Insulin resistance in limb and trunk partial lipodystrophy (type 2 Köbberling-Dunnigan syndrome)

We studied insulin action in two patients with limb and trunk partial lipodystrophy with hirsutism and acanthosis nigricans. Glucose was normal in one of the patients and slightly above normal in the other during an oral glucose tolerance test (OGTT). An intravenous glucose tolerance test (IVGTT) was normal in both patients. Basal and glucose-stimulated insulin levels were elevated in both the OGTT and IVGTT in both patients. The response of plasma glucose to exogenously administered insulin was decreased. A euglycemic-hyperinsulinemic clamp performed in patient no. 2 indicated insulin resistance, which was not corrected by reducing the increased basal level of serum free fatty acids (FFAs). Binding of insulin to neck adipocytes was normal in both subjects, but glucose transport and oxidation in these cells was impaired. Insulin binding to abdominal adipocytes was increased in one patient whose adipocytes displayed higher glucose transport at low insulin concentrations. Glucose oxidation was decreased in abdominal adipocytes of both patients. We conclude that insulin resistance in Köbberling-Dunnigan type 2 partial lipodystrophy is not related to an alteration of the insulin molecule or to changes in insulin binding, but is more likely associated with a postreceptor defect, since glucose oxidation was impaired in adipocytes of the neck and abdomen.     

Uncontrolled diabetes mellitus and hyperglucagonemia associated with an islet cell carcinoma.

A 53 year old woman presented with diabetes mellitus, hyperglucagonemia (600 to 1,500 pg/ml), clinical hyperparathyroidism and an abdominal mass diagnosed on biopsy as an islet cell carcinoma. Glucagon content of the tumor was 0.78 mug/g wet weight. Hourly blood samples during a 24 hour period revealed a direct correlation between plasma glucose and glucagon. The oral administration of glucose paradoxically increased whereas the intravenous administration decreased plasma glucagon. Circulating glucagon levels were markedly increased with arginine and epinephrine infusion. Both short- and long-term administration of alpha adrenergic blockade depressed the glucagon response to epinephrine infusion. In contrast, long-term alpha adrenergic blockade increased glucagon secretion despite improved glucose tolerance during a second 24 hour study. Although the patient demonstrated overt clinical and chemical findings of hyperparathyroidism, parathyroid hormone (PTH) was not detected in her plasma. The pattern of tumor growth was consistent with an origin from pancreatic islets. We conclude that (1) the tumor was responsive to physiologic stimuli known to affect glucagon secretion; (2) elevations of plasma glucagon levels with oral and dietary glucose suggest regulation of secretion by intestinal factors; and (3) improvement of glucose tolerance with alpha adrenergic blockade may be related to increased insulin secretion.     

Body fat distribution and metabolic derangements in patients with familial partial lipodystrophy associated with mandibuloacral dysplasia

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder that is characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial sutures, joint contractures, and mottled cutaneous pigmentation. It is also associated with partial lipodystrophy, but the pattern of fat loss has not been well characterized. We studied body fat distribution in two male and two female patients with MAD by anthropometry, dual energy x-ray absorptiometry, and magnetic resonance imaging. Blood glucose and insulin responses during an oral glucose tolerance test and fasting serum lipoproteins were determined. Three of the four subjects had loss of sc fat from the extremities with normal or slight excess in the neck and truncal regions (termed type A pattern). In contrast, one patient had generalized loss of sc fat involving the face, trunk, and extremities (type B pattern). All of the patients had normal glucose tolerance but had fasting and postprandial hyperinsulinemia suggestive of insulin resistance. Elevated serum triglycerides with low high-density lipoprotein cholesterol levels were noted in three subjects. We conclude that familial partial lipodystrophy associated with MAD presents with two types of body fat distribution patterns, both of which are associated with insulin resistance and its metabolic complications.     

Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy.

