Immunoreactive Glucagon Levels Research Articles

Adrenergic Modulation of Pancreatic Hormone Secretion in Utero: Studies in Fetal Sheep

To assess the functional maturity of adrenergic modulation of plasma concentration of glucose, as well as immunoreactive glucagon (IRG) and immunoreactive insulin (IRI) secretion in utero, adrenergic agonists with or without beta (propranolol) or alpha (phentolamine) antagonists were infused to the chronically catheterized sheep fetus (n = 35) late in the third trimester. Mean +/- S.E. days at study was 129.5 +/- 1.5; term is 150 days. In 9 separate studies at gestational age 129 +/- 1 days, the infusion of saline for 3 hr was not associated with significant changes in the basal levels of glucose, IRG, or IRI. With epinephrine, 6 microgram/min (n = 6) glucose rose from 16.7 +/- 3.6 to 41.9 +/- 9.7 mg/dl, IRG rose from 75 +/- 8 to 219 +/- 45 pg/ml, and IRI fell from 22.6 +/- 1.7 to 12.7 +/- 3.5 microunits/ml (P less than 0.05 for each). Propranolol alone (n = 4) did not alter basal glucose or IRG but significantly suppressed IRI. Propranolol did, however, markedly attentuate the rise in glucose and IRG while exaggerating the fall in IRI during epinephrine infusion. Qualitatively similar but smaller responses were obtained with epinephrine, 0.4 microgram/min (n = 10). Similarly, elevation of glucose and suppression of IRI was obtained with norepinephrine, 2 microgram/min (n = 5), but IRG levels did not rise significantly. Alpha-Adrenergic blockade alone augmented IRI from 18 +/- 3 to 38 +/- 5 microunits/ml without affecting glucose or IRG concentrations; during alpha blockade, norepinephrine infusion failed to induce the rise in glucose, IRG remained unchanged, and IRI remained elevated (n = 5). 2-Deoxy-D-glucose, 200 mg IV over 30 min, did not affect glucose, IRG, or IRI (n = 5). Thus, appropriate adrenergic modulation of plasma concentrations of glucose, and of IRG and IRI secretion is established in the third trimester.

A decreased response of cyclic adenosine monophosphate concentrations to glucagon in liver slices from streptozotocin-induced diabetic rats.

Responses to glucagon from the adenylate cyclasecyclic adenosine monophosphate (cAMP) system in liver slices from control and streptozotocin-induced diabetic rats were compared. Tissue cAMP levels were similar in the basal state but responded poorly to glucagon (20 pg/ml-2 microgram/ml) in diabetic rats. Insulin treatment of diabetic rats in vivo led to a reversal of the glucagon stimulation towards the values in the control rats. The basal and glucagon-stimulated activities of adenylate cyclase in crude membrane fractions were similar in both groups. Plasma immunoreactive glucagon levels in diabetic rats were approximately three times higher than those in normal rats. Liver slices obtained from normal rats, which were injected with glucagon (0.2 mg, i.m.) 45 min previously, also showed an impaired responsiveness to glucagon of tissue cAMP levels, while no significant difference in adenylate cyclase activity was observed between the normal and glucagon-treated rats. These results suggest that the responsiveness of liver slices from the streptozotocin-induced diabetic rat has been modified by the preceding hyperglucagonemia. The reason for the observed differences between slices and crude membranes is not known.

The effect of long-distance running on plasma immunoreactive glucagon levels.

Twelve highly conditioned long-distance runners were studied to determine the effects of marathon (42 km) and 10,000 m running on plasma immunoreactive glucagon (IRG), serum immunoreactive insulin (IRI), and serum glucose (G) levels. Blood samples were drawn just prior to and immediately upon completion of the run. Marathon running resulted in no significant change in G, IRI, or IRG levels. After running 10,000 m, plasma IRG levels did not change significantly, while IRI and G increased significantly. In evaluating the pooled data from both runs, a significant inverse correlation was observed between delta G and delta IRG. This relationship between delta G and delta IRG suggests that glucagon plays a role in maintaining normal blood glucose levels during strenuous exercise.

The effect of glucose and tolbutamide on immunoreactive somatostatin release from perifused pancreatic islets of normal and streptozotocin diabetic rats.

