Simultaneous Infusion Of Glucose Research Articles

Intracerebroventricular infusion of bombesin modulates GIP secretion in conscious dogs

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin with important role in glucose homeostasis and energy conservation. Thus far, the neural mechanisms involved in the regulation of GIP secretion, have not yet been fully elucidated. The aim of this study was to evaluate a possible effect of intracerebroventricular administration of Bombesin in the regulation of GIP secretion. Methods Thirty-two adult dogs were used in this study. In group 1 the animals received a bolus icv infusion of 200 ng bombesin or an equivalent amount of artificial cerebrospinal fluid (aCSF). In group 2 the animals received a continuous icv infusion of bombesin or aCSF over a 3-h period. In group 3 the experiment of group 2 was repeated with a simultaneous intraduodenal infusion of a glucose load through the Mann–Bollman fistula. Blood samples were taken from cannulation of a hind limb and plasma levels of glucose, insulin and GIP were assayed. Results Bolus icv infusion of bombesin produced an increase in glucose and GIP levels without a respective increase in plasma insulin levels. Continuous icv infusion and the simultaneous infusion of glucose intraduodenally increased significantly GIP, glucose and insulin levels. Conclusions Intracerebroventricular levels of bombesin seems to involve in the neural regulation of GIP secretion independently of the presence of nutrients and to potentiate GIP secretion during a glucose load.

Preclinical safety and antitumor efficacy of insulin combined with irradiation

Background and purpose We have previously reported that insulin significantly enhances tumor oxygenation ( pO 2) and increases radiation-induced tumor regrowth delay in experimental models. Considering the large radiosensitizing effect, clinical trials might be envisioned. The aim of the present pre-clinical study was to obtain a more complete set of safety and efficacy data which would further justify the commencement of such clinical trials. Material and methods Toxicity on normal (early and late-responding) tissues was measured by the intestinal crypt regeneration assay and the late leg contracture assay. Efficacy in terms of enhancement of pO 2 (measured by in vivo EPR oximetry) and increase in radiation-induced tumor regrowth delay was evaluated with a dose–response study on mice bearing FSaII fibrosarcoma. Results The effect on regrowth delay was directly correlated with the effect on the tumor pO 2, with a maximal effect using 400 mU kg −1 insulin. Importantly, there was no increase in the radiation toxicity for normal tissues. Finally, we found that the hypoglycaemia induced by insulin can be corrected by simultaneous glucose infusion without modification of efficacy. Conclusion Insulin here demonstrated a therapeutic gain and a lack of toxicity to normal tissues. The results of this study fully justify further larger preclinical assays such as the use of fractionated irradiation and a tumor control dose assay, before determining the utility of insulin as a radiosensitizer for human patients in the clinic.

Efeitos da metformina na disfunção endotelial da circulação renal induzida pela hiperglicemia em coelhos não diabéticos

To assess the effects of metformin (Met) on the endothelial dysfunction of the renal circulation of non-diabetic rabbits acutely induced by levels of glucose usually observed in diabetic patients in daily clinical practice. Isolated perfused kidneys from non-diabetic rabbits were exposed for 3 h to normal (100 mg/dl--control group) or high (270 mg/dl) D-glucose with or without Met (100 microM). The glucose levels used correspond to 2 h post-breakfast median values (272 mg/dl) obtained from a cohort of 780 type 2 diabetic (DM2) outpatients seen in our service. Vascular reactivity was evaluated with endothelium-dependent (ED) [acetylcholine-ACh] and independent (EI) [sodium nitroprusside-SNP] vasodilating agents. Kidneys perfused with high glucose had ED maximal vasodilation blunted in comparison to controls (respectively 25 +/- 3 and 41 +/- 3%; p < 0.01). A 3 h Met infusion restored the vasodilating effect of ACh in the renal circulation in the presence of high glucose, no different from controls (respectively 43 +/- 1.5 vs. 41 +/- 3% p > 0.05). Met did not affect maximum vasodilation induced by ACh in the presence of normal glucose levels. Finally, renal vasodilation induced by SNP was not modified by simultaneous infusion of glucose and Met. Acute hyperglycemia corresponding to the range observed in patients with DM2 induces endothelial dysfunction in the renal circulation of normal rabbits. Acute treatment with Met was able to protect the renal circulation against the effects of high glucose. The mechanisms involved in this protector effect deserve further investigation.