We evaluated metabolic and clinical features of 71 HIV-infected patients with lipodystrophy by comparing them with 213 healthy control subjects, matched for age and body mass index, from the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were compared separately with 90 matched control subjects from the Framingham Offspring Study. Fasting glucose, insulin, and lipid levels; glucose and insulin response to standard oral glucose challenge; and anthropometric measurements were determined. HIV-infected patients with lipodystrophy demonstrated significantly increased waist-to-hip ratios, fasting insulin levels, and diastolic blood pressure compared with controls. Patients with lipodystrophy were more likely to have impaired glucose tolerance, diabetes, hypertriglyceridemia, and reduced levels of high-density lipoprotein (HDL) cholesterol than were controls. With the exception of HDL cholesterol level, these risk factors for cardiovascular disease (CVD) were markedly attenuated in patients without lipodystrophy and were not significantly different in comparison with controls. These data demonstrate a metabolic syndrome characterized by profound insulin resistance and hyperlipidemia. CVD risk factors are markedly elevated in HIV-infected patients with fat redistribution.     

Further support for heterogeneity of insulin response and insulin sensitivity in non-obese subjects with glucose intolerance

The relationship of insulin secretion and insulin sensitivity was studied in 67 age- and body weight-matched non-obese subjects, classified as having a normal glucose tolerance or glucose intolerance (50 g oral glucose load). Insulin response was studied by means of a 2 h glucose infusion. For the determination of insulin sensitivity a 1 h priming dose-constant insulin infusion technique was used. The per cent decrease of plasma glucose level at comparable steady-state insulin levels served as a measure of body sensitivity to exogenous insulin. In patients with glucose intolerance the early (delta IRI area 0-5 min) and late (delta IRI area 30-120 min) insulin responses to iv glucose were significantly reduced in comparison to controls. Controls and subjects with glucose intolerance showed considerable heterogeneity of insulin responses. Patients with glucose intolerance and relative insulin deficiency were not less responsive to insulin than subjects with normal glucose tolerance. There was, however, a wide variation of insulin sensitivity within the two groups. There was a weak significant inverse correlation between insulin response to glucose and insulin sensitivity for the two groups combined and for controls and subjects with glucose intolerance separately. The results demonstrate that the majority of non-obese patients with glucose intolerance and relative insulin deficiency does not exhibit a reduced responsiveness to insulin and therefore hypoinsulinaemia but not insulin resistance is the primary defect for an abnormal glucose tolerance in these group of subjects.     

Lipodystrophy, insulin resistance, and adiponectin concentration in HIV-infected children and adolescents

Alterations of fat distribution and insulin resistance are associated with increased risk of metabolic derangements and cardiovascular disease. HIV-infected adult patients on antiretroviral treatment often show lipodystrophy, insulin resistance and hypoadiponectinemia, but data in children are controversial. We investigated serum adiponectin concentration in a cohort of HIV-infected youths, and we assessed the relationships with lipodystrophy and insulin resistance. We studied 36 HIV-infected patients (aged 5.0 - 19.4 years), and 171 healthy subjects (aged 4.9 - 17.9 years) for adiponectin measurements. All patients underwent body composition assessment by dual-energy x-ray absorptiometry, and an oral glucose tolerance test to determine the fasting insulin concentration, the insulin area under the curve (AUC), and the HOMA index. Adiponectin serum concentration was measured by an immunoenzymatic assay. Sixteen patients had central fat accumulation, 6 had peripheral lipoatrophy, 5 had a mixed phenotype, and the remaining 9 were non-lipodystrophic. Fasting insulin, insulin AUC, and HOMA index were significantly higher in patients with central fat adiposity and mixed phenotype than in the other two groups. The patients of the former two groups had adiponectin concentration much lower than healthy controls, and patients with peripheral lipoatrophy or normal phenotype had normal concentration. Low adiponectin concentration is associated to central fat and mixed lipohypertrophy, and to signs of insulin resistance in HIV-infected youths. Strict monitoring of metabolic and cardiovascular evolution should be performed in these patients.     

Familial partial lipodystrophy: Complications of obesity in the non-obese?

