Counterregulatory Hormone Responses Research Articles

Oral glucose augments the counterregulatory hormone response during insulin-induced hypoglycemia in humans.

It has been suggested that the counterregulatory hormone (CRH) response to acute hypoglycemia is triggered via glucose sensors situated in either the hypothalamus or the portohepatic area. If the latter were critical during hypoglycemia, one would anticipate that ingestion of glucose, by raising glucose levels in the portal circulation, should attenuate CRH responses previously described in animal studies. To evaluate the effect of raising portal, but not peripheral, glucose levels during insulin-induced hypoglycemia, we performed hypoglycemic clamp studies in five healthy adult males on two occasions. On one occasion, subjects received oral glucose (OG) (25 g) during hypoglycemia; and on one occasion, noncarbohydrate-containing drink of equal volume, while maintaining plasma glucose at 55 +/- 2 mg/dL (3.08 mmol/L). As a result, there were no significant differences in systemic plasma glucose levels between the two hypoglycemic clamp studies, and basal CRH concentrations were also similar. As expected, there was a brisk rise in all CRH during the control (hypoglycemia+noncarbohydrate drink) study. In the experimental study, administration of OG (hypoglycemia+OG), to raise intraportal glucose levels during systemic hypoglycemia, did not attenuate CRH responses. Indeed, OG enhanced the rise in epinephrine, glucagon, and GH. Increases in cortisol and norepinephrine did not differ between the two studies. Therefore, our data suggest that increasing the level of glucose in the portal vein above that in the systemic circulation, during hypoglycemia, enhances (rather than suppresses) CRH responses. Thus, ingestion of glucose may reverse hypoglycemia directly by provision of substrate, as well as indirectly by stimulating counteregulatory mechanisms.

Troglitazone amplifies counterregulatory responses to hypoglycemia in nondiabetic subjects.

As insulin sensitizers, thiazolidinediones could affect the hormonal counterregulatory response to hypoglycemia via the modulatory effect of insulin on counterregulation. In addition, recent studies suggest that thiazolidinediones may influence key steps in glucose sensing and glucoregulatory hormone secretion. We therefore evaluated the effects of a short course of troglitazone on counterregulatory hormones in response to mild hypoglycemia in eight lean nondiabetic subjects. Subjects received either troglitazone (400 mg/day) or placebo for 7 days before stepped hypoglycemia clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/L target plasma glucose steps, 50 min each). The glycemic thresholds for secretion of epinephrine (3.77 +/- 0.05 mmol/L) and glucagon (3.83 +/- 0.11 mmol/L) were reset to a higher plasma glucose concentration after troglitazone [4.05 +/- 0.05 mmol/L (P = 0.003) and 4.10 +/- 0.05 mmol/L (P = 0.03), respectively]. In addition, the magnitude of the rise in epinephrine and glucagon concentrations was higher with troglitazone (28% and 11%, respectively; P < 0.05 for both), whereas plasma norepinephrine, GH, and cortisol were comparable in both sets of studies. Endogenous glucose production, measured with [3-(3)H]glucose, rose by 33% (P < 0.05) in the troglitazone studies compared with 17% (P = NS) after placebo. We conclude that thiazolidinediones may induce an amplification of the counterregulatory response to hypoglycemia characterized by a shift in the glycemic threshold for and an increase in the magnitude of glucagon and epinephrine secretion, and subsequent activation of glucose production.

Oral Glucose Augments the Counterregulatory Hormone Response during Insulin-Induced Hypoglycemia in Humans

Oral Glucose Augments the Counterregulatory Hormone Response during Insulin-Induced Hypoglycemia in Humans

Stress-Induced Hyperglycemia

Stress hyperglycemia is common and likely to be associated with at least some of the same complications as hyperglycemia in true diabetes mellitus, such as poor wound healing and a higher infection rate. The predominant cause is the intense counterregulatory hormone and cytokine responses of critical illness, often compounded by excessive dextrose administration, usually as TPN. Although randomized data suggesting benefit of controlling hyperglycemia in hospitalized patients are paltry, prospective controlled trials are feasible and should be initiated. In the interim, the practice at the authors' institution is to use insulin to lower plasma glucose concentrations to a safe range of 150 mg/dL to 200 mg/dL in all patients.