The patterns of immunoreactive somatostatin (IRS) responses to glucose and tolbutamide were investigated in perifused pancreatic islets of both normal and diabetic rats.The incubation chamber of the perifusion apparatus for the islets was devised with a 2.5 ml disposable syringe. By the method of Lacy, the pancreatic islets were isolated from diabetic rats about 30 days after a single intravenous injection of streptozotocin (STZ, 60 mg/kg body weight) and from normal rats of comparable body weight. The fasting blood glucose was 437±3 mg/100 ml in the diabetic rats and 120±5 mg/100 ml in normal ones. The concentration of IRS in each effluent was measured by the specific double antibody radioimmunoassay for somatostatin.During the initial 20 min incubation period with the medium containing 2.8 mM glucose, the levels of IRS were 11.3±1.0 pg/100 islets/2 min in normal islets and 32.0±3.4 pg/100 islets/2 min in diabetic islets. The latter value was significantly higher than the former (p<0.001). IRS levels gradually rose following 16.7 mM glucose and reached the maximal values with 30.2±5.7 pg/100 islets/2 min at 66 min in normal islets and with 56.8±13.3 pg/100 islets/2 min at 88 min in diabetic islets. The levels of IRS in diabetic islets were significantly higher than those of normal islets (p<0.001) throughout the experimental period. In the case of tolbutamide the IRS levels increased promptly to 51.9±6.6 pg/100 islets/2 min in diabetic islets and to 23.7±4.6 pg/100 islets/2 min in normal islets 2 min after initiation of the infusion. The former value was significantly higher than the latter (p<0.001). The levels of immunoreactive glucagon (IRG) in response to tolbutamide were significantly higher in the diabetic islets than in normal islets (p<0.001). These results indicate that there exists a hypersecrecretion of IRS from STZ-induced diabetic rats during the infusion with glucose and tolbutamide.

A study of the physiological role of glucagon. Passive immunization with antiserum specific for pancreatic glucagon in rats.

To investigate the physiological role of glucagon in the maintenance of euglycemia, the effect of the neutralization of glucagon by an antiserum specific for glucagon on blood glucose and C-peptide immunoreactivity (CPR) levels was studied in the basal as well as in the hyperglucagonemic states caused by hypoglycemia or an intravenous infusion of arginine in rats. The antiserum employed in this study was raised in rabbits by subcutaneous injection as a conjugate of BSA and the C-terminal fragment of glucagon. Since the antiserum was found to contain 896 ng/ml of antibody-bound glucagon, the antigen-stripped glucagon antibody was prepared. Its affinity constant and binding capacity were 2.57 x 10(10) M-1 and 147 nM, respectively. After the administration of 1 ml of the antiserum in 24-hr-fasted rats, no free immuno reactive glucagon (IRG) was detected during the experiment for 60 min. Likewise, antiserum treatment prevented a rise in the plasma IRG level following an arginine infusion and insulin-induced hypoglycemia. Plasma CPR levels tended to be lower in antiserum-treated rats than in the control in any conditions covered by the present study. However, changes in blood glucose levels the both groups were comparable. These results demonstrate that in the presence of glucagon antibodies euglycemia can be maintained with a reduced supply of insulin.

Studies on glucagon secretion in obese rats with hypothalamic lesions (author's transl)

Glucagon secretion was studied in rats with electrolytic lesions of the bilateral ventromedial hypothalamic area (VMH-L) under various experimental conditions. The results obtained are as follows: 1. The basal plasma level of immunoreactive glucagon (IRG) was lowered in VMH-L rats 5 and 10 weeks after the operation. Plasma IRG levels after 24-hour starvation and during the arginine load were more significantly decreased in the VMH-L rats than in the control group. 2. The basal plasma level of immunoreactive insulin (IRI) showed significant positive correlations with body weight and Lee's index in these rats. The basal plasma level of IRG showed significant negative correlations with body weight, Lee's index and basal plasma IRI level. 3. In response to the arginine load, the plasma IRI level was significantly increased in VMH-L rats immediately after the operation, and the plasma IRG level was more significantly decreased in VMH-L rats 1 week after the operation than in the control group. 4. The response of plasma IRG to the arginine load was also lowered more in VMH-L rats than in rats pair-fed for 4 weeks after the operation. 5. 15 weeks after the operation, there was no significant difference in response of plasma IRI and IRG to the subcutaneous injection of epinephrine between VMH-L and control rats. These findings indicate that hypoglucagonemia in the VMH-L rats was induced by various factors, such as disorder of the autonomic nervous system, excessive insulin release, etc. The impairment of glucagon secretion may contribute to the development of obesity observed in rats with VMH-lesions.