Changes in blood pressure and plasma catecholamine levels during prolonged hyperinsulinemia

Hyperinsulinemia has been shown to induce activation of the sympathetic nervous system and vasodilatation. Whether these effects result in changes in blood pressure (BP) is discussed controversially. We measured BP and plasma catecholamine levels in 30 healthy men during a 60-minute baseline phase and 360-minute period of insulin infusion. In a double-blind, between-subject comparison, insulin was infused at a low rate (1.5 mU insulin/kg per minute) in one half of the subjects and at a high rate (15 mU/kg per minute) in the other half. Throughout the experiments, blood glucose levels were held constantly within the normal range by a simultaneous infusion of glucose. Serum insulin levels increased to a plateau of 543 ± 34 pmol/L during low rate and to 24 029 ± 1595 pmol/L during high rate of insulin infusion. Compared with baseline, insulin infusion of either rate significantly increased systolic BP, BP amplitude, and heart rate (all P < .05). In comparison with the low rate of insulin infusion, the high rate provoked a more pronounced increase in heart rate ( P < .02) and systolic BP ( P < .05) but tended to decrease diastolic BP ( P < .08) summing up to a distinctly more increased BP amplitude ( P < .05). Plasma norepinephrine as well as epinephrine levels did not significantly change during the low-rate insulin infusion but significantly increased during high-rate insulin infusion (both P < .05). By showing a dose-dependent increasing influence of insulin on systolic BP and circulating catecholamine levels, the present study provides experimental evidence for the notion that hyperinsulinemia contributes to the development of hypertension.

Endothelin-1 Induces Insulin Resistance in Conscious Rats

Since endothelin-1 (ET-1) might regulate insulin secretion and glucose metabolism, we carried out experiments to study the effect of ET-1 in conscious rats by injecting ET-1 (0.5 or 1.0 μg/100 g body weight, i.p.) and examining the plasma glucose (PG) and insulin (PI) concentrations and PG/PI ratios continuously for 3 hours after the injection. Compared to the saline controls, ET-1 increased PG and PG/PI ratios in a dose-dependent manner. Oral glucose tolerance test (OGTT) performed at 30 min after the injection showed that PG levels stayed significantly higher in rats preinjected with ET-1 than rats with saline injection, although the change in PI levels was not different. Simultaneous infusion of glucose and insulin to somatostatin-primed rats with ET-1 or saline injection resulted in significantly higher steady state plasma glucose (SSPG) levels and SSPG/PI ratios in rats injected with ET-1 than control rats with saline. These results unequivocally indicated that intraperitoneally administered ET-1 induces insulin resistance in conscious rats.

Effects of hyper- and hypoglycemia on blood growth hormone level in free-feeding rats with anterolateral deafferentation of the medial basal hypothalamus

In rats with anterolateral deafferentation of the medial basal hypothalamus, the growth hormone (GH) level in the blood showed irregular and small fluctuations instead of the usual high bursts and low trough level, and the baseline GH level was higher than that in sham-operated rats. Continuous infusion of a glucose solution to operated rats increased the baseline level, GH pulse and pulse amplitude. I.v. bolus injection of the glucose solution resulted in a significant but transient increase in GH level. Insulin-induced hypoglycemia decreased the blood GH level in operated rats more effectively than in sham-operated ones and that was prevented by simultaneous infusion of glucose. Since SS influence on GH secretion had been largely eliminated in rats with anterolateral deafferentation of the medial basal hypothalamus, it is highly unlikely that the effects of hyperglycemia or hypoglycemia on GH secretion were the consequence of altered SS secretion.

Coordinate regulation of amylin and insulin expression in response to hypoglycemia and fasting.

Amylin is a 37-amino acid peptide synthesized in the pancreatic beta-cell and cosecreted with insulin. In situ hybridization of nondiabetic rat pancreas shows that insulin and amylin RNA are both localized within the islet of Langerhans in a similar distribution. After 12 days of insulin-induced hypoglycemia (mean blood glucose 3.0 +/- 0.4 mM [54 +/- 8 mg/dl]), both insulin and amylin RNA fell greater than 95%. However, maintenance of euglycemia by simultaneous infusion of glucose with insulin did not suppress insulin or amylin RNA. Fasting suppressed amylin and insulin secretion from the isolated, perfused pancreas 70 and 58%, respectively, and with refeeding, secretion rates recovered to fed levels. Despite these changes in the rates of secretion, the relative ratio of amylin to insulin was not significantly different in fed, fasted, or refed rats. The molar ratio of insulin to amylin was estimated to be 100:2.3-2.6. Both insulin and amylin RNA was suppressed approximately 50% in response to fasting. Thus, although the absolute amounts of insulin and amylin change substantially under the conditions tested, the relative amounts of these peptides do not change.

