values in both groups (116 +/- 15 and 109 +/- 11 pmol/l) and plasma FFA concentrations rose in a linear fashion. Our data suggest that suppression of plasma FFA concentrations by glucose and insulin is qualitatively similar in healthy nonobese and obese subjects, the latter having higher FFA values. Insulin action on FFA metabolism isn ot grossly impaired in obese subjects who are clearly insulin resistant as far as glucose metabolism is concerned.     

Impact of acute epinephrine removal on hepatic glucose metabolism during stress hormone infusion.

We examined the effect of acute discontinuation of an epinephrine (EPI) infusion on hepatic glucose metabolism during stress hormone infusion (SHI). Glucose metabolism was assessed in 11 conscious, 20-hour fasted dogs using tracer and arteriovenous techniques after a 3-day exposure to SHI. SHI increased EPI, norepinephrine, cortisol, and glucagon levels (approximately sixfold to 10-fold), which led to marked hyperglycemia, hyperinsulinemia, and accelerated glucose metabolism. On day 3, EPI infusion was acutely discontinued for 180 minutes in five dogs while infusion of the other hormones was continued (SHI - EPI). In the remaining six dogs, all hormones were continued for the duration of the study (SHI + EPI). In SHI - EPI, EPI levels decreased from 1,678+/-191 to 161+/-47 pg/mL. Isoglycemia (183+/-10 to 185+/-15 mg/dL) was maintained with an exogenous glucose infusion. Arterial insulin levels increased from 41+/-8 to 64+/-8 microU/mL. Whole-body glucose utilization increased from 3.5+/-0.5 to 9.4+/-1.9 mg/kg/min. Nonesterified fatty acids ([NEFAs] 763+/-292 to 147+/-32 micromol/L) decreased. Net hepatic glucose output decreased (2.6+/-0.6 to 0.1+/-0.3 mg/kg/min). In SHI + EPI, hepatic glucose metabolism remained unaltered. In summary, EPI plays a pivotal role during SHI by stimulating glucose production and inhibiting glucose utilization. In part, these effects are mediated by restraining pancreatic insulin secretion.     

Prolonged insulin resistance following insulin-induced hypoglycaemia

Summary Nineteen normal male volunteers underwent a 10-h glucose clamp study to examine the duration and mechanism of insulin resistance after hypoglycaemia. Dextrose delivery by the Biostator to maintain the target blood glucose level fell below baseline 2 h after induction of hypoglycaemia and remained suppressed for at least 7 h after insulin hypoglycaemia. Insulin secretion as manifested by C-peptide levels remained suppressed for 3–4 h after insulin hypoglycaemia despite return of blood glucose to baseline by 90 min. Glucose kinetic data (3-³H-glucose) performed in six of the subjects indicated that the prolonged insulin resistance was due to significantly increased hepatic glucose production and to suppressed glucose utilisation, persisting for at least 4 h after counterregulatory hormone levels had returned to normal. Post-hypoglycaemic insulin resistance as determined by dextrose delivery was markedly attenuated and the rise in hepatic glucose output totally eliminated in five hypopituitary subjects without growth hormone or cortisol responses to hypoglycaemia. We conclude that post-hypoglycaemic insulin resistance occurs in non-diabetic subjects and persists for at least 7 h following hypoglycaemia. This prolonged insulin resistance is largely related to release of growth hormone and cortisol.     

The importance of plasma free insulin and counterregulatory hormones for the recovery of blood glucose following hypoglycaemia in type 1 diabetics

After induction of hypoglycaemia in 31 Type 1 (insulin-dependent) patients, the 10 patients with the slowest recovery of blood glucose from hypoglycaemia were arbitrarily compared with the 10 patients with the fastest recovery of blood glucose. No differences were found between the two groups regarding response of glucagon to hypoglycaemia, whereas the epinephrine (2-fold), norepinephrine (2.4-fold) and cortisol responses were significantly greater in the group with the slow recovery. The plasma free insulin concentrations were higher (2-fold) in the group with slow recovery from 30 min after stop of insulin and throughout the study. This may be explained by a 3-fold greater amount of insulin binding antibodies in this group compared to the group with fast recovery from hypoglycaemia. An inverse significant correlation was demonstrated between the rates of recovery and the amounts of insulin binding antibodies in all the patients (P less than 0.02). This implicates that enhanced counterregulatory hormone responses in the group with the slow recovery from hypoglycaemia could not compensate for the hypoglycaemic effect of a concomitant higher plasma free insulin concentration. Insulin binding antibodies, acting as a depot of circulating insulin, may be a risk factor of prolonged hypoglycaemia in Type 1 diabetics.     

Exercise-induced hypoglycaemia and subcutaneous insulin infusion

To assess whether exercise-induced hypoglycaemia could be prevented by interruption of insulin infusion (3 h) we studied diabetic patients treated with continuous subcutaneous insulin infusion (CSII). The studies were performed in 7 insulin-dependent diabetics (aged 31.4 +/- 4.8 (mean +/- SD) years, duration of diabetes 16.9 +/- 5.4 years), after an overnight fast and in the afternoon, 4 h after the last pre-meal bolus injection (exercise and control period). Bicycle exercise (45 min at 60% of maximum oxygen consumption) was started 30 min after the insulin infusion was stopped. During exercise there was a more pronounced decline in blood glucose in the afternoon (2.2 +/- 0.3 mmol/l, mean +/- SEM) than in the morning (1.4 +/- 0.4 mmol/l) (p less than 0.01). This corresponded to higher mean levels of free insulin during exercise in the afternoon (20 +/- 4.5 mU/I vs 12.0 +/- 1.0 mU/l, in the morning). Interruption of insulin delivery for 3 h resulted in a moderate increase of blood glucose, a gradual decrease of free insulin, and a moderate increase in free fatty acids and beta-hydroxybutyrate. During exercise in the afternoon 3 diabetics suffered from symptomatic hypoglycaemia (BG less than 2.8 mmol/l). In contrast with most of the other patients they showed no decline of free insulin during exercise. Thus even after interruption of basal rate insulin infusion moderate postprandial exercise may lead to hypoglycaemia if there is relative hyperinsulinism.