The urine cyclic AMP response to parathyroid extract (PTE) administration in normal subjects and patients with parathyroid dysfunction.

Fourteen normal subjects, 21 patients with primary hyperparathyroidism, and 12 patients with hypoparathyroidism were studied to evaluate the effects of an excess or deficiency of endogenous parathyroid hormone (PTH) and of serum calcium and phosphate upon urinary cyclic AMP and phosphate responses to PTE administration in man. Preoperatively, the hyperparathyroid patients were hypercalcemic and hypo- or normophosphatemic; post-operatively, they were hypo- or eucalcemic and euphosphatemic. The hypoparathyroid patients were hypocalcemic and hyperphosphatemic. Hourly urine specimens were collected from 8:00 a.m. to 12:00 noon on two consecutive days and analyzed for their cyclic AMP, phosphate, and creatinine contents. On the second day, 200 USP units of PTE were administered intravenously over a period of 5 min beginning at 9:00 a.m. Cyclic AMP excretion in the control period, prior to PTE infusion, was significantly elevated in the hyperparathyroid patients preoperatively, but fell to normal postoperatively, and was significantly depressed in the hypoparathyroid patients. Phosphate excretion during the same control period was significantly elevated to near maximal levels in the hyperparathyroid patients preoperatively, but fell to normal postoperatively and was not significantly different from normal in the hypoparathyroid patients. Following PTE administration, the same maximal levels of cyclic AMP and phosphate excretions were observed in all of the groups studied. Thus, there were no apparent effects of endogenous PTH levels or serum calcium and phosphate levels on the maximum excretion rates of cyclic AMP or phosphate following PTE administration in patients with hyper- or hypoparathyroidism.     

Hyperglucagonemia in liver cirrhosis with portal-systemic venous anastomoses: responses of plasma glucagon and gastric inhibitory polypeptide to oral or intravenous glucose in cirrhotics with normal or elevated fasting plasma glucose levels.

Plasma immunoreactive glucagon (IRG) was examined in volunteers with biopsy-proven cirrhosis of the liver after recovery from surgical portal--caval anastomosis. A wide range of increased total plasma IRG concentrations was found after overnight fast in groups of cirrhotic subjects with and without fasting hyperglycemia. Gel filtration chromatography of plasma showed a major component in the 3500-mol wt fraction in all cases so studied. Administration of glucose i.v. caused rapid suppression of total plasma IRG in normoglycemic and non-insulin-dependent hyperglycemic cirrhotic subjects. After administration of oral glucose, total plasma IRG was suppressed rapidly in normoglycemic cirrhotic subjects, while non-insulin-dependent hyperglycemic cirrhotic subjects exhibited delayed but prolonged suppression. Chromatography of selected plasma with glucose-suppressed total IRG showed a major decrease in the 3500-mol wt component in every case. Exaggerated increments of plasma gastric inhibitory polypeptide were demonstrable in both groups of cirrhotic individuals after administration of oral glucose, and it is speculated that this peptide may contribute to stimulation of glucagon secretion in liver disease associated with insulin deficiency.     

The glucoregulatory response to intravenous glucose infusion in normal man: Roles of insulin and glucose

In order to differentiate the roles of hyperinsulinemia and hyperglycemia per se in the homeostatic response to i.v. glucose administration, two groups of normal subjects were given either glucose alone (3.5 mg kg^?1 min^?1) or glucose (3 mg kg^?1 min^?1) in conjunction with somatostatin (500 μg hr^?1), insulin (0.15 mU kg^?1 min^?1) and glucagon (1 ng kg^?1 min^?1). Glucose kinetics were measured by the primed-constant infusion of 3-³H-glucose. During the infusion of glucose alone, plasma glucose stabilized at levels 45–50 mg/dl above the fasting values. Endogenous glucose output was markedly suppressed by 85%–90% while glucose uptake rose to values very close to the infusion rate of exogenous glucose. Glucose clearance remained unchanged. Plasma insulin rose three-fourfold while plasma glucagon fell by 25%–30%. When glucose was infused with somatostatin, insulin, and glucagon, plasma insulin was maintained at levels 50% above baseline while glucagon remained at preinfusion levels. Under these conditions, the infusion of exogenous glucose resulted in a progressive increase of plasma glucose which did not stabilize until the end of the study period (190 mg/dl at 120 min). Endogenous glucose production was consistently suppressed (52%) but significantly less than observed with the infusion of glucose alone (p < 0.01). Glucose uptake increased to the same extent as with glucose alone, despite the more pronounced hyperglycemia. Thus, glucose clearance fell significantly below baseline (25%–30%; p < 0.01). These data demonstrate that hyperglycemia per se (fixed, near basal levels of insulin and glucagon) certainly contributes to the glucoregulatory response to i.v. glucose administration by both inhibiting endogenous glucose output and increasing tissue glucose uptake. However, the extra-insulin evoked by hyperglycemia is necessary for the glucoregulatory system to respond to the glucose load with maximal effectiveness.     