Effect of synthetic human glucose‐dependent insulinotropic polypeptide (hGIP) on the release of insulin in man

During an oral glucose tolerance test (oGTT) and an isoglycaemic intravenous glucose infusion, blood glucose and the responses of insulin and glucose-dependent insulinotropic polypeptide (GIP) were measured in six healthy volunteers. On a subsequent occasion a constant infusion of human synthetic GIP (2 pmol kg-1 min-1 for 30 min and 0.5 pmol kg-1 min-1 for another 30 min was given to each subject, again with a simultaneous infusion of glucose to maintain isoglycaemia to the oGTT. During the oGTT, plasma GIP concentrations rose from 92 +/- 18 pmol 1(-1) to 257 +/- 42 pmol 1(-1) 60 min after ingestion of glucose (mean +/- SEM). When glucose was administered intravenously plasma GIP levels did not rise significantly over basal. The infusion of hGIP mimicked the physiological plasma GIP response after oral glucose during the first 60 min of the study. Plasma insulin concentrations were significantly lower between 45 and 60 min than during the oGTT (438 +/- 67 vs. 200 +/- 48 pmol 1(-1); P less than 0.02; 465 +/- 96 vs. 207 +/- 48 pmol 1(-1); P less than 0.01). However, the total and incremental integrated insulin responses during the first 60 min of the study were, though lower, not significantly different from the oGTT experiment when glucose and hGIP were infused simultaneously. Thus, in the presence of mild physiological hyperglycaemia, human GIP is able to enhance the initial insulin response almost equivalently to the stimulus provided by oral glucose. Decreased insulin concentrations during porcine GIP infusions in previous experiments might be due to sequence differences between human and porcine GIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism of intravenously administered maltose in renal tubules in humans

To investigate how urinary excretion rates (UERs) of maltose and glucose are determined after intravenous maltose infusion, maltose and glucose solutions were infused at various rates and the relationships between UERs of maltose and glucose and their plasma concentrations were examined. Results showed the existence of a threshold plasma maltose concentration for the urinary excretions of maltose and glucose and the existence of a maximum rate of urinary glucose excretion after maltose infusion. Elevation of plasma glucose concentration by simultaneous glucose infusion increased urinary glucose excretion but did not increase urinary maltose excretion; the relationship between plasma total sugar concentration and urinary total sugar excretion was unchanged. Results suggest that maltose administered intravenously is hydrolyzed to glucose by maltase in renal tubules and reabsorbed as glucose competitively with glucose derived from plasma and that the maximum utilization of intravenously infused maltose is determined by the tubular glucose reabsorption capacity.

ALCOHOL DECREASES INSULIN SENSITIVITY IN HEALTHY SUBJECTS

To study the effect of alcohol on glucose and insulin metabolism, a simultaneous infusion of glucose and insulin was given for 150 min to healthy volunteers, once during alcohol and once during calorie-free gingerale (control) ingestion. During alcohol intake, the average steady-state (between 100 and 150 min) glucose of 5.44 +/- 0.39 mmol/l. and the average steady-state insulin of 6.3 +/- 1.1 ng/ml were significantly higher than those (4.0 +/- 0.39 mmol/l. of glucose and 4.4 +/- 0.6 ng/ml of insulin) observed during the control state. Despite the higher steady-state insulin concentrations, the glucose metabolism was significantly less during alcohol ingestion. These findings suggest alcohol-induced impairment in glucose metabolism is caused by a decreased tissue sensitivity to insulin.

Regulation of urea production by glucose infusion in vivo.

We have investigated the acute in vivo regulation of urea production in normal postabsorptive volunteers by administering a primed constant infusion of 15N2-urea to measure urea production during the constant intravenous infusion of equivalent molar quantities of exogenous nitrogen, given as alanine or glutamine, either with or without a simultaneous infusion of glucose at 4 mg.kg-.min-1. These responses were compared with the response to the infusion of glucose alone. Both amino acid infusions elicited significant (P less than 0.05) and identical (26%) increases in urea production over 4 h. When the glucose infusion was added to the amino acid infusions, urea production remained constant, despite the comparable increases in plasma total nonessential amino nitrogen, as were observed with the amino acid infusions alone. Glucose infused alone elicited a significant (P less than 0.05) reduction (18%) in urea production but no corresponding change in plasma total amino nitrogen. We conclude that 1) infused glucose or its hormonal response suppresses urea production by blunting the normal hepatic ureagenic response to a fixed nitrogen load, 2) this suppressive effect is not mediated via a reduction in substrate (nitrogen) supply, and 3) the inhibition of hepatic gluconeogenesis from amino acids represents one component of this suppressive effect, and direct suppression of urea cycle activity probably represents another component.

