Plasma Concentrations Of Immunoreactive Insulin Research Articles

Pharmacokinetic-pharmacodynamic modelling of human insulin: validity of pharmacological availability as a substitute for extent of bioavailability.

A method for assessing the extent of bioavailability (EBA) of human insulin from pharmacological data was determined. The time course governing increases in the plasma concentration of immuno-reactive insulin (IRI), as well as its pharmacological effects (glucodynamics), was determined after the intravascular administration of varying doses of human insulin. Pharmacokinetic (PK), pharmacodynamic (PD), and link models were constructed to elucidate the quantitative relationship between plasma IRI levels and pharmacological effects. After extravascular administration of the test formulation, only the time course governing the observed pharmacological effects was determined. The pharmacological data was translated into theoretical plasma concentration data, using the PK-PD model. Following this, the area under the theoretical plasma concentration-time curve (AUC) of the test formulation was calculated. The EBA was then estimated against a reference (intravascular) formulation, using a conventional equation. Since the pharmacological effects of insulin were observed to be highly dosing-rate-dependent, the PD model used in this study was modified to apply over a wide range of infusion rates. The results of the PK-PD analysis indicate that the doses administered can be accurately predicted from pharmacological data. To validate this method, the EBAs of controlled release formulations (the Osmotic Mini Pumps) of insulin, subcutaneously administered to the rat, were estimated. The EBA values obtained (92-96%) fell within a reasonable range. The area under the effect-time curves (AUE) obtained following subcutaneous applications of the Osmotic Mini Pump were calculated in a model-independent manner, in addition to pharmacological availabilities (PA), which were estimated against the reference (intravascular) formulations. The estimated PA values varied from 312% to 78%, in accordance with the intravascular input rates of the reference formulations. This indicates that PA should not be used as a substitute for EBA, unless data involving similar intravascular dosing rates to that of the reference formulations is available.

THEIN VIVOINTERACTION BETWEEN GLICLAZIDE AND GLIBENCLAMIDE AND INSULIN ON GLUCOSE DISPOSAL IN THE RAT

Many reports suggest that extrapancreatic actions contribute to the antidiabetic effect of sulphonylurea drugs (SUs). In this work, the ability of two SUs, namely, gliclazide and glibenclamide, to augment insulin action was studiedin vivo. Both drugs elevated the plasma concentration of immunoreactive insulin (IRI) and lowered the plasma concentrations of glucose and non-esterified fatty acids (NEFA) in normal intact rats. These changes were not reproduced in alloxan-diabetic or eviscerated rats. The actions of insulin on plasma glucose and NEFA were not augmented by gliclazide in alloxan-diabetic rats. Neither gliclazide nor glibenclamide (given acutely and for 30 days) augmented the actions of exogenously administered insulin in reducing plasma glucose or NEFA concentrations in intact or eviscerated animals. It was concluded that these SUs do not produce their acute or chronic effects on blood glucose by augmenting the actions of insulin.@e$g0@p18

Crucial role of milk-borne insulin in the development of pancreatic amylase at the onset of weaning in rats.

The development of pancreatic amylase activity was examined in rats fed in regular cages or in special cages, designed so the pups could not reach solid food to prevent weaning. In both groups, the amylase activity in zymogen granules increased in rat pups aged 14 days, peaked at 18 days, and thereafter remained at a 1.6-fold higher level than at 14 days of age. An increase in the plasma concentration of immunoreactive insulin preceded the increase of amylase activity, whereas the plasma concentration of C-peptide, indicating the secretion rate of endogenous insulin, remained unchanged. The administration of insulin at 20 ng/ml (the physiological concentration) in the milk formula caused an increase in the plasma insulin concentration of 17-day-old pups. In addition, increased pancreatic amylase activity was observed in 17-day-old rats raised on milk formula to which insulin was added. We propose that the increase of amylase activity at the beginning of weaning is dependent on the milk-borne insulin and not on the dietary change in rats.