The increased frequency of metabolic perturbations in overweight individuals whose fat is predominantly central, as compared with those whose fat is more generalized in distribution suggests that characteristics of fat other than an excess promote the morbidity of the obese. In this report we describe the location and quantity of body fat together with the status of carbohydrate and lipid metabolism in 8 females affected with familial partial lipodystrophy, a rare condition in which peripheral subcutaneous fat is mostly absent while there is retention or an increase in central adiposity. The 8 subjects had normal or reduced amounts of body fat as determined by body density measurements. Computerized axial tomograms in two subjects showed that there was normal to increased amounts of intra-abdominal fat and irregular pockets of subcutaneous fat overlying the abdomen. Plasma triglycerides varied but were elevated in all subjects ranging from 171 to 3720 mg/dl (normal = 103 ± 36). Mild sustained elevations in mean systolic blood pressure (> 135 mm Hg) occurred in 4. Two of the 8 had fasting hyperglycemia (>140 mg/dL) and a third was intolerant to oral, but not to intravenous glucose. Fasting serum insulin concentrations were uniformly elevated (22 to 51 uU/ml) and, in most instances, responded to both glucose and arginine with exaggerated increments, but there was no delay in insulin release. Mild insulin resistance was documented by the failure to respond to standard insulin injections, and there were decreased insulin receptors on erythrocytes. Basal plasma glucagon concentrations were generally elevated, did not suppress during oral glucose administrations and rose 2 to 5 times basal levels during intravenous infusion of arginine.These studies emphasize that the various complications of the obese, especially those with centralized obesity, are seen in a non-obese condition characterized by an increase in the ratio of central to peripheral fat.     

Nonketotic diabetes mellitus: Insulin deficiency or insulin resistance?

Ninety-five nonobese, nonketotic subjects were divided into five groups (one normal and four with varying degrees of glucose intolerance) according to their plasma glucose responses during an oral glucose tolerance test. These five groups were then compared on the basis of their insulin response during the oral glucose tolerance test and on the ability of exogenously infused insulin to limit hyperglycemia during a continuous infusion of glucose and insulin, while endogenous insulin was inhibited by the infusion of epinephrine and propranolol. The mean plasma insulin response of patients with either borderline abnormalities of glucose tolerance or chemical diabetes was equal to or greater than that of normal subjects at all points during the glucose tolerance test. Thus, the glucose intolerance of these two patient groups cannot be attributed to a lack of insulin. On the other hand, the mean insulin response of patients with moderate fasting hyperglycemia (plasma glucose of 110 to 150 mg/100 ml) was somewhat attenuated, and patients with severe fasting hyperglycemia (plasma glucose > 150 mg/100 ml) had unequivocal insulin deficiency. In contrast, all four patient groups with abnormal carbohydrate metabolism were more resistant than normal subjects to the action of insulin. These results indicate that there is a very complex relationship between insulin deficiency and insulin resistance in patients currently classified as having nonketotic diabetes. Patients with either borderline abnormal glucose tolerance or chemical diabetes are more resistant to insulin than normal subjects, and are not insulin deficient. In these patients it seems reasonable to assume that their glucose intolerance is a direct function of their insulin resistance. Patients with severe fasting hyperglycemia are suffering from both insulin deficiency and insulin resistance, and the relationship between these two variables in the genesis of hyperglycemia in these subjects remains obscure. It seems apparent from these studies that nonketotic diabetes mellitus can no longer be considered to be a simple function of insulin lack, and that in order to understand this syndrome we will need to increase our knowledge of the relationship between insulin deficiency and insulin resistance in these patients.     

Endocrine pancreatic function in pheochromocytoma

In six patients with pheochromocytoma oral glucose tolerance test (OGTT) and arginine test were carried out. Blood insulin and glucagon response were investigated. In subjects with adrenal tumor glycemic curve pattern was typical: a rapid and exaggerated increase of glycemia followed by an abrupt drop. Absolute insulinemic response to oral glucose was normal, but inappropriate to glycemic stimulus. Arginine infusion provoked a slightly above normal increase in blood glucose and a normal increase in blood glucagon. In three of the patients studied postoperatively, reduced glycemic response to glucose was observed, whereas there were no evident variations in blood insulin and glucagon response. These data suggest that in pheochromocytoma impaired glucose tolerance is partly due to the reduced insulin response to oral glucose load.     