AN‘ARTIFICIAL BETA CELL’FOR CONTROL OF DIABETES MELLITUS: EFFECT ON PLASMA GLUCAGON LEVELS

We have investigated the use of a glucose-controlled insulin infusion system, or artificial beta cell. On the feedback day, mean plasma glucose was significantly effect of improved control on plasma glucagon levels. Five insulin-requiring diabetic subjects in stable control were hospitalized for two 24 h periods. During one, they were given their usual dose(s) of subcutaneous insulin. In the other, the 'feedback' day, insulin administration was under feedback control by the artificial beta cell. One the feedback day, mean plasma glucose was significantly-lower in all subjects. Variability in plasma glucose throughout the day was also significantly less on the feedback day. All five subjects showed a significant fall in serum immunoreactive glucagon levels on the feedback day, suggesting that the glucagon abnormalities of diabetes may be secondary to the insulin deficiency, rather than a second primary defect of diabetes.

Changes in glucagon levels after four to five weeks of glucoregulation by portable insulin infusion pumps.

Near-normal glucoregulation was maintained in five patients with juvenile-onset diabetes mellitus for 4--5 wk with a preprogrammed, continuous, subcutaneous insulin infusion using a portable battery-powered infusion pump. This form of therapy significantly lowered immunoreactive glucagon (IRG) levels below those observed while on conventional insulin treatment at several times during the 24-h profile. The maximum IRG levels were also reduced in all five subjects. Thus, a flexible system of insulin delivery, as is provided by certain open-loop pump systems, can overcome inappropriate glucagon secretion that occurs with conventional insulin therapy.

Glucagon metabolism in normal subjects and in cirrhotic patients before and after portasystemic venous shunt surgery.

The effect of portasystemic shunt surgery on basal immunoreactive glucagon (IRG) levels, metabolic clearance rate (MCR) and t 1/2 for glucagon decay, and basal systemic delivery rate (BSDR) of glucagon was investigated in paired studies in ten cirrhotic subjects. The degree of hepatocellular dysfunction and extent of portasystemic venous shunting was also recorded. Basal IRG levels were highest in the post-shunt (mean +/- SEM, 382 +/- 73 pg/ml) as compared to the pre-shunt (213 +/- 27 pg/ml; P less than 0.05) cirrhotic and control (53 +/- 13 pg/ml; P less than 0.005) groups. The MCR of glucagon was similar in control (13.0 +/- 1.3 ml/kg/min) and pre-shunt cirrhotic patients (13.3 +/- 1.7 ml/kg/min) but was significantly (P less than 0.02) decreased in the post-shunt cirrhotics (7.6 +/- 1.3 ml/kg/min). The t 1/2 for glucagon decay was similar in the control and cirrhotic groups. The BSDR, an estimate of pancreatic A cell secretion, was increased four-fold (P less than 0.01) in the pre-shunt (3042 +/- 454 pg/kg/min) and post-shunt (2518 +/- 535 pg/kg/min) cirrhotic groups, as compared to controls (750 +/- 244 pg/kg/min). It is concluded that (a) in the presence of cirrhosis, the magnitude of portasystemic shunting is important in determining the degree of hyperglucagonaemia; (b) in preshunt cirrhotics raised basal IRG levels are principally due to A cell hypersecretion of glucagon whereas in post-shunt cirrhotics riased IRG levels reflect both A cell hypersecretion and delayed clearance of glucagon; and (c) acute shunting of splanchnic venous blood away from the liver reduces the clearance of glucagon, suggesting that, in man, the liver contributes to the clearance of circulating glucagon.

Effect of portasystemic venous shunt surgery on hyperglucagonaemia in cirrhosis: paired studies of pre- and post-shunted subjects.