Pancreatic Expression and Secretion of Human Islet Amyloid Polypeptide in a Transgenic Mouse

Islet amyloid polypeptide (IAPP) is a secretory product of the pancreatic beta-cell, which is the primary constituent of the islet amyloid that develops in type II diabetes. To study the role the inherent amyloidogenicity of human IAPP (hIAPP) plays in the formation of islet amyloid deposits and to investigate a possible hormonal role for IAPP, transgenic mice expressing hIAPP were developed. The transgene was composed of a fragment of an hIAPP cDNA linked to the rat insulin II promoter. One line of transgenic mice expressed the transgene and synthesized hIAPP in their pancreatic islets. IAPP-like immunoreactivity in pancreatic extracts and plasma were two- to threefold greater in the transgenic mice compared with nontransgenic control mice. Although plasma concentrations of immunoreactive insulin (IRI) and glucose were equal in transgenic and control mice, the pancreatic content of IRI was nearly twofold greater in the transgenic animals, and proinsulin mRNA was significantly elevated, suggesting increased rates of insulin biosynthesis. Pancreatic samples obtained from transgenic mice up to 19 months of age had no evidence of islet amyloid. These results indicate that an increased level of synthesis of the amyloidogenic hIAPP is not sufficient to cause islet amyloid deposition. However, the increased synthesis and storage of insulin in the islets of the transgenic mice are consistent with either a direct regulatory effect of IAPP on the beta-cell or indirect stimulation of insulin production through IAPP-induced insulin resistance.

Growth hormone concentration and disappearance rate, insulin-like growth factors I and II and insulin levels in iron-deficient veal calves.

In calves with severe iron (Fe) deficiency, insulin-like growth factor (IGF)-I levels and IGF-I responses to exogenous growth hormone (GH) are reduced, while insulin-dependent glucose utilization is enhanced. Blood plasma concentrations of immunoreactive insulin (IRI), IGF-I, IGF-II and GH, and the half-life of blood plasma GH [after an i.v. injection of recombinant bovine GH (rbGH; 100 micrograms rbGH/kg body weight)] were measured in 20 calves at body weights between 160 and 190 kg. Calves were fed milk replacers containing 50 or 10 mg Fe/kg (groups Fe50 and Fe10, respectively). Daily weight gain and feed utilization were similar in both groups. Group Fe10 developed mild Fe deficiency anemia and blood plasma urea-nitrogen concentrations were higher (p < 0.05) than in group Fe50. IGF-I and IGF-II concentrations did not vary consistently over a 10-hour period and were not significantly influenced by different Fe intakes. The IRI concentration increased transiently (p < 0.05) after feed intake, but the total response was (not significantly) smaller in Fe-deficient calves. Plasma GH concentration changed episodically and was similar in both groups. Loss of GH from the circulation after i.v. rbGH injection, estimated by biexponential analysis, during the distribution or alpha phase (first 16 min) was similar in both groups, but during the beta phase was shorter (p < 0.05) in group Fe10 than in group Fe50 (29.9 and 34.2 min, respectively). The increased disappearance rate of GH, seen even in mild Fe deficiency, may contribute to reduced GH levels and IGF-I responses to GH in severe Fe deficiency.

Comparison of Indices of Islet B‐cell Function in Type 2 Diabetes in Relation to Insulin Effectiveness and Clinical Outcome

The most appropriate way to estimate islet B-cell function in Type 2 diabetes is unclear, and this has led to many different techniques of measurement being used. We have examined the associations to two fasting and four glucose-stimulated indices of islet B-cell function in members of a group of 249 Type 2 patients, seeking correlations with concurrent glucose tolerance and antilipolytic effect, and with subsequent clinical outcome. The six B-cell indices were interrelated to variable degrees (rs -0.21 to +0.92). Early glucose-stimulated insulin output (incremental 1st-phase insulin area) was not significantly positively correlated with the fasting plasma concentration of immunoreactive insulin at any time. Fasting immunoreactive insulin and 'minimal model' islet B-cell parameters were poorly related to the rate constant for glucose clearance and the degree of antilipolysis (rs values between -0.13 and +0.40). Homeostatic model assessment of the fasting islet B-cell function was more consistently related to these metabolic effects. Incremental first-phase insulin area was the islet B-cell index most consistently related to metabolic abnormalities (rs up to +0.56), and to subsequent need for oral hypoglycaemic or exogenous insulin therapy. No index of islet B-cell function was consistently associated with the subsequent development of diabetic tissue damage.