Effects of sauna and glucose intake on TSH and thyroid hormone levels in plasma of euthyroid subjects

The effect of sauna on thyroid function parameters and its modification by glucose was studied in young euthyroid male volunteers. A 30-minute stay in sauna resulted in an increase in plasma TSH; the response was exaggerated if glycemia had been increased by oral glucose intake at the beginning of the experiment. Plasma rT 3 also increased in sauna, this response was, however, blunted by the higher glycemia. TSH response to sauna was definitely present in young men (aged 20 to 25) and absent in middle-aged ones (50 to 55). To explore the mechanism of the effect of increased glycemia, TRH tests were performed and dopamine infusions were administered with and without glucose pretreatment. Increased glycemia did not affect TSH and T 3 response to TRH in young volunteers; however, 90 minutes after the administration, plasma rT 3 levels were significantly lower in glucose pretreated subjects than in those receiving TRH injections after water pretreatment. Simultaneous infusion of glucose prevented the inhibitory effect of dopamine infusion on plasma TSH. It was concluded that glucose directly modulates the effect of sauna on plasma TSH at a suprapituitary level, while the inhibiting effect of glucose on plasma rT 3 response to sauna and TRH is probably mediated by the insulin effect on thyroid hormone metabolism.

Insulin receptors and insulin sensitivity in normo and hyperinsulinemic obese patients.

The authors have studied insulin receptors on peripheral blood monocytes and insulin sensitivity, evaluated by simultaneous infusion of glucose, insulin and somatostatin in 10 control subjects and in 20 obese patients with normal glucose tolerance. The obese patients have been divided into two groups, normo (NO) and hyperinsulinemic (HO), according to the total insulin response during OGTT. We considered HO patients with insulin response higher than M + 2DS of controls. Obese patients showed, in comparison to the controls, a lower specific binding and higher degree of insulin resistance. The subdivision of obese patients allowed us to distinguish two groups. The first was characterized by basal hyperinsulinemia, normal insulin response to the stimulus, reduced number of insulin receptors and normal or slightly reduced sensitivity. The second group showed high basal and after stimulus insulinemic values, reduced number of insulin receptors and high level of insulin resistance. When we compared the two groups of obeses we found that the first has a shorter duration of obesity and lower blood glucose values after OGTT. However both groups show the same reduction of insulin bound and the same degree of basal hyperinsulinemia. These data suggest that a reduction of insulin receptors is not the main factor responsible for insulin resistance in obesity. Furthermore, the presence of basal hyperinsulinemia and normal insulin sensitivity in our first group suggests that the modification of basal insulin concentrations is not dependent on the presence of insulin resistance.

Effect of fat emulsions containing medium-chain triglycerides and glucose on ketone body production and excretion.

The parenteral application of fat emulsions containing medium-chain triglycerides results in an increase of ketone bodies as expression of the rapid metabolism of medium-chain triglycerides. Although ketoacidosis could not be watched, it should be of advantage to reduce the ketonemia. This might be reached by application of carbohydrates. The simultaneous infusion of glucose--given to 10 healthy persons--together with a 10% fat emulsion containing 75% medium-chain triglycerides almost completely inhibited the increase of ketone bodies in serum and its urinary excretion. Other prosperous metabolic effects, eg, the rapid clearance of the triglycerides from the serum were not affected by this regimen.

Effects of hypertonic glucose on the rates of plasma clearance and CO2 production of intravenously administered intralipid emulsion in dogs.