The antilipolytic effect of insulin in human adipose tissue in obesity,diabetes mellitus,hyperinsulinemia, and starvation

The antilipolytic effect of insulin in vitro was investigated in conditions known to be associated with resistance to the effect of insulin on glucose metabolism. Human subcutaneous adipose tissue was obtained from 14 obese subjects before and during starvation for 7 days, 12 untreated non-insulin dependent diabetics (NIDDM), 6 untreated insulin dependent diabetics (IDDM), and 10 nonobese control subjects. The tissue was incubated with and without insulin in concentration ranging from 1–10.000 μU/ml. Responsiveness (maximum effect) and sensitivity to insulin were determined under basal induction conditions, since insulin had a bimodal effect on noradrenaline stimulated lipolysis. Under normal conditions both insulin sensitivity and insulin responsiveness were positively correlated with the basal rate of lipolysis. In obesity, IDDM and NIDDM there were no change in insulin sensitivity or in insulin responsiveness. When the obese subjects were divided into one hyperinsulinemic group (6 individuals) and one group with normal fasting serum insulin levels (7 individuals) a similar antilipolytic effect of insulin was observed in the two groups. During starvation there was a 20-fold increase in insulin sensitivity (p < 0.01) but no change in insulin responsiveness in femoral fat and only a decrease in responsiveness (p < 0.01) in abdominal fat. The present data supports the view that antilipolysis in human fat cells is not involved in the insulin resistance seen in obesity, starvation, diabetes and hyperinsulinemia.     

Effect of somatostatin on the plasma amino acid response to ingested protein in man.

To evaluate the effect of somatostatin on the plasma amino acid response to ingested protein and amino acids, normal subjects received a 6-hr intravenous infusion of somatostatin or saline initiated 2 hr before consuming a lean beef meal (3 g/kg) or oral leucine (5 g). The effect of somatostatin on intravenous leucine disposal was also examined. In the saline control study, the branched-chain amino acids exhibited the largest elevations in plasma concentration after protein ingestion. Somatostatin markedly reduced the protein-induced increments in plasma branched-chain amino acids by 50%–75% (p < 0.001) throughout the study period. This effect was not attributable to augmented systemic disposal of these amino acids since somatostatin exaggerated by 70%–75% the rise in plasma leucine produced by intravenous leucine (p < 0.05). Somato-statin also blunted by 40%–80% the elevations in most other amino acids after protein feeding. When leucine alone was ingested, somatostatin delayed the peak rise in plasma leucine by 1 hr, but did not alter the total area under the plasma leucine response curve. We conclude that somatostatin causes a sustained reduction in the systemic availability of amino acids contained in ingested protein, while availability of free leucine is only transiently delayed. These findings raise the possibility that somatostatin reduces systemic availability of protein-derived amino acids primarily by interfering with the digestive process.     

Prostaglandins, their intermediates and precursors: Cardiovascular actions and regulatory roles in normal and abnormal circulatory systems

The characterization of newly found unstable metabolites of arachidonic acid has provided new perspectives for cardiovascular regulatory mechanisms and new insights into disorders of the circulatory system. Since these intermediates are often more potent on and more specific for cardiovascular structures than the classical prostaglandins, they are more likely candidates as physiologic mediators of circulatory events. Their instability in vitro need not preclude these roles; on the contrary, the limited pharmacology described to date suggests that they function purely as local hormones. As such, changes in the rate of generation of these unstable but potent compounds would provide an excellent control system. The stable prostaglandins may represent only overflow of degradation products of the active mediators associated with pathologic events. For example, the discovery of prostacyclin and the realization that this prostaglandin and not PGE₂ is the primary metabolite of arachidonic acid in blood vessels emphasizes the need to reinterpret many of the previously held hypotheses that proposed that prostaglandins of the E series contributed to the regulation of vessel tone and blood pressure. Moreover, the contribution made by abnormal prostaglandin mechanisms to hypertensive disease should now take into account that a deficiency of prostacyclin and not PGE₂ could be a major factor causing the elevated tension developed in vascular smooth muscle and the augmented vessel responsiveness to stimuli associated with hypertension.¹²     