Reference intervals for glucose, beta-cell polypeptides, and counterregulatory factors during prolonged fasting.

To establish reference intervals for the pancreatic beta-cell response and the counterregulatory hormone response to prolonged fasting, we studied 33 healthy subjects (16 males, 17 females) during a 72-h fast. Glucose, insulin, C-peptide, and proinsulin levels decreased (P < 0.001), and the levels of counterregulatory factors increased during the fast [P < 0.05; glucagon and free fatty acids (FFA) with a linear increase and epinephrine, norepinephrine, and cortisol with a clear underlying circadian rhythm]. Growth hormone secretion increased from the first to third day of fasting (P < 0.05) but actually decreased from the second to third day of fasting (P = 0.03). Males had higher glucose and glucagon levels and lower FFA levels during the fast (P < 0.05), whereas no effect of gender on beta-cell polypeptides was observed. A high body mass index resulted in higher insulin and C-peptide levels during the fast (P < 0.05). In conclusion, we have provided reference intervals for glucoregulatory factors during a 72-h fast. We observed a diminished beta-cell response concomitant with an increased secretion of counterregulatory hormones. These results should be of clinical and scientific value in the investigation of hypoglycemic disorders.

Symptomatic and counterregulatory hormonal responses to acute hypoglycaemia induced by insulin aspart and soluble human insulin in Type 1 diabetes

Symptomatic and counterregulatory hormonal responses to acute hypoglycaemia induced by insulin aspart and soluble human insulin in Type 1 diabetes

Changes of glucose transporters in the cerebral adaptation to hypoglycemia

Repeated hypoglycemia increases the glycemic thresholds of responses of counterregulatory hormones and of symptoms to subsequent hypoglycemia. This may in part be due to cerebral adaptation to hypoglycemia, which involves glucose transporter-1 (GLUT1) and glucose transporter-3 (GLUT3). To investigate the role of brain GLUT1 and GLUT3 in cerebral adaptation to chronic hypoglycemia, GLUT1 and GLUT3 mRNA and protein expressions were determined in rat brain using RT-PCR and Western blot analyses after 4- and 8-day hypoglycemic insults. Hypoglycemia was induced in rats by twice daily subcutaneous injection of intermediate-acting insulin with dosage adjustment according to the blood glucose levels. Target level of hypoglycemia (<2.5 mmol/l) was achieved at least once a day in all rats included. Control rats received saline injections. Blood glucose levels during the 4 and 8 days of insulin treatment were 2.18±0.12 and 2.68±0.07 mmol/l, respectively. Following the 4 and 8 days of hypoglycemia, GLUT1 mRNA levels did not significantly change. GLUT3 mRNA expressions after the 4 days of hypoglycemia increased by 36.9±9.4% compared with that in control rats ( P=0.031), but after the 8 days of hypoglycemia, did not change. On Western blot analysis of total particulate rat brain membrane, amount of 55-kDa isoform of GLUT1 protein did not change after 4- and 8-day hypoglycemia (88.1±4.9% of control, P=0.240; 92.1±1.4% of control, P=0.096, respectively). In contrast, the expression of GLUT3 protein in the 4-day hypoglycemic rats increased by 51.4±8.4% compared with that in control rats ( P=0.004). After the 8 days of hypoglycemia, the expression also tended to increase by 44.9±14.4% ( P=0.119). There was an inverse correlation between the amount of GLUT3 protein expression and mean blood glucose levels in 4-day hypoglycemic and control rats ( r=−0.886, P=0.019). These data suggest that GLUT3 isoform plays a role in the cerebral adaptation to chronic hypoglycemia.

Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose.