Simultaneous infusion of glucose and Intralipid was carried out on dogs to evaluate the effect of glucose on utilization of the fat emulsion. For control experiments, normal saline was used in place of glucose. Results of these studies revealed that clearance of Intralipid and also of triglyceride and free fatty acid (FFA) from the plasma did not differ between the dogs receiving glucose and those receiving saline infusion. The rates of Intralipid clearance were 0.049 +/- 0.003 and 0.047 +/- 0.003 per minute (n = 16), respectively. Study with radioactive [14C]Intralipid also gave similar rates of 14C clearance from the plasma, 0.037 +/- 0.003 and 0.040 +/- 0.003 per minute (n = 4), respectively for the two groups. These suggested that clearance of Intralipid from the plasma was not affected by glucose. However, data on expired 14CO2 revealed that oxidation of the fat, which yielded CO2 as end product, was inhibited by glucose. The amount of 14CO2 expired in 2 hours was 10.4 +/- 1.4% for the saline group, which was significantly reduced to 3.0 +/- 0.4% (n = 4; p less than 0.01) for the glucose group. In each group, CO2 production was much delayed as compared to fat clearance from the plasma. Thus, the rate of clearance of Intralipid from plasma does not reflect the actual utilization of fat emulsion. In accordance with an experiment with insulin, it appears that suppression of CO2 production is directly related to plasma insulin levels.

Insulin infusion in conscious dogs. Effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines.

Cardiovascular actions of insulin were studied by intravenous infusions of insulin (4 and 8 mU/kg per min) in normal conscious dogs. This resulted in increases in cardiac output, heart rate, and left ventricular derivative of pressure with respect to time (dP/dt) and dP/dt/P, as blood glucose was reduced. The inotropic and chronotropic effects of insulin were not related to hypoglycemia, as they persisted even when blood glucose was restored to control values or when it was prevented from falling by a simultaneous infusion of glucose. These cardiac effects were accompanied by increases in plasma catecholamines, and were abolished by propranolol pretreatment. Both plasma epinephrine and norepinephrine increased during insulin hypoglycemia, but only norepinephrine increased during insulin infusion when euglycemia was maintained. Mean arterial blood pressure did not change significantly during insulin hypoglycemia, but rose if euglycemia was maintained, probably due to the selective increase in norepinephrine in the latter condition. A pressor response also occurred in propranolol-pretreated dogs during insulin hypoglycemia, but was abolished when the animals also had been pretreated with phentolamine, indicating that the vasoconstrictor action of insulin was mediated via alpha adrenergic receptors. Insulin infusion increased left ventricular work and myocardial blood flow in dogs with and without hypoglycemia. Myocardial blood flow, however, did not change significantly during insulin infusion in dogs pretreated with propranolol. As propranolol also diminished the inotropic response, it appears that the increase in myocardial blood flow caused by insulin in the normal dog is causally related to the increased myocardial metabolic demand. Insulin also produced vasomotor effects on other vascular beds. In skeletal muscle, blood flow was increased under all study conditions, except during insulin hypoglycemia after propranolol-pretreatment when unopposed alpha-mediated vasoconstriction was present. The persistent increase in flow during both alpha and beta adrenergic blockade suggests that insulin has a direct dilator effect on skeletal muscle vasculature. In the adrenal gland, flow was increased except during euglycemia, when no rise in plasma epinephrine was observed, suggesting coupling between adrenal flow and catecholamine release. In the splanchnic bed, flow was decreased during euglycemia, when plasma norepinephrine rose, and during beta adrenergic blockade with propranolol, when unopposed alpha-mediated vasoconstriction also predominated. A similar pattern was found in the kidney, except that renal blood flow also fell after combined alpha and beta adrenergic blockade. The results show that the vasomotor effects on regional flows are mediated both via adrenergic mechanisms, and in the case of skeletal muscle and kidney, via mechanisms unrelated to sympathetic stimulation.

Effect of Caerulein upon Insulin and Glucagon Secretion in Dogs

In order to investigate the action of caerulein upon insulin and glucagon secretion, experimental studies were carried out using anesthetized dogs, in which graded doses of caerulein were infused into the pancreatic artery, and insulin and glucagon were measured in the blood obtained from the pancreatic vein. When caerulein was administered at a rate of 15 ng/min, neigher changes of blood glucose in the femoral artery nor plasma levels of insulin or glucagon in the pancreatic vein were prominent. Caerulein infusion at a rate of 120, 240 or 480 ng/min caused a prompt rise of plasma insulin and a delayed increase of plasma glucagon in the pancreatin vein. Blood glucose in the femoral artery increased only with caerulein doses of 240 ng/min or more. A significant increase in pancreatic vein blood flow rate was demonstrated after the infusion of caerulein at a rate of 240 ng/min or more. Neither caerulein-induced insulin secretion nor glucagon secretion was influenced by a simultaneous infusion of glucose. In contrast, caerulein-induced glucagon secretion was exaggreated by a simultaneous arginine infusion. It was concluded from the present experiments that caerulein infusion into the pancreatic artery resulted in increased secretion of insulin and glucagon from the pancreas.