Gastric inhibitory polypeptide (GIP) and insulin release in response to oral and intravenous glucose in uremic patients

Eight patients with advanced renal failure of long duration were studied 1 day after hemodialysis. A 50 g oral glucose load (OGTT) and an intravenous glucose infusion (IVGI), giving the same plasma glucose profile as the OGTT, were carried our in order to study the relation between Gastric Inhibitory Polypeptide (GIP) plasma levels after oral glucose and the insulin release during OGTT and IVGI. The plasma GIP increase during OGTT was significantly elevated compared to a group of eight healthy volunteers. The insulin potentiation during OGTT in relation to GIP was significantly depressed in the uremic patients. It is proposed that a factor of intestinal origin is released during intake of carbohydrates, which blocks the B-cell response to the combined glucose-GIP stimulus. Alternatively, the concentrations of plasma GIp measured have included GIp fragments without insulin releasing capability.     

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.     

Effects of ethanol ingestion on glucose tolerance and insulin secretion in normal and diabetic subjects

To investigate the effect of ethanol on carbohydrate homeostasis in circumstances in which food and ethanol are usually ingested, ethanol was administered hourly in the afternoon prior to the ingestion of a glucose load at 5:00 p.m. in a group of normal subjects and in mild diabetics. In both groups the blood glucose levels following the glucose load were $\text{30–80 mg}\text{100 ml}$ lower and the early insulin secretory response (15–45 min) was 35%–40% higher after ethanol ingestion. In contrast, ethanol intake had no effect on the glucagon response to glucose ingestion. These data suggest that ethanol enhances glucose-stimulated insulin secretion. The dampened blood glucose rise observed with ethanol may be related to the augmented insulin response or to decreased gastrointestinal absorption of glucose. In mild diabetic patients, moderate intake of ethanol is without acute deleterious effects on carbohydrate homeostasis and may in some instances improve the blood glucose response to ingested carbohydrate.     

The effect of glucose on the growth hormone response to glucagon and propranolol-glucagon in normal subjects.

The mean (+/- SE) peak level of serum growth hormone (GH) after intramuscular injection of glucagon in ten normal adult men was 15.1 +/- 2.1 ng/ml; glucose infusion suppressed the mean peak GH to 9.6 +/- 3.7 ug/ml (p less than 0.05). Pretreatment of eight of these subjects with propranolol caused a modest increase in the mean peak GH after glucagon (19.4 +/- 2.8 ng/ml) but did not improve the mean peak GH after glucagon when glucose was infused (8.7 +/- 2.8 ng/ml). Individual analysis of the peak GH showed that glucose infusion did not uniformly suppress the peak GH after glucagon; in seven subjects the peak GH was suppressed but in three it was not. Conclusions: (1) The GH response after glucagon is usually due to a fall in serum glucose after the initial rise in serum glucose induced by glucagon. (2) Nevertheless, since glucose does not consistently inhibit the GH response after glucagon, a second mechanism probably exists by which glucagon stimulates GH secretion. (3) Glucose completely suppresses the propranolol-induced increase in the GH response to glucagon; an adrenergic mechanism may be involved in the control of GH secretion by glucose.     

A role for endogenous prostaglandins in defective glucose potentiation of nonglucose insulin secretagogues in diabetics