Effect of fructose feeding on insulin secretion and insulin action in the rat

Insulin secretion and insulin action were studied in rats fed either a diet containing (as percent of calories) 66% fructose, 22% protein, and 12% fat, or standard rat chow (60% vegetable starch, 29% protein, 11% fat) for 7 days. Plasma glucose concentration following either an oral glucose or fructose load ($\text{180 mg}\text{100 g body weight}$) were slightly higher in the fructose-fed rats, and this was associated with a much greater elevation of plasma insulin concentrations. The ability of insulin to stimulate disposal of glucose load was determined during the continuous infusion of epinephrine, propranolol, glucose, and insulin. Under these conditions the steady state plasma insulin levels were the same in the two groups of rats, whereas the steady state plasma glucose levels were almost twice as high in the fructose fed rats. Thus, fructose feeding for 7 days resulted in an increase in the insulin response to an oral carbohydrate challenge, as well as to a loss of normal insulin sensitivity.     

Fat feeding decreases insulin responsiveness of adipose tissue lipoprotein lipase

The acute effect of fat feeding on the insulin-mediated stimulatory response of adipose tissue lipoprotein lipase (ATLPL) was examined in normal-weight subjects. After two days of isocaloric-formula feeding, subjects were divided into the following four groups: intravenous (IV) saline alone (sal) (n = 5), IV saline and 67 g of oral corn oil ingested at the outset of the infusion (sal/fat) (n = 5), IV insulin (40 mU/m2/min) and glucose to maintain euglycemia (ins/glu) (n = 9), and IV insulin and glucose and oral corn oil (ins/glu/fat) (n = 8). Triglycerides fell less in the ins/glu/fat group than in the ins/glu group (0 +/- 8% v 35 +/- 5%, means +/- SEM, at three hours, P less than 0.01; 15 +/- 8% v 43 +/- 6% at six hours, P less than 0.02). ATLPL in the sal and sal/fat groups did not change during the six-hour period. When the responsiveness of ATLPL was compared between ins/glu/fat subjects and ins/glu subjects, decreases were seen at both three and six hours (-0.3 +/- 3.0 v 15.1 +/- 5.4 nEq/g/min, P less than 0.05; 6.7 +/- 2.7 v 27.9 +/- 3.9 nEq/g/min, P less than 0.001). The glucose infusion rates needed to maintain euglycemia were also decreased by fat feeding, 229 +/- 18 v 287 +/- 20 mg/m2/min (P less than 0.05). Thus, fat feeding with insulin and glucose infusions diminishes the insulin responsiveness of ATLPL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carbohydrate and lipid oxidation in normal human subjects: its influence on glucose tolerance and insulin response to glucose

Two types of glucose tolerance tests (OGTT and 90-min glucose infusions) were carried out on 33 normal subjects in whom free fatty acid levels were either raised by neutral fat infusion or lowered by β-pyridyl carbinol infusion. With continuous measurement of O₂ consumption and of nonprotein respiratory quotient during these tests, it could be demonstrated that the fat infusion before glucose load was followed by an increased lipid oxidation and that carbohydrate oxidation was diminished. The glucose load (without fat infusion) induced a rapid increase of carbohydrate oxidation and a decrease of lipid oxidation. When FFA was raised, a glucose load was followed by increased carbohydrate oxidation less than was observed in cases where glucose only was given. Glucose tolerance was found to be depressed by the simultaneous administration of lipids, while insulin response to glucose load was significantly increased. These observations find support in the known inhibition of glucose oxidation induced by fatty acid oxidation. Glucose intolerance and insulin insensitivity appear to be a consequence of this mechanism. Decreased lipid oxidation, increased carbohydrate oxidation, improved glucose tolerance, and lower insulin response to glucose load with apparent “insulin hypersensitivity” was observed while lowering free fatty acid levels with a β-pyridyl carbinol infusion.     

Generalized lipodystrophy: in vivo evidence for hypermetabolism and insulin-resistant lipid, glucose, and amino acid kinetics.