Insulin and glucose in neonatal calves after peroral insulin and intravenous glucose administration

Effects of peroral insulin on plasma concentrations of immunoreactive insulin (IRI) and glucose in newborn calves were studied. Bovine insulin was administered in amounts of 0.5 mg/kg body weight immediately preceding first colostrum. Thereafter, neither an increased IRI response nor a lowering of blood glucose level were observed, indicating that insulin was either not absorbed from the intestine or possibly retained in the liver. Feeding of whole milk was followed by a higher rise in IRI and glucose concentrations than feeding of colostrum after po insulin. However, when compared with 1-3-month old calves, IRI responses to feeding and to iv infused glucose were markedly smaller on the first and second day of life respectively, while glucose responses were similar. This indicates that insulin secretory mechanisms are not fully developed in the newborn calf.

Reduced insulin removal and erythrocyte insulin binding in obese children.

To study the relationship between childhood obesity, weight loss, hyperinsulinaemia and the erythrocyte insulin receptor, we measured the plasma concentrations of immunoreactive insulin (IRI) and C-peptide and the binding of 125I-insulin to erythrocytes in 12 obese children with a mean age +/- SD of 11.4 +/- 2.5 years and a mean relative weight score +/- SD of 4.8 +/- 1.4 and 12 age-matched normal-weight children. Eight obese children were re-evaluated after 1 year's participation in a weight reduction programme. The obese children had higher fasting plasma concentrations of IRI (P less than 0.01) and C-peptide (P less than 0.05) and a lower C-peptide to IRI molar ratio (P less than 0.01) than the normal-weight children. The obese children had in addition a reduced erythrocyte insulin binding (P less than 0.05 or less) over the physiological range of circulating insulin concentration. There was a negative correlation (r = -0.60; P less than 0.01) between the insulin tracer binding and the relative weight. The weight reduction programme resulted in a decrease of 1.0 SD (P less than 0.05) in the mean relative weight score. At the end of the therapy the obese children had lower fasting blood glucose levels (P less than 0.05) and lower plasma IRI concentrations at 90 min (P less than 0.05) after an oral glucose load than at the onset of therapy. There were no significant differences between the insulin binding characteristics at the commencement and at the end of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Response of Insulin, Glucagon, and Growth Hormone to Intravenous Glucose Challenge in Cows Fed High Fat Diets

Effect of feeding high fat diets on peripheral plasma concentrations of immunoreactive insulin, glucagon, and growth hormone following intravenous glucose challenge (100mg D-glucose/kg body weight) at 50 and 100 d of lactation in 16 multiparous Holstein cows was evaluated. The high fat diet contained 18.5% whole cottonseed on a dry matter basis as the source of extra dietary fat. Feeding the high fat diet had no apparent effect on energy balance. Basal plasma insulin and insulin:glucagon ratio were increased in cows fed the high fat diet relative to those of controls. Glucagon, insulin, and insulin:glucagon ratio response to glucose challenge were not affected by diet. Response of growth hormone to glucose challenge at 50 d of lactation was depressed in cows fed the high fat diet. Plasma glucose peaked at greater concentrations in cows fed the high fat diet. Feeding a high fat diet to dairy cows appears to increase basal insulin concentration and insulin:glucagon ratio, which has actions opposed to glucose synthesis. Thus, endocrine effects of a high fat diet appear to favor decreased milk production.

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In F344 rats bearing transplantable 3-methylcholanthrene (CAS: 56-49-5)-induced sarcomas, plasma concentrations of immunoreactive insulin were decreased following the development of mild or severe anorexia. Plasma levels of immunoreactive glucagon and lactate were elevated in severely anorectic tumor-bearing (TB) rats, while plasma glucose concentrations remained normal. Both groups of TB rats exhibited decreased plasma levels of serine, glutamine, citrulline, and tryptophan and increased concentrations of alanine. Plasma levels of proline and phenylalanine were also elevated in the severely anorectic TB rats. In a second experiment, 7 daily treatments with insulin corrected the anorexia for 6 days and increased body weights of TB rats. Plasma concentrations of lactate and immunoreactive glucagon were decreased, and the abnormal plasma concentrations of glutamine, proline, analine, and phenylalanine were altered toward normal following the insulin treatments. Therefore, these data are consistent with insulin treatments benefiting the TB host by increasing feeding, increasing body weight, reducing tumor glycolysis and metabolism, reducing gluconeogenesis, and reducing host catabolism, while not stimulating tumor growth. Thus insulin therapy may have potential benefits in cancer treatment by shifting glucose metabolism toward the host and away from the tumor.