Hypoglycaemic release of gastrin in man.

In order to study the nature of the release of gastrin by insulin, 8 unoperated ulcer patients were submitted to 2 insulin tests. After insulin an increase in serum gastrin concentrations from 117 + 16.1 to 162 + 15.2 pg per ml (53 to 73.6 pmol/1), mean + S. E. M., was found. Hypoglycaemia was prevented by simultaneous glucose infusion during the second test, which showed no increase in serum gastrin concentrations. The role played by the antrum was evaluated in 15 patients treated with resection of the distal part of the stomach, and in 3 patients treated with resection of the upper part of the stomach. After insulin no increase was found in the former, while a definite increase was found in the latter patients. It is suggested that the gastrin response to insulin is caused by hypoglycaemia, and that it is of antral origin.

Studies of pancreatic alpha cell function in normal and diabetic subjects.

The development of a glucagon radioimmunoassay with a relatively high degree of specificity for pancreatic glucagon made possible studies of alpha cell function in healthy nondiabetic subjects and in patients with diabetes mellitus. In the former group mean fasting plasma glucagon averaged 108 mumug/ml (SEM +/-10). In 12 juvenile-type diabetics fasting glucagon averaged 110 (+/-9) and in 33 adult-type diabetics the average was 114 (+/-8). The diabetic averages did not differ significantly from the nondiabetic subjects; however, when hyperglycemia was induced by glucose infusion in the nondiabetic subjects so as to simulate the fasting hyperglycemia of the diabetics, mean glucagon fell to 57 mumug (+/-8), which was significantly below the diabetic mean. In 28 healthy subjects the infusion of arginine elicited a rise in glucagon of at least 100 mumug/ml with a peak level averaging 331 mumug/ml (+/-22) at 40 min. This response to arginine was diminished but not abolished during hyperglycemia induced by simultaneous glucose infusion. In everyone of 45 diabetic subjects tested the infusion of arginine elicited a rise in glucagon of at least 140 mumug/ml to levels significantly greater than in nondiabetics. The peak glucagon level in juvenile-type diabetics averaged 458 mumug/ml (SEM +/-36) and in adult-type diabetics averaged 452 mumug/ml (SEM +/-38). The glucagon response to arginine was unrelated to duration of diabetes, to body weight, type of diabetic treatment, or to other known factors. Marked hyperresponsiveness of glucagon to arginine infusion was observed in two patients with advanced Kimmelsteil-Wilson disease. Glucagon levels were markedly elevated in certain patients with severe diabetic ketoacidosis before treatment with insulin. The findings suggest that alpha cell function is inappropriately increased in diabetes mellitus and could play a significant role in the diabetic syndrome.

Studies in Vivo and in Vitro of Glucose-Stimulated Insulin Release: The Effects of Metabolizable Sugars, Tolbutamide, and 2-Deoxyglucose

The role of glucose as a stimulant to pancreatic insulin release was studied in the intact dog and in rat pancreas incubated in vitro. The infusion of the metabolizable sugars, glucose, fructose, and mannose, as well as tolbutamide into the pancreatico-duodenal and splenic arteries in the anesthetized dog resulted in increased portal vein insulin-like activity, using the epididymal fat pad assay. Normal saline and pyruvate infusions resulted in no significant increase in insulin-like activity. Infusion into the dog of the glucose analogue, 2-deoxyglucose, at high concentration resulted in no stimulation of insulin release, but in fact blocked the pancreaic response to simultaneous glucose infusion. It appeared that the ratio of glucose: 2-deoxyglucose was a determinant in the degree of inhibition. Plasma ratios of &amp;lt; 1.5 resulted in inhibition. Incubation of rat pancreas with 2-deoxyglucose in the presence of glucose showed that 2-deoxyglucose inhibited the release of immunoassayable insulin. The inhibition was dependent upon the concentration of 2-deoxyglucose and the ratio of glucose: 2-deoxyglucose. In view of the metabolic blocking action of 2-deoxyglucose in the utilization of glucose-6-phosphate, it is suggested that the glucose stimulated insulin release occurs after the formation and further metabolism of glucoses-6-phosphate.