Stable isotope tracers and indirect calorimetry were used to evaluate whole-body energy, glucose, lipid, and amino acid metabolism in a patient with generalized lipodystrophy during basal conditions and in response to insulin therapy. The results were compared with those obtained in previous studies in normal volunteers. The basal rate of glucose production (33.7 mumol/kg.min) was three times higher than normal. The basal rate of glycerol appearance in blood, an index of lipolysis, was 60% greater than normal when expressed per kilogram body weight (3.82 mumol/kg.min), but was more than 10 times normal when expressed per kilogram body fat mass (123.2 mumol/kg.min) because of the marked decrease in body fat in our patient (3% of total body weight). Leucine rate of appearance, an index of protein breakdown, and nonoxidative leucine disposal, an index of protein synthesis, were also greater than normal. Resting energy expenditure (REE) was 30% greater than normal. The effect of insulin infusion on these metabolic parameters was markedly blunted. These metabolic abnormalities help explain many of the clinical findings such as hyperglycemia, hypertriglyceridemia, fat depletion, hepatomegaly, and steatosis observed in patients with lipodystrophy. Ineffective insulin function in many tissues appears to be an important factor in the pathophysiology of lipodystrophy.     

Leptin receptor gene polymorphisms are associated with insulin in obese women with impaired glucose tolerance.

Leptin receptors are present on beta-cells as well as on muscle and fat cells, thus enabling leptin to modulate both insulin secretion and insulin action. Leptin inhibits especially the glucose-stimulated insulin secretion from pancreatic cells. The leptin receptor (LEPR) gene could thus play a role in the regulation of glucose and insulin after an oral glucose load. Therefore, the relationship between LEPR polymorphisms and glucose and insulin response to an oral glucose tolerance test (OGTT) was investigated. Three LEPR polymorphisms (Lys(109)Arg, Gln(223)Arg, and Lys(656)Asn) were typed on genomic DNA of 358 overweight and obese women, aged 18-60 yr. Based on an OGTT, 269 subjects were defined with normal glucose tolerance, and 89 with impaired glucose tolerance (IGT). Associations between genotypes and glucose metabolism were analyzed with a general linear models procedure in pre- and postmenopausal women separately, after adjusting the data for age and fat mass. In postmenopausal women with IGT (n = 24), associations were found with Lys(109)Arg and Lys(656)Asn for fasting insulin (P = 0.05) and with Lys(109)Arg and Gln(223)Arg for the insulin response to an OGTT (P < 0.02). In the same group, trends were found with Lys(656)Asn for fasting glucose as well as in response to the OGTT. In premenopausal women with IGT (n = 65), associations were found with Lys(109)Arg and Lys(656)Asn for overall glucose response to the glucose load. In contrast, no associations with insulin or glucose were found in women with normal glucose tolerance. In conclusion, these data indicate that LEPR polymorphisms are associated with insulin and glucose metabolism in women with impaired glucose homeostasis.     

PARTIAL AND TOTAL LIPODYSTROPHY: CHANGES IN CIRCULATING SUGAR, FREE FATTY ACIDS, INSULIN AND GROWTH HORMONE FOLLOWING THE ADMINISTRATION OF GLUCOSE AND OF INSULIN

The effect of glucose or insulin administration in a group of five patients with partial lipodystrophy and three with total lipodystrophy was studied. In only one patient was the glucose tolerance curve abnormal. Mean fasting serum insulin, growth hormone, free fatty acids (FFA) and triglycerides were all significantly elevated. The serum insulin response to glucose was grossly elevated. Insulin resistance was present. The serum insulin was shown to be immunologically normal, Exogenous insulin disappeared at a normal rate from the circulation, suggesting that the elevated insulin levels in the fasting state and after glucose were due to hypersecretion. Serum growth hormone levels failed to suppress normally after glucose. Serum FFA fell after glucose or insulin administration. In one patient treated with propranolol unusual insulin responses to the administration of glucose were observed. A working hypothesis capable of explaining the metabolic changes in lipodystrophy is proposed.     