Erythrocyte Insulin Binding in Preterm Newborn Infants

To characterize the erythrocyte insulin receptor in newborn infants we studied the binding of 125I-insulin to the erythrocytes from 42 preterm infants (14 at birth, 14 aged 2-7 days, and 14 aged 8-16 days) with a mean gestational age of 34.1 wk, and from 32 term infants (16 at birth and 16 aged 2-7 days). The insulin binding to cord blood erythrocytes from preterm infants was significantly higher than that of cord blood cells from term infants and to postnatal cells from preterm as well as term infants. The erythrocytes from preterm infants aged 2-7 days bound more insulin than cells from preterm infants aged 8-16 days. The maximum insulin binding (specific insulin binding at tracer concentration of insulin) correlated negatively with the gestational age both at birth and over the 1st postnatal wk. In the preterm infants there was a strong negative correlation between the maximum insulin binding and postnatal age. The enhanced insulin binding to cord blood erythrocytes from preterm infants was due to both an increased receptor concentration and a high affinity for insulin. The increased affinity persisted over the 1st wk of life. In preterm infants older than 1 wk the insulin binding characteristics were basically similar to those in term newborn infants. In all infants studied the receptor concentration seemed to be postnatal age dependent while the receptor affinity was gestational age dependent. No correlation was found between the insulin binding data and the plasma concentrations of immunoreactive insulin or C-peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of two cholecystokinin variants, CCK-39 and CCK-8, on basal and stimulated insulin secretion.

The effects of two different cholecystokinin variants, CCK-39 and the carboxyl-terminal octa-peptide CCK-8, on basal and stimulated insulin secretion were studied in the mouse. It was found that both peptides had a dose-dependent stimulating action on insulin secretion with a maximal response of similar magnitude at a dose level of about 5 nmol/kg body weight. This dose induced an increase of plasma concentrations of immunoreactive insulin of about 100 microU/ml. The calculated half-maximal dose was 2.12 nmol/kg for CCK-39 and 3.18 nmol/kg for CCK-8. The insulin-secretory response to CCK-39 and CCK-8 in the absence of other secretagogues was partially abolished by pretreatment with the cholinergic blocker methylatropine as well as with the beta-adrenoceptor blocker L-propranolol. Thus, this great insulin-secretory response to the two peptides seemed to be dependent on intact muscarinic and beta-adrenergic receptors. CCK-39 or CCK-8 administered in a threshold dose prior to half-maximal doses of D-glucose, the cholinergic agonist carbachol, or the beta-adrenergic agonist L-isopropylnoradrenaline (L-IPNA), respectively, displayed different influences on insulin release. CCK-39 potentiated glucose- as well as carbachol-induced insulin secretion, whereas it did not influence L-IPNA-induced insulin release. An equimolar dose of CCK-8, on the contrary, had no apparent effect on either glucose-, carbachol-, or L-IPNA-induced insulin release. This observation indicates that stimulated insulin release is influenced by amino acid sequences other than those of the C-terminal octapeptide in CCK-39 and that the response of the stimulated insulin-secreting cells to CCK-39 is dependent on the nature of the secretagogue.

Effects of autonomic blockade by methylatropine and optical isomers and propranolol on plasma insulin levels in the basal state and after stimulation.

The effects of autonomic blockade on plasma concentrations of immunoreactive insulin in the basal state and after stimulation with 4 different secretagogues were investigated in vivo in conscious mice. The muscarinic blocker methylatropine slightly depressed basal insulin, and almost totally abolished the insulin response to the cholinergic agonist carbachol, whereas the insulin response to glucose and glucagon was unaffected. Contrary to these findings, the insulin response to the beta 2-adrenoceptor agonist terbutaline was potentiated, by about 75%. The beta-adrenoceptor blocker L-propranolol depressed basal insulin by about 60%, and totally abolished the insulin responses to glucagon and terbutaline. The insulin response to glucose was slightly reduced and that to carbachol was unaffected by L-propranolol. The stereoisomer D-propranolol which is devoid of beta-adrenoceptor blocking activity but exerts local anaesthetic effect of the same potency as the Lpisomer, was without effect on basal insulin levels and the insulin responses to the different secretagogues. It is concluded that basal concentrations of immunoreactive insulin is substantially dependent on intact beta-adrenoceptors and more moderately dependent on intact muscarinic receptors. The insulin responses to terbutaline and glucagon are closely connected to beta-adrenoceptors, and the response to carbachol to the muscarinic receptors. Glucose-induced insulin response seems largely unaffected by autonomic receptor blockade although a slight reduction after beta-adrenoceptor blockade is demonstrable.