Increasing plasma glucose levels improves memory in patients with Alzheimer disease (AD). Increasing plasma glucose levels also increases endogenous insulin levels, raising the question of whether memory improvement is due to changes in insulin, independent of hyperglycemia. We address this question by examining memory and counterregulatory hormone response during hyperglycemia when endogenous insulin was suppressed by concomitant infusion of the somatostatin analogue octreotide (Sandostatin). Twenty-three patients with AD and 14 similarly aged healthy adults participated in 4 metabolic conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57 pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h); (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting insulin and glucose); and (4) an active control condition in which somatostatin alone was infused (150 mg/h). Declarative memory (story recall) and selective attention (Stroop interference test) were measured during steady metabolic states. Patients with AD showed improved memory during hyperinsulinemia relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory for patients with AD (P<.05). Hyperinsulinemia increased cortisol levels in subjects with AD, whereas somatostatin alone lowered cortisol concentrations. These results confirm that elevated insulin without hyperglycemia enhances memory in adults with AD, and indicate that insulin is essential for hyperglycemic memory facilitation. These results also suggest a potential therapeutic role for somatostatin in AD.

Individualized low-dose growth hormone (GH) treatment in GH-deficient adults with childhood-onset disease: Metabolic effects during fasting and hypoglycemia

Growth hormone (GH) has insulin-antagonistic effects, and GH secretion is augmented during fasting and hypoglycemia. In the present study, 10 patients aged 21 to 28 years with childhood-onset GH deficiency (GHD) were studied during a 24-hour fast and a hypoglycemic glucose clamp before and after 9 months of GH replacement. During the 24-hour fast, blood glucose, serum insulin, and serum free fatty acid (FFA) levels were measured. In the hypoglycemic clamp, the counterregulatory hormones (plasma catecholamines, serum glucagon, and serum cortisol), serum insulin-like growth factor (IGF) binding protein-1 (IGFBP-1), serum FFA, and glucose uptake were measured. The GH dose was adjusted to the response of serum IGF-I, and the median GH dose was 0.14 IU/kg/wk (range, 0.08 to 0.19). At the end of the study, serum IGF-I levels were normalized in all but one patient, in whom serum IGF-I was above the normal range. Nine months of GH treatment did not cause any significant changes in the blood glucose level, insulin to glucose ratio, or serum FFA level during the 24-hour fast, and none of the patients experienced hypoglycemia either before or after GH treatment. However, GH therapy resulted in increased insulin resistance during hypoglycemia, without changes in the counterregulatory hormonal responses, serum IGFBP-1, or serum FFA.

Effect of pancreatic transplantation on counterregulatory hormonal responses to hypoglycaemia.

Introduction In December 1966, two patients with advanced complications of type 1 diabetes received combined pancreas and kidney allografts at the University of Minnesota, USA. These two operations heralded the possibility of a more effective treatment for type 1 diabetes. Since those first operations advances in surgical techniques, improved quality of immunosuppressive therapies, and better strategies of patient surveillance have increased patient survival rates and operative morbidity. The most recent data from the International Pancreas Transplant Registry reveal success rates (defined as insulin independence at ≥ 1 year) for pancreas transplantation performed simultaneously with kidney transplantation of 70% or more and mortality rates 10% or less at 1 year [1]. Perhaps the most significant limitation to improved patient survival rates today is the nature of the patients actually undergoing surgery who are usually of a self-selected group of type 1 diabetic subjects with long duration disease and multiple complications (including autonomic neuropathy and end-stage renal disease). These factors in themselves entail a drastically reduced long-term survival rate. Pancreas transplantation has also been proposed as a possible treatment for individuals with recurrent severe hypoglycaemia [2]. This is in the light of some recent studies that have suggested that the impaired counterregulatory responses to insulin-induced hypoglycaemia, so common to type 1 diabetes of long duration [3], are reversed following pancreas transplantation [2, 4, 5]. This review will discuss the literature that has emerged over the last 10 years on the effect of pancreas transplantation on hormonal counterregulation to insulin-induced hypoglycaemia. Initially, we will briefly comment on our current understanding of the nature of the counterregulatory hormonal response to hypoglycaemia, how that response may be abnormal in type 1 diabetes, and what information pancreas transplantation provides about the aetiology of these abnormalities.