Noninsulin dependent diabetics have insulin responses to nonglucose secretagogues that are subnormal for their plasma glucose levels. Since endogenous prostaglandins have been implicated in the abnormal insulin responses to glucose in diabetics, the present study was performed to explore whether prostaglandins might also play a role in the defective insulin responses to nonglucose stimuli. We examined the effects of infusions of either prostaglandin E₂ (PGE₂) or sodium salicylate (SS), a PG synthesis inhibitor, on the acute insulin responses (AIR's) to arginine and isoproterenol and on the glucose potentiation of the insulin response to arginine in both normal and diabetic subjects. The AIR to arginine was augmented by SS in diabetics (SS = 61 ± 12 μU/ml, control = 37 ± 5 μU/ml, n = 11, p < .01). SS, however, had no effect on the AIR to arginine in normal subjects (SS = 39 ± 4 μU/ml, control = 34 ± 4 μU/ml, n = 6, p = ns). Similarly, SS augmented the AIR to an isoproterenol pulse in diabetics (SS = 38 ± 9 μU/ml, control = 18 ± 3, n = 9, p < .05) but not in normal subjects (SS = 19 ± 4 μU/ml, control = 21 ± 4 μU/ml, n = 8, p = ns), suggesting a SS-sensitive defect in the insulin response to these nonglucose stimuli in diabetics. Conversely, PGE₂ inhibited the AIR to arginine in diabetics (PGE = 28 ± 5 μU/ml, control = 39 ± 7 μU/ml, n = 7, p < .05), but not in normal subjects (PGE = 74 ± 7 μU/ml, control = 80 ± 14 μU/ml, n = 5, p = ns). The effect of SS on glucose potentiation of the AIR to arginine was studied by measuring the AIR to arginine at two different levels of plasma glucose, one before and one after an insulin infusion, with glucose potentiation defined as the ratio ΔAIR/Δprestimulus glucose. Glucose potentiation was significantly less in diabetics than in normals and SS significantly improved glucose potentiation toward normal values in diabetics but did not change glucose potentiation in normals. These findings suggest that endogenous PG's may play a role in the defective glucose potentiation of the AIR to nonglucose secretagogues in diabetics resulting in impaired insulin responses to these stimuli. This defect is partially reversible by an inhibitor of PG synthesis.     

Variations in plasma glucose,insulin, growth hormone and catecholamines in response to insulin in trained and non-trained subjects

Previous studies have shown a reduced insulin secretion in trained subjects challenged by a glucose load. In the present study the response to insulin of 8 athletes was compared to that of 8 non-trained subjects. The disappearance of plasma insulin was not different between the two groups, but the level of hypoglycemia was greater in the trained subjects. The injection of insulin increased the plasma levels of epinephrine (E) and norepinephrine (NE) in both groups of subjects, but the raise in E was greater in the trained subjects. Similarly, the increase of growth hormone (GH) was greater in the trained subjects. These findings substantiate previous results showing a decreased insulinic index and an increased insulin binding to monocytes in trained subjects. It is also suggested that the enhanced E and GH secretion found in trained subjects injected with insulin, is possibly related to the greater fall in plasma glucose in the trained subjects compared to the non-trained subjects.     

An adverse effect of insulin on the oxygen-release capacity of red blood cells in nonacidotic diabetics.

Oxyhemoglobin dissociation curves (ODC) were performed on blood from newly diagnosed, nonketotic diabetics prior to and following initial insulin treatment and from ambulatory juvenile diabetics before and after their usual morning insulin. In 10 newly discovered diabetics the average P50 at in vivo pH was normal prior to insulin (26.2 mm Hg), decreased to 24.5 mm Hg (p less than 0.005) on the day following the initial insulin administration, and was within normal limits (26.9 mm Hg) when the diabetes was finally well controlled and red cell 2,3-diphosphoglycerate (2,3-DPG) had risen to elevated levels. Oxygen affinity of hemoglobin was closely correlated with the content of red cell 2,3-DPG (r = 0.61, p less than 0.001) but was unrelated to the level of hemoglobin Alc. In 40 juvenile patients the average P50 was also normal prior to insulin administration but was significantly lower 3-4 hr after they had received their usual insulin dose (p less than 0.001). The study indicates that insulin administration to diabetics with high blood glucose levels may lead to transient decreases in red cell 2,3-DPG and in oxygen-releasing capacity of the red blood cells.     

The effect of alpha-glucosidase inhibition on intestinal disaccharidase activity in normal and diabetic mice