Insulin resistance in soleus muscle from obese Zucker rats. Involvement of several defective sites

1. The effect of insulin upon glucose transport and metabolism in soleus muscles of genetically obese (fa/fa) and heterozygote lean Zucker rats was investigated at 5-6 weeks and 10-11 weeks of age. Weight-standardized strips of soleus muscles were used rather than the intact muscle in order to circumvent problems of diffusion of substrates. 2. In younger obese rats (5-6 weeks), plasma concentrations of immunoreactive insulin were twice those of controls, whereas their circulating triacylglycerol concentrations were normal. Insulin effects upon 2-deoxyglucose uptake and glucose metabolism by soleus muscles of these rats were characterized by both a decreased sensitivity and a decrease in the maximal response of this tissue to the hormone. 3. In older obese rats (10-11 weeks), circulating concentrations of insulin and triacylglycerols were both abnormally elevated. A decrease of 25-35% in insulin-binding capacity to muscles of obese rats was observed. The soleus muscles from the older obese animals also displayed decreased sensitivity and maximal response to insulin. However, at a low insulin concentration (0.1m-i.u./ml), 2-deoxyglucose uptake by muscles of older obese rats was stimulated, but such a concentration was ineffective in stimulating glucose incorporation into glycogen, and glucose metabolism by glycolysis. 4. Endogenous lipid utilization by muscle was calculated from the measurements of O(2) consumption, and glucose oxidation to CO(2). The rate of utilization of fatty acids was normal in muscles of younger obese animals, but increased in those of the older obese rats. Increased basal concentrations of citrate, glucose 6-phosphate and glycogen were found in muscles of older obese rats and may reflect intracellular inhibition of glucose metabolism as a result of increased lipid utilization. 5. Thus several abnormalities are responsible for insulin resistance of muscles from obese Zucker rats among which we have observed decreased insulin binding, decreased glucose transport and increased utilization of endogenous fatty acid which could inhibit glucose utilization.

The effects of levodopa on plasma glucose in two strains of rat

The effects of levodopa on plasma glucose were examined in two strains of rats. In fasted Wistar rats levodopa produced a dose-dependent hyperglycaemic response which was augmented by pretreatment with nialamide. This response in nialamide-treated rats was prevented by pretreatment with phentolamine and converted to a hypoglycaemic response. Phentolamine increased the plasma concentration of immunoreactive insulin (IRI). In phentolamine-pretreated rats levodopa produced a further marked increase in the plasma IRI concentration. It is suggested that the prevention of levodopa hyperglycaemia by phentolamine is due to the marked increase in the plasma IRI concentration produced by pretreatment with phentolamine. Moreover the fall in the plasma glucose concentration produced by levodopa in phentolamine-pretreated rats is likely to be due, at least in part, to the additional increase in the plasma IRI concentration produced by levodopa under these conditions. In contrast, in fasted Sprague-Dawley rats pretreated with nialamide, levodopa produced either no effect on plasma glucose, or in larger doses, a marked hypoglycaemic effect followed by death. This hypoglycaemic effect was accompanied by a decrease in the plasma IRI concentration.

Validation of I.V. small-dose insulin infusion therapy in diabetic ketoacidosis of depancreatized dogs.

A validation of small-dose insulin infusion therapy was studied by the constant i.v. infusion of various doses of insulin into ketoacidotic depancreatized dogs. Constant insulin infusion of 5 x B, 10 X B, 30 X B and 50 X B (B = 225 microunit/kg/min) was performed for 3 h by mechanical pump. The following results were obtained: (1) plasma concentrations of immunoreactive insulin (IRI) increased proportionally to the dose of infused insulin, but the higher IRI did not result in a greater fall in plasma glucose concentration, correspondingly; the mean rate of fall in plasma glucose concentration of 5 x B was not significantly lower than that of 50 x B; beta-hydroxybutyrate and arterial pH improvements were observed in each group during the 3-h insulin infusion. These data suggested that for the improvement of diabetic ketoacidosis, the insulin infusion rate of more than 30 x B, which raised the plasma IRI levels above the physiological range, was not essential; (2) the necessity of potassium supplementation during the small-dose insulin infusion was suggested if the pre-treatment level of serum potassium was low. These results confirmed that in the absence of infection or severe acidosis small-dose insulin infusion therapy is as effective as the conventional large-dose insulin therapy.

Suppression of insulin secretion during induced hypocalcemia.

