Suppression of basal, but not of glucose-stimulated insulin secretion by human insulin in healthy and obese hyperinsulinemic subjects

To evaluate the suppressive effect of biosynthetic human insulin (BHI; 2.5 U/m2 . h) on basal and glucose-stimulated insulin secretion in healthy and obese hyperinsulinemic subjects, the plasma C-peptide response was measured during maintenance of euglycemia and hyperglycemia by means of the glucose clamp technique. In five healthy subjects in whom arterial insulin concentration was increased to 94 +/- 8 microU/mL, but euglycemia was maintained at the fasting level. C-peptide concentration fell from 1.3 +/- 1.0 ng/mL by 21 +/- 8% (P less than 0.05). When hyperglycemia of 7 mmol/L above basal was induced by a variable glucose infusion, the C-peptide response was similar in the control (5.0 +/- 0.6 ng/mL) and BHI experiments (4.7 +/- 0.6 ng/mL) and was paralleled by an identical increase in plasma insulin above the prevailing insulin concentration. In seven obese patients plasma C-peptide fell from 3.5 +/- 0.4 to 2.8 +/- 0.5 ng/mL (P less than 0.05) when BHI was infused at the same rate of euglycemia maintained as in the lean subjects. As in healthy subjects, however, the plasma C-peptide response to the hyperglycemic stimulus (8.7 +/- 0.9 ng/mL) was not altered by BHI (7.9 +/- 0.8 ng/mL). Glucose utilization as determined by the glucose infusion rate necessary to maintain the desired glucose level was reduced by half in the obese patients compared with that of normal subjects. From these data we conclude that in healthy as well as obese hyperinsulinemic subjects, insulin at concentrations capable of suppressing its basal secretion fails to suppress its glucose-stimulated secretion.     

Starvation enhances the ability of insulin to inhibit its own secretion

To examine whether decreased insulin secretion during starvation is related to a change in the ability of insulin to inhibit its own secretion, plasma C-peptide was measured after plasma insulin levels were acutely raised by intravenous (IV) insulin infusion in a dose of 40 and 80 mU/M2/min in obese subjects before and after a 72 hour fast. Plasma glucose concentration was maintained +/- 4% of basal levels by a variable glucose infusion. During the 80 mU infusion, at plasma insulin levels of 200 microU/mL, plasma C-peptide fell by 0.17 pmol/mL in the fed state. In the fasted state, despite basal levels that were 36% lower, C-peptide decreased by 0.21 pmol/mL. Highly significant increases in percent suppression after fasting were noted during both 40 mU and 80 mU studies. The plasma C-peptide response was related to the insulin infusion dose in both the fed and fasted state. In contrast, alpha cell suppression by insulin, as determined by plasma glucagon levels, was not altered by fasting. It is concluded that enhanced inhibitory influences of insulin on the beta cell during starvation may be a physiologically important mechanism for diminished insulin secretion during the transition from the fed to the fasting state.     

Comparison of the inhibitory effect of insulin and hypoglycemia on insulin secretion in humans

Although both insulin and hypoglycemia are known to inhibit endogenous insulin secretion, their potency to suppress insulin secretion has not been directly compared thus far. The serum C-peptide concentration was measured during 28 euglycemic and 28 stepwise hypoglycemic (4.1,3.6, 3.1, and 2.6 mmol/L) clamp experiments using either a low-rate (1.5 mU x min(-1) x kg(-1)) or high-rate (15.0 mU x mU(-1) x kg(-1)) insulin infusion. The experiments lasted 6 hours and were performed in 28 lean healthy men. During both the euglycemic and hypoglycemic clamps, serum insulin was approximately 40-fold higher during the high-rates versus low-rate insulin infusion (euglycemia, 24,029 +/- 1,595 v 543 +/- 34 pmol/L; hypoglycemia, 23,624 +/- 1,587 v 622 +/- 32 pmol/L). Under euglycemic conditions, serum C-peptide decreased from 0.54 +/- 0.04 to 0.41 +/- 0.05 nmol/L during the low-rate insulin infusion (P < .05) and from 0.55 +/- 0.07 to 0.27 +/- 0.09 nmol/L during the high-rate insulin infusion (P < .001). Under hypoglycemic conditions, serum C-peptide decreased from 0.50 +/- 0.03 to 0.02 +/- 0.01 nmol/L during the low-rate insulin infusion (P< .001) and from 0.46 +/- 0.07 to 0.02 +/- 0.01 nmol/L during the high-rate insulin infusion (P< .001). In the euglycemic clamp condition, the high-rate insulin infusion reduced the