Response of the pituitary-adrenal axis to hypoglycemic stress in women with the polycystic ovary syndrome.

The role of the adrenals in the polycystic ovary syndrome (PCOS) is debated. Both single steroid-converting enzyme abnormalities and increased adrenal activity have received support. The conventional Synacthen test using pharmacological doses of ACTH results in unphysiological levels of ACTH. Therefore, we used insulin-induced hypoglycemia (0.15 IU/kg BW) to asses the responses of ACTH, cortisol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, and androstenedione in 18 women with PCOS and in 17 normal women of similar age and body mass index. The blood glucose concentration at 30 min was 2 mmol/L or less in all women, i.e. well below the threshold of the hormonal counterregulatory response. The women with PCOS showed a lower ACTH response, expressed as the maximum increment above basal [mean (95% confidence interval): PCOS, 11.1 (6.9-15.3); controls, 19.9 (13.8-26) pmol/L; P < 0.05], but a quantitatively comparable [PCOS, 207.2 (148.5-266.5); controls, 167.1 (100.6-233.2) nmol/L; P = NS] and more prompt cortisol response than the controls (by chi2 test, P < 0.05), resulting in a higher molar ratio between the maximum increments of cortisol and ACTH [PCOS, 13.9 (8.7-19); controls, 8.8 (5.7-12); P < 0.05]. The women with PCOS did, however, show a more rapid decline in cortisol levels than the controls (P < 0.05 at 120 and 180 min). The responses of the androgens and intermediate adrenal steroids were similar in women with PCOS and controls. The findings suggest an adaptation to increased adrenal reactivity to endogenous ACTH in women with PCOS. Exposure to hypoglycemia as a model of stress was not followed by hypersecretion of adrenal androgens and revealed no signs of steroid enzyme disturbances in women with PCOS.

Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients.

The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.

Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM.

We examined the effect of glycemic control of NIDDM on counterregulatory hormone responses to hypoglycemia and compared the effect with that seen in patients with IDDM. Eleven subjects with NIDDM and eight age- and weight-matched control subjects and ten subjects with IDDM and ten age- and weight-matched control subjects were studied. All subjects underwent a stepped hypoglycemic-hyper-insulinemic clamp study during which plasma glucose levels were lowered in a stepwise manner from 5.0 to 2.2 mmol/l in steps of 0.6 mmol/l every 30 min. Counterregulatory hormones (epinephrine, norepinephrine, glucagon, ACTH, cortisol, and growth hormone [GH]) were measured, and a symptom survey was administered during the last 10 min of each 30-min interval. The threshold for release of epinephrine, norepinephrine, ACTH, and cortisol occurred at higher plasma glucose levels in NIDDM than in IDDM patients (P < 0.05-0.01). The glucose threshold for release of epinephrine and norepinephrine correlated with glycemic control as measured by glycosylated hemoglobin (P < 0.05-0.01). However, for a given level of glycemic control, the threshold for release of epinephrine and norepinephrine occurred at a higher glucose level in NIDDM versus IDDM patients (P < 0.05-0.01). At the nadir level of hypoglycemia, glucagon, ACTH, and cortisol levels were all higher in NIDDM compared with IDDM subjects, whereas GH levels were lower. Glycemic control alters counterregulatory responses to hypoglycemia in NIDDM as has been previously reported in IDDM. However, at similar levels of glycemic control, NIDDM patients release counterregulatory hormones at a higher plasma glucose level than patients with IDDM. In addition, subjects with NIDDM maintain their glucagon response to hypoglycemia. These data suggest that patients with NIDDM may be at reduced risk of severe hypoglycemia when compared with a group of IDDM patients in similar glycemic control, thus providing a more favorable risk-benefit ratio for intensive diabetes therapy in NIDDM.

Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type I diabetes mellitus.