A requirement of calcium ion for normal insulin secretion in the pig during the intravenous glucose tolerance test (IGTT) was demonstrated in vivo. In the normocalcemic state, plasma concentrations of immunoreactive insulin (IRI) usually increased 4- to S-fold during the IGTT. However, increases in plasma concentrations of IRI during the IGTT were barely detectable in pigs with hypocalcemia. Intravenous infusions of glucose and calcium borogluconate simultaneously in hypocalcemic pigs resulted in an immediate rise in plasma concentrations of IRI. (Endocrinology 93: 761, 1973)

Hormonal control of intermediary metabolism in obese hyperglycemic mice. II. Levels of plasma free fatty acid and immunoreactive insulin and liver glycogen.

In mice with genetic obesity, the plasma concentration of total free fatty acid (FFA) was not significantly raised, and no abnormality was detected in the response of the plasma level of FFA to noradrenaline. The plasma concentration of immunoreactive insulin (IRI) in the fed state was higher in obese than lean mice, even if glucose was given to lean mice. The content of liver glycogen was consistently higher in obese mice. Following deprivation of food, plasma concentration of IRI decreased in obese mice, and that of FFA rose at the same rate as in lean mice. In obese mice which had been fasted for twenty-four hours or fed on a restricted quantity of food, the plasma level of IRI remained higher than in lean mice. On oral administration of glucose to fasted mice, the decline in plasma FFA concentration, compared to that in animals which received saline, was similar in obese and lean mice. In response to glucose, the plasma IRI concentration increased rapidly in obese mice. These results suggest that there is no primary impairment of adipose tissue triglyceride breakdown (“lipolysis”) in genetically obese mice, and that the hypersecretion of insulin in response to ingestion of food may more closely reflect their primary disorder.

Effect of diuretics on mouse blood sugar following single dose administration.

1. Frusemide, in doses which were maximal or supramaximal in respect of its natriuretic, diuretic and kaliuretic properties, produced a dose dependent, transient hyperglycaemic response in the mouse.2. Bilateral nephrectomy resulted in a complete abolition of the hyperglycaemic response.3. The hyperglycaemic response was accompanied by a decrease in liver glycogen and was significantly attenuated by adrenalectomy, adrenal demedullation and pretreatment with dihydroergotamine (DHE).4. In the nephrectomized mouse frusemide treatment produced a marked reduction in intravenous glucose tolerance and a reduction in the plasma concentration of immunoreactive insulin following glucose administration. The drug had no detectable effect upon insulin sensitivity.5. Hydrochlorothiazide exerted no detectable effect on mouse blood sugar.6. Ethacrynic acid hyperglycaemia was obtainable after intraperitoneal or intramuscular injection, but not after intravenous injection. Intravenously administered ethacrynic acid exerted no effect upon intravenous glucose tolerance or insulin sensitivity in the nephrectomized mouse.

Glucose intolerance in nonischemic cardiac disease. Role of cardiac output and adrenergic function.

To investigate hemodynamic and neurohumoral factors as a basis for glucose intolerance in cardiac patients without ischemic heart disease, intravenous glucose tolerance tests were performed on 70 patients aged 14 to 69 years. The mean glucose fractional disappearance rate (G k ) for 41 patients less than age 50 was 1.19 ± 0.07% fall in glucose/min, while in 19 normal subjects, it was 1.60 ± 0.14, P &lt;0.01. The decreased G k was independent of age and lipid levels, and was directly related to a reduced plasma concentration of immunoreactive insulin. The glucose response to tolbutamide of 40 patients was similarly reduced and correlated with G k . Since enhanced adrenergic stimulation may be present in cardiac patients with resultant reduction of insulin secretion, the effects of alpha-and beta-adrenergic blockade were examined in two groups of cardiac patients. G k was unchanged after administration of phenoxybenzamine and propranolol. Since a reduced cardiac output correlated with diminished G k , the influence of sustained improvement after corrective cardiac surgery was evaluated in 13 patients. Postsurgical increments of resting cardiac output were usually associated with lower fasting insulin levels, enhanced clearance of administered glucose, and a more rapid rise of plasma insulin to higher peak levels, followed by a relatively rapid decline. Enhanced insulin response to tolbutamide after surgery in seven of these patients was also demonstrated. It is suggested that chronically reduced levels of cardiac output can result in reduced insulin secretion and in glucose intolerance and that these may be reversed with improved cardiac function.