Acarbose is a potent alpha-glycosidase inhibitor which decreases postprandial hyperglycemia when administered with a carbohydrate-containing meal. The genetically diabetic mouse C57 BLKsJ db/db represents a model of type II, noninsulin dependent diabetes mellitus. Characteristic features of this animal include hyperglycemia, hyperinsulinemia, hyperphagia, and the development of obesity and widespread pathologic abnormalities. To evaluate the effects of Acarbose on intestinal disaccharidase activity, groups of normal and diabetic mice were given Acarbose as a drug-food mixture in doses of 20 (A-20) and $\text{40 (A-40) mg}\text{100 g}$ food. Sucrase activity was measured in intestinal homogenates and on the mucosal surface of proximal, middle, and distal segments of jejunoileum. In normal mice, sucrase activity was significantly increased in mid- and distal-intestinal segments following 2 wk of Acarbose in both A-20 and A-40 groups. No changes were noted following 5 and 10 days of drug treatment. Acarbose did not influence body weight, food:water intake or fasting blood glucose. When compared to normal mice, untreated diabetics had significantly more protein, DNA, and sucrase activity throughout the small intestine. Following 10 wk of Acarbose administration, both A-20 and A-40 groups showed increased sucrase activity in intestinal homogenates of distal segments. Surface mucosal sucrase activity however was slightly decreased in proximal intestinal segments as a result of drug therapy, with no changes in middle and distal segments. Acarbose did not influence body weight, food intake or fasting blood glucose, but water consumption and glucosuria were significantly decreased. Experimental diabetes mellitus is associated with significant alterations in enzyme activity and protein content of the brush border membrane of the small intestine. Acarbose administration influences both sucrase activity and distribution in normal and diabetic mice. The mechanisms responsible for these changes and their potential clinical importance remain to be determined.     

The metabolic response to the euglycemic insulin clamp in type I diabetes and normal humans

The euglycemic insulin clamp has been utilized extensively to measure in vivo tissue sensitivity to insulin under various circumstances. Insulin sensitivity is determined from the amount of glucose metabolized under steady state conditions. To assess the effect of abnormalities in other insulin responsive metabolic pathways on glucose metabolism and thus insulin sensitivity as measured by the glucose clamp, the concentration of lactate, pyruvate, 3-hydroxybutyrate, glycerol, alanine, and free fatty acids were measured at baseline and during a two-hour euglycemic clamp in 13 nonobese subjects with type I diabetes. The observed responses were compared to 11 normal controls. Insulin sensitivity as measured by M (glucose metabolized), MCRg (metabolic clearance of glucose), and M/I ratio (glucose metabolized per unit insulin) were all significantly decreased in the diabetic subjects (P less than 0.005). Free fatty acids (FFA) and 3-hydroxybutyrate were significantly elevated at baseline in the diabetic subjects (P less than 0.05) and decreased significantly at 60 and 120 minutes in both groups. Baseline blood pyruvate and lactate concentrations were similar in the control and diabetic subjects. Pyruvate increased significantly at 60 minutes in both groups (P less than 0.05) and returned to baseline in the control subjects but remained elevated at 120 minutes in the diabetic subjects (P less than 0.001). Lactate increased similarly in both groups and remained elevated at 60 and 120 minutes. In summary, insulin sensitivity as assessed by the euglycemic insulin clamp is decreased in type I diabetes. However, specific differences in the concentration of several other metabolites both at baseline and in response to hyperinsulinemia were also identified in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of acetylsalicylic acid on plasma glucose, insulin, glucagon, and growth hormone levels following tolbutamide stimulation in man.

The effects of acetylsalicylic acid (ASA), a known inhibitor of prostaglandin (PG) synthesis, on plasma glucose, insulin, glucagon and growth hormone (GH) responses to tolbutamide were examined in ten normal volunteers. Treatment with 3.2 g ASA daily for 3 days caused a significant reduction in basal plasma glucose levels (p less than 0.05); by contrast, basal insulin rose from 23 +/- 2 to 31 +/- 2 microU/ml (p less than 0.01). No significant changes in the basal concentrations of glucagon and GH were found after ASA. Insulin response to tolbutamide was significantly augmented after ASA (p less than 0.01) while GH response to hypoglycemia was reduced (p less than 0.05). The pattern of plasma glucose and glucagon was not significantly modified by the treatment. Since ASA seems to have an action opposite to PGE on insulin and GH secretion, it is possible that the ASA may work through inhibition of PG synthesis.     

Effects of acute endotoxemia and glucose administration on circulating leukocyte populations in normal and diabetic subjects.

Effects of intravenous endotoxin and glucose administration on circulating leukocyte populations were compared in seven normal subjects and seven patients with juvenile-onset diabetes by means of automated cytochemical differential counting to quantitate each cell type. Both groups had comparable control cell counts that were unaffected by glucose tolerance testing but altered significantly by endotoxin. Different patterns of response to endotoxin were observed for different circulating cell types. The response of diabetics was parallel to that of normals but showed lower neutrophil and monocyte rebound, longer lasting depression of lymphocytes and eosinophils, and greater rebound of basophils on the day following endotoxin exposure. Characterization of distinctive normal response patterns of circulating leukocyte populations to endotoxin and comparison with responses in diabetes revealed abnormalities under conditions of stress that may impair the diabetic's ability to cope with acute infection.     