Defective glucose counterregulation and hypoglycemia unawareness are both well-recognized risk factors for recurrent episodes of severe hypoglycemia in patients with type I diabetes. At present, no conventional therapy is available to routinely overcome these acquired impairments in long-standing diabetes. To test the hypothesis that successful intraportal islet transplantation could improve this syndrome, hormonal counterregulatory responses and symptoms were studied during stepped hypoglycemic clamp tests before and after intraportal islet transplantation in three patients with type I diabetes who were prone to severe hypoglycemia. As compared with matched nondiabetic control subjects, before islet transplantation, glucagon responses were absent while epinephrine and cortisol responses were either markedly decreased or absent in all diabetic subjects. One patient also had decreased norepinephrine and growth hormone responses. Autonomic warning symptoms were absent in all patients during hypoglycemia. One month after successful islet transplantation, there was no improvement in the glucagon response. However, glycemic thresholds and/or peak incremental responses of epinephrine, norepinephrine, and cortisol improved in all patients. Moreover, all patients had developed autonomic warning symptoms so that glycemic thresholds were detectable within the examined range. We conclude that intraportal islet transplantation does not restore hypoglycemia-induced glucagon secretion, but it improves the responses of most counterregulatory hormones and hypoglycemic warning symptoms even in long-standing type I diabetes.

Decreased Epinephrine Response to Hypoglycemia During Sleep.

Nocturnal hypoglycemia is not uncommon among patients taking insulin. This study examined whether the counter-regulatory hormone response to

A novel presentation of Addison disease: Hypoglycemia unawareness in an adolescent with insulin-dependent diabetes mellitus

A 16-year-old boy with insulin-dependent diabetes mellitus (IDDM) and a history of marginal glycemic control had severe hypoglycemia unawareness and a marked decrease in insulin requirement. His counterregulatory hormone response at the time of hypoglycemia suggested adrenocortical and adrenomedullary dysfunction. Further testing confirmed Addison disease. The patient's hypoglycemia unawareness was reversed by glucocorticoid replacement, although the plasma epinephrine response to hypoglycemia remained undetectable. (J Pediatr 1998;132:882-4)

Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes.

To determine the effects of glycemic control on the counterregulatory responses to hypoglycemia in type 2 diabetes. Seven poorly controlled type 2 diabetes patients (mean HbA1c, 11.3 +/- 1.1%) were studied by stepped hyperinsulinemic hypoglycemic clamp (nadir, 2.4 mmol/l) before and after improving glycemic control with insulin treatment. Counterregulatory hormones, symptoms, and four-choice reaction time were measured at each glucose plateau. In patients with poorly controlled type 2 diabetes, counterregulatory hormone responses began at higher plasma glucose levels than did those in healthy subjects (epinephrine, 4.4 +/- 0.2 vs. 3.7 +/- 0.2 mmol/l, P = 0.011). After significant improvement in glycemic control (mean HbA1c, 8.1 +/- 0.9%, P < 0.001) was achieved without severe hypoglycemia, hormonal responses started at much lower plasma glucose levels (e.g., epinephrine, 3.5 +/- 0.3 mmol/l, P = 0.005) and were significantly reduced in magnitude (e.g., area under epinephrine response curve, 306 +/- 93 vs. 690 +/- 107 nmol.min-1.l-1, P = 0.012). This was accompanied by a change in the plasma glucose threshold at which hypoglycemic symptoms first developed from 3.6 +/- 0.2 to 3.0 +/- 0.2 mmol/l (P = 0.019). In contrast, the plasma glucose threshold at which four-choice reaction time deteriorated did not change significantly (3.1 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l, P = 0.125). Counterregulatory responses begin at normoglycemia in poorly controlled type 2 diabetes. Improving glycemic control with insulin therapy normalizes hormonal responses but lowers the plasma glucose levels at which hypoglycemic symptoms develop to levels associated with impairment of four-choice reaction time, a marker of cognitive function. This process potentially increases the risk of severe hypoglycemia, but to a lesser extent than occurs in type 1 disease.