Insulin secretion and body composition in obesity

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

Peripheral insulin resistance in primary hyperparathyroidism

Carbohydrate metabolism was investigated in 9 patients with symptomatic primary hyperparathyroidism. Before and after parathyroidectomy intravenous and oral glucose tolerance tests, tolbutamide test, arginine infusion test and insulin tolerance test were performed. During intravenous and oral glucose tolerance tests, patients with primary hyperparathyroidism exhibited hyperinsulinemia and impaired glucose tolerance without normalization after surgery. Tolbutamide-induced insulin release did not differ pre- or postoperatively. After restoration of normocalcemia and normophosphatemia we found significantly lower glucose and insulin levels following arginine infusion and a significantly increased hypoglycemic response to parenterally administered insulin, probably indicating partial improvement of glucose tolerance after surgery. Our findings suggest that biochemical abnormalities associated with primary hyperparathyroidism, like hypercalcemia, hypophosphatemia, and elevated parathyroid hormone levels may cause and sustain a form of endogenous insulin resistance, which consequently leads to hyperinsulinemia and to impaired glucose tolerance. Since hyperinsulinemia as well as impaired glucose tolerance seem to be only slowly and partially reversible in symptomatic primary hyperparathyroidism, these data could be considered as an additional argument for early surgical intervention in this disorder.     

Enhanced plasma norepinephrine response to upright posture and oral glucose administration in elderly human subjects

Plasma norepinephrine (NE) levels in response to upright posture and to oral glucose ingestion were measured in healthy young and old (> 65 yr of age) subjects. Peak plasma NE concentrations with standing were higher in the elderly (1334 ± 146 pg/ml versus 855 ± 46; p < 0.05) and plasma NE remained elevated in the elderly compared with the young subjects even after 15 min of recumbent resting. Following oral glucose plasma NE rose higher in the elderly (79% compared with 32% in the young) and peaked later (120 min after ingestion compared with 60 min in the young). Cardiovascular changes with upright posture and with oral glucose were similar in young and old. Alterations in disappearance of NE from the circulation could not account for the greater elevations in plasma NE concentration in the elderly either, since the rates of fall in circulating NE levels following termination of an NE infusion were the same in both groups. The metabolic clearance rate of NE was unchanged. Thus, the plasma NE responses to stimulation by standing and by oral glucose ingestion are enhanced in elderly subjects.     

Mechanism of action of phenetylbiguanide (phenformin) in normal subjects. II. Intestinal absorption versus nonintestinal effects

Administration of phenformin to normal adult controls in a single dose of 200 mg decreased fasting blood sugar and increased the tolerance to acute oral and intravenous glucose loads and to chronic glucose infusion with lower insulin levels, suggesting an effect of the drug on blood glucose independently of its action of the rate of intestinal glucose absorption.     

Exercise-induced hepatic glucose output is precisely sensitive to the rate of systemic glucose supply

It has previously been established that a glucose infusion causing hyperglycemia and alterations in the levels of glucoregulatory hormones suppresses the exercise-induced increment in systemic glucose appearance (Ra). In an attempt to define the mechanisms responsible for this suppression of Ra, five normal subjects were exercised for 60 minutes on a bicycle ergometer at 60% Vo2 max on two occasions. On both occasions Ra was measured by a nonsteady state technique using a constant infusion of 3-3H-glucose. On the second occasion, an IV infusion of glucose was administered in a stepwise fashion to simulate in timing and magnitude the measured Ra response from the first study. Endogenous glucose production in the second study, estimated by subtracting the amount of glucose infused from the measured Ra response, did not increase above basal (endogenous glucose output response = 0.5 +/- 8.4 mmol/60 min v control study 60.2 +/- 6.6 mmol/60 min, P less than 0.01). The suppression of Ra was associated with a small but significant effect on venous plasma glucose (increment above basal less than 0.3 mmol/L, P less than 0.05) and a significant change in glucose metabolic clearance rate during the second 30 minutes of exercise. Serum insulin, C-peptide, cortisol, growth hormone, and plasma glucagon responses to exercise were not significantly affected by glucose infusion and the ratio of circulating insulin to glucagon was also not affected. These results indicate that hepatic glucose output during exercise is precisely sensitive to glucose supply. The feedback inhibition is presumably mediated by a small increase in plasma glucose but cannot readily be accounted for by changes in glucoregulatory hormones.(ABSTRACT TRUNCATED AT 250 WORDS)