Daily variations of plasma glucose and insulin in physically-trained and sedentary subjects

The variations in plasma glucose and insulin levels were measured at 30-minute intervals throughout the day in physically trained and in sedentary subjects. The subjects exercised for 75 minutes at 65% of VO2max in the first experiment and refrained from heavy exercise in the second experiment. In all situations the physically trained subjects overall had lower plasma glucose and insulin levels than the nontrained subjects. In addition, the positive correlation between plasma glucose and plasma insulin levels observed in the physically trained subjects was significantly smaller than that note in the nontrained subjects, indicating reduced insulin requirements in physically-trained persons. During the period of exercise, glucose levels increased significantly in the trained subjects only. In the period that followed exercise, that is between 1:30 PM and 9:00 PM, the physically trained subjects had plasma glucose levels that were higher than those noted during the comparable hours not preceded by exercise; no comparable difference were found with insulin. Calculation of the total area for insulin indicated a reduction of insulin requirement of about 40% associated with physical training.     

The physiologic action of insulin on glucose uptake and its relevance to the interpretation of the metabolic clearance rate of glucose

Glucose uptake (Ru) is dependent upon the concentrations of both glucose and insulin. The metabolic clearance rate of glucose (MCRG), has been used as an in vivo measure of insulin action, because it was said to be independent of the prevailing glucose concentration. The validity of this assumption has recently been challenged. In this study, the effect of insulin concentration on the rate of glucose uptake (Ru) and on the MCRG was studied during euglycemia (5.1 +/- 0.3 mmol/L) and moderate hyperglycemia (10.4 +/- 0.5 mmol/L) in 17 experiments on nine normal ambulant volunteers. Stable plasma insulin levels were maintained with fixed infusion rates of insulin (0-300 mU/kg/h) and somatostatin (7.5 micrograms/min). At low insulin concentrations (less than 5 microU/mL) the increase in glucose uptake in response to hyperglycemia was small (5.3 +/- 2.3 mumol/kg/min). In contrast, with insulin levels more than 25 microU/mL, there was a steep rise in glucose uptake with hyperglycemia (55 +/- 3 mumol/kg/min; range: 44-74 mumol/kg/min). The metabolic clearance rate of glucose fell by an average of 32% with hyperglycemia in the studies at the lowest insulin levels (2.2 +/- 0.6 v 1.5 +/- 0.1 mL/kg/min; 0.15 greater than P greater than 0.1). There was no change in the MCRG in the subjects studied at higher insulin levels. It is concluded that (1) low concentrations of insulin are essential for the increase in glucose disposal during hyperglycemia; and (2) provided insulin levels are more than 25 microU/mL and plasma glucose less than 11 mmol/L, MCRG is independent of the plasma glucose concentration and is therefore a valid measure of insulin-mediated glucose uptake.     

Disassociation of the plasma insulin response from the blood glucose concentration during glucose infusions in normal dogs

Twenty-two anesthetized dogs were given a constant glucose infusion (14 mg/kg/min) for 360 min, while blood glucose concentration was continuously monitored. Plasma insulin concentration was measured every 30 min. The blood glucose peaked at 60 min and then steadily fell (mean fall, $\text{56}\text{mg}\text{100}\text{ml}$), while plasma insulin continuously rose (mean rise, 65 μU/ml). This suggests that blood glucose concentratiion was not the primary stimulus for insulin secretion. In a second series of experiments, five dogs received glucose infusions as described above. One week later, each dog was reinfused with a larger total glucose load, regulated by continuous blood glucose monitoring to exactly reproduce the blood glucose response observed during the first infusion. Plasma insulin concentrations during the high load infusions were significantly higher than during the low load infusions. Thus, changes in glucose load produced changes in plasma insulin concentration, even though blood glucose levels were held constant. Thus, using two different approaches, we have demonstrated that plasma insulin levels can be dissociated from the coexisting blood glucose concentration. These results suggest that the level of blood glucose may not be the primary determinant of the insulin response to glucose during the chronic phase of insulin secretion.