Hypoglycemia in children with diabetes: incidence, counterregulation and cognitive dysfunction.

Hypoglycemia remains a critical problem in the treatment of IDDM and often limits our ability to consistently achieve excellent glycemic control. Ongoing studies will be important to increase our understanding of the factors responsible for its occurrence and the impact that hypoglycemia may have, particularly for the brain. Significant differences have been documented between adults and children in the incidence of this complication of insulin therapy as well as in the counterregulatory hormone responses to hypoglycemia and its effects on the CNS. While children with diabetes still need insulin treatment, the prevention of hypoglycemia will be a central aim of management. This will depend on effective and expert diabetes education and support for the patient and his or her family along with better efforts to achieve more physiological insulin replacement.

Return of β-adrenergic sensitivity in a patient with insulinoma after removal of the tumour

Beta-adrenergic sensitivity and counterregulatory hormone and symptomatic responses to hypoglycaemia were studied in a 22-year-old man before and 3 and 34 weeks after removal of an insulinoma. The beta-adrenergic sensitivity was measured by the effect of an isoprenaline infusion on the heart rate, and the dose needed to increase the heart rate by 25 beats min(-1) (I25) calculated from regression lines. The glucose thresholds for the hormonal responses and symptoms were studied during a gradual fall in plasma glucose using a hypoglycaemic clamp technique. As compared with preoperative values, beta-adrenergic sensitivity was unchanged 3 weeks after surgery, but showed a marked improvement after 34 weeks, the I25 (in microg isoprenaline) being 0.96, 0.86, and 0.56, respectively. The hormone responses to hypoglycaemia were earlier, but with no improvement in symptom generation at 3 weeks. After 34 weeks, the thresholds for both hormone release and symptom generation occurred at a plasma glucose approximately 1 mmol l(-1) higher than before surgery. Thus, in our patient, there was a marked improvement in beta-adrenergic sensitivity, an earlier release of counterregulatory hormones, and an earlier recognition of hypoglycaemic symptoms after surgery. However, the restoration of these responses took more than 3 weeks.

Impaired counterregulatory hormonal and metabolic response to exhaustive exercise in obese subjects.

A reduction of postprandial thermogenesis has been described in obesity; insulin resistance and/or decreased sympathetic nervous system activity seem to play the major role in its pathogenesis. On the other hand, a normal energy expenditure during exercise has been reported. At present, the response and the role of catecholamines in energy metabolism during exercise in obesity have not been well clarified yet. The aim of this work was to study the metabolic and hormonal changes caused by intense exercise in obesity. Nine obese subjects and ten normal weight controls were submitted to exhaustive exercise on a cycloergometer. Blood glucose, free fatty acids (FFA), glycerol, lactate, beta-OH-butyrate, insulin, glucagon, plasma growth hormone (HGH), catecholamine plasma levels were assayed before and at the end of exercise, and after a recovery period. The energy cost of exercise was evaluated by indirect calorimetry. In our experiment muscular exercise did not provoke any change in blood glucose and FFA plasma levels in either of our groups. In the obese subjects the insulin plasma levels were higher than in the controls. Glucagon plasma levels did not change. The exercise responses of norepinephrine (NE) (4.28 +/- 0.74 vs 8.81 +/- 1.35 nmol/l; P < 0.01), epinephrine (E) (234.21 +/- 64.18 vs 560.51 +/- 83.38 pmol/l; P < 0.01) and plasma growth hormone (HGH) (134.84 +/- 58.97 vs 825.92 +/- 195.25 pmol/l; P < 0.01) were significantly lower in obese subjects. At the end of exercise, the thermic effect of exercise did not differ between obese and control subjects (0.335 +/- 0.038 vs 0.425 +/- 0.040 kJ/min x kg fat-free mass. Our findings indicate that an impaired counterregulatory hormone response to exercise exists in obese subjects. The thermic effect of exercise does not seem to be affected by either the reduced catecholamine response nor insulin resistance.