The effect of liver disease on glucagon metabolism was examined in nine patients with chronic liver disease who were studied both before and after the creation of a surgical portasystemic shunt. Hepatocellular function did not deteriorate after shunt surgery. However, hepatic perfusion with splanchnic venous blood, as determined by scintisplenoportography, decreased after shunt surgery in six subjects but appeared unaltered in three. Basal plasma immunoreactive glucagon (IRG) levels in the pre-shunt cirrhotic group were significantly greater (p <0.005) than in control subjects and further increased (p <0.05) after shunt surgery. Moreover, the increase in basal IRG after shunt was evident only in patients in whom portasystemic shunting was demonstrably increased by surgery. Despite the higher basal IRG levels postoperatively, shunt surgery in the cirrhotics did not alter basal glucose and insulin levels or the glucose and insulin response to a glucose or protein load. Circulating IRG was heterogeneous in the pre-shunt cirrhotic patients: the 9000 molecular weight fraction comprised 27+/-4%, the 3500 mol. wt. fraction 71+/-4%, and the > 40 000 mol. wt. fraction was minimal. After shunt surgery, the relative proportion of the 9000 mol. wt. fraction of IRG (13+/-3%) decreased significantly (p <0.05) and this fall was associated with a corresponding increase in the 3,500 mol. wt. fraction (84+/-4%). It is concluded that, in cirrhosis, hyperglucagonaemia is: (1) dependent on the degree of portasystemic shunting rather than impaired hepatocellular function; (2) predominantly due to increased circulating 3500 molecular weight glucagon; and (3) not a major factor in the pathogenesis of carbohydrate intolerance in liver disease.

Altered regulation of pancreatic glucagon in male rats during aging

Immunoreactive pancreatic glucagon levels in portal vein blood following intragastric glucose administration were determined in fasted male Sprague-Dawley rats of 2-, 12-, and 24-months of age. Immunoreactive glucagon levels decline to less than one-half the fasting values in 2-month old rats following glucose administration, whereas immunoreactive glucagon levels increase two to three times the fasting values in 12- and 24-month old rats under the same conditions. Glucagon inhibits glucose-stimulated hepatic glucokinase adaptation and may interfere with insulin action in the regulation of hepatic glucose balance. Therefore, differences in the availability of glucagon may contribute significantly to delayed hepatic glucokinase adaptation in rats during aging.

Evaluation of the control of glucagon secretion by the parasympathetic nervous system in man

To evaluate the influence of the parasympathetic nervous system on human glucagon secretion, we have measured the plasma immunoreactive glucagon (IRG) levels after the administration of edrophonium, bethanechol chloride, and 2-deoxy-glucose, and have compared the IRG responses to hypoglycemia in normal, atropinized, and vagotomized man. Edrophonium administered i.v. and bethanechol chloride administered s.c. did not affect IRG levels. Two-deoxy-glucose resulted in symptomatic neuroglucopenia with resultant vagal discharge, as evidenced by increased gastric acid secretion; but no changes in IRG concentrations were observed. The IRG response to insulin-induced hypoglycemia in normal subjects was not influenced by the administration of atropine. In seven subjects with a truncal vagotomy and no increased gastric acid secretion during insulin-induced hypoglycemia, IRG increases were indistinguishable from those of control subjects in terms of timing, peak level obtained, or total glucagon response. We conclude that the cholinergic system is unlikely to play an important role in modulating glucagon secretion in man.

Effects of insulin on the response of immunoreactive glucagon to an intravenous glucose load in human diabetes

The effects of exogenous insulin upon the response of immunoreactive glucagon (IRG) to i.v. glucose were studied in diabetic and nondiabetic subjects. In nondiabetics, a rapid injection of 25 g of glucose lowered plasma IRG levels. In adult-onset diabetics, the glucose-induced decline in IRG was normal despite a subnormal glucose-induced insulin rise, in contrast to impaired IRG suppressibility previously reported when such patients received an oral glucose load. The magnitude of their glucose-induced IRG decline was not augmented by exogenous insulin, even when insulin levels were acutely raised above 300 μU/ml. In juvenile-type diabetics, basal IRG levels were normal following overnight insulin infusion, but the glucose-induced IRG decline was only half that of the nondiabetics. However, it became normal when hyperinsulinemia was acutely produced by supplementary insulin. Thus, whenever insulin levels rise in response to an increase in hyperglycemia, as they do spontaneously in nondiabetics and in adult-type diabetics and as they do when juvenile diabetics are given supplementary insulin together with the glucose bolus, the decline in IRG in response to an i.v. glucose load is as great as in nondiabetics. The findings are compatible with the view that glucose-induced suppression of IRG may require a concomitant rise in insulin.

Reduction of plasma triglyceride concentration by acute stress in man

Three different forms of stress all resulted in acute reduction of plasma triglyceride concentrations. Pyrogen reactions in two hypertriglyceridemic men resulted in the lowering of very-low-density lipoprotein (VLDL) triglyceride levels by 93% and 73% due to decreased secretion of this lipoprotein into plasma. More modest reductions in plasma triglycerides were observed after 2-deoxyglucose-induced intracellular glucopenia and insulin-induced hypoglycemia. With hypoglycemia, the lowering of plasma triglyceride concentration correlated significantly with the stimulation of urinary epinephrine output ( r = 0.86) but with neither the urinary norepinephrine response nor with the increase in plasma immunoreactive glucagon levels. To further test whether these changes in plasma triglyceride levels were mediated via the sympathetic nervous system, hypoglycemia was evoked by insulin in subjects with traumatic spinal cord transections. Two such subjects, who demonstrated sympathetic stimulation in response to hypoglycemia, had evidence of reduced VLDL secretion into plasma, while in two who had no evidence of an adrenergic response, VLDL secretion was not inhibited. Thus, acute lowering of plasma triglyceride concentrations by certain forms of stress appears to be mediated via the sympathetic nervous system.

Is submaxillary gland immunoreactive glucagon important in carbohydrate homeostasis?

Previous investigators have shown rat submaxillary gland extracts to contain large amounts of material immunologically similar to pancreatic glucagon (SM-IRG). The present studies were designed to assess any physiologic contribution of this material to plasma immunoreactive glucagon (IRG) levels and to overall carbohydrate homeostasis in the rat. Bilateral submaxillary glandectomy or sham surgery was performed on adult male rats. After 2–4 wk, these animals were subjected to arginine or epinephrine infusion, fasting, insulin-induced hypoglycemia, or oral glucose loads. No measurable differences could be found between animals with or without submaxillary glands with respect to basal plasma levels of IRG, immunoreactive insulin (IRI), blood glucose (BG), or to the response of these parameters to any of the conditions tested. Furthermore, when eviscerated animals (without gastrointestinal tract or pancreas, but with intact liver and kidneys) were studied with or without submaxillary glands, no significant differences were found in either basal or stimulated levels of plasma IRG and BG. We conclude that SM-IRG makes no significant contribution to either plasma IRG or the metabolism of carbohydrates in the rat, even when other known sources of IRG have been surgically removed. While being unable to document any apparent role for SM-IRG in the maintenance of carbohydrate homestasis, we did observe dynamic changes in the glandular content of SM-IRG that occurred with the onset of puberty in both male and female weanling rats. The possibility, thus, remains that SM-IRG may be physiologically important, but in areas not necessarily related to carbohydrate metabolism.

Differential effect of isoproterenol on acute glucagon and insulin release in man

In man, the infusion of arginine or isoproterenol elevates immunoreactive glucagon and insulin levels. Since arginine administered as a pulse stimulates the acute secretion of both hormones, and an insulin rise is observed after the bolus injection of isoproterenol, these findings probably represent a direct effect of arginine and isoproterenol on islet cells. To determine if there is an acute alpha-cell response to isoproterenol, we have administered this beta-adrenergic agonist as a bolus to healthy volunteers. Arginine administered as a pulse elicited both insulin and glucagon responses whereas pulses of isoproterenol, at half maximal and maximal insulin-stimulating doses, had little effect on glucagon levels. This relative insensitivity of the alpha cells to stimulation by isoproterenol suggests that endogenous beta-adrenergic tone may have a stronger influence on insulin than on glucagon secretion. Furthermore, these findings raise the possibility that beta-adrenergic regulation of plasma glucagon levels in vivo occurs by an indirect mechanism rather than a direct effect on the alpha cells.

Glucagon-Insulin Interactions in Patients with Insulin-Producing Pancreatic Islet Lesions*

Abstract In 16 patients with benign, insulin-producing pancreatic islet cell lesions, basal plasma levels of immunoreactive glucagon (IRG), insulin (IRI), GH, and glucose were studied to assess possible interactions of glucagon and insulin in states of chronic insulin excess. Basal plasma levels of IRG were in the normal range despite hypoglycemia and hyperinsulinemia. Median plasma IRG did not correlate with median plasma total IRI (r = −0.371) or the insulin component of IRI (corrected for proinsulin proportion) (r = −0.097). Median plasma IRG and glucose correlated negatively (r = −0.617; P < 0.05). The median insulin components of IRI and glucose did not correlate (r = −0.108). When augmented hypoglycemia was induced acutely by tolbutamide, plasma levels of IRG and GH increased significantly despite concurrent exaggerated hyperinsulinemia. During 70-h fasting in one patient with insulinoma, plasma levels of IRG were not different from those observed in a healthy subject matched according to prevailing...

Reflex adrenergic control of endocrine pancreas evoked by unloading of carotid baroreceptors in cats

The effects of unloading of the carotid baroreceptors on arterial plasma glucose concentration as well as on portal plasma immunoreactive glucagon (IRG) and insulin (IRI) concentrations were studied in anestethized, vagotomized cats either by sectioning the sinus nerves or by lowering the pressure in the isolated carotid sinuses. Complete elimination of the carotid baroreceptor discharge by cutting the sinus nerves caused an increase in the arterial plasma glucose concentration by 100% and an increase in the portal IRG level by about 200%, whereas the portal IRI concentration decreased to 50% of its basal value. These baroreceptor-induced changes of the plasma IRG and IRI levels seemed to be graded in relation to the drop in carotid blood pressure and they were clearly detectable when the pressure was lowered from 120 to 90 mmHg in the isolated carotid sinus preparation. The described reflex hyperglycemia, hyperglucagonemia and hypoinsulinemia were mediated to the pancreas and liver mainly by the sympatho-adrenal system, since cutting the splanchnic nerves above the adrenal glands abolished the hyperglycemia and hypoinsulinemic responses and markedly depressed the magnitude of the hyperglucagonemic response. In adrenalectomized cats, complete unloading of the baroreceptors evoked both hyperglucagonemia and hypoinsulinemia although the magnitude of the hormonal responses was diminished. In animals where the pancreas and liver were sympathectomized but the adrenal glands left intact, cutting the sinus nerves evoked a doubling of the IRG level and a slight increase in plasma glucose, but no significant change of the IRI level. I.v. infusion of adrenaline (1 microgram/kg X min) or noradrenaline (5 microgram/kg X min) caused pronounced increases in IRG and plasma glucose and a clear-cut reduction of IRI. We conclude that the function of the endocrine pancreas in the cat can be influenced by variations in the blood pressure by means of a reflex control which originates from arterial baroreceptors. This reflex adjustment of the endocrine pancreas is mediated chiefly by two links of the sympatho-adrenal system, namely by catecholamine-release from the adrenal medulla and, more importantly, by a direct adrenergic nerve fibre influence on the alpha- and beta- cells.

The metabolic clearance of endogenous immunoreactive glucagon and exogenous glucagon in pancreatectomized and sham-operated pigs.

Hyperglucagonemia follows feeding in the pancreatectomized pig as it does in the pancreatectomized dog and man, but the cause of the rise in glucagon concentration is unknown. We report here the metabolic clearance and t½ of exogenous porcine glucagon infused into pigs and of endogenous immunoreactive glucagon (IRG) depressed by infusion of somatostatin. Somatostatin suppressed IRG levels to 70% of basal levels in pancreatectomized (P) pigs within 20 min of commencement of infusion and to 30% thereof in shamoperated (S) pigs within 50–60 min of commencement of infusion. In the S animals there was a breakthrough rebound within 6-8 h to levels approximately 175% of basal despite continued somatostatin infusion, while in the P animals a breakthrough to levels just above basal took place at 2 h in only two of seven animals. In the remaining five animals there was no rebound phenomenon. The half-life times determined from the slopes of disappearance were 42 ± 13 min in S animals and 55 ± 10 in P animals. In co...

Gastric Inhibitory Polypeptide in Acquired Pancreatic Diabetes: Effects of Insulin Treatment*

Oral glucose tolerance tests were done in eight insulin-requiring pancreatic diabetic patients to study the effect of withdrawal of insulin treatment on gut hormone release. Basal levels of gastric inhibitory polypeptide (GIP), glucagon-like immunoreactivity, and immunoreactive glucagon levels rose on insulin withdrawal, more so in patients on short-acting insulin, and were lowered by insulin treatment. Insulin treatment did not affect the GIP, glucagon-like immunoreactivity, or IRG responses to oral glucose. Improved glucose tolerance was greater in patients receiving soluble insulin than in those receiving lente insulin, and there was a significant positive linear correlation between basal plasma GIP and blood glucose levels in these patients. Therefore, it is suggested that insulin treatment lowers basal hormones levels, possibly via a metabolic effect, whereas the hormone responses to oral glucose may be controlled by several factors unrelated to insulin administration or changes in glucose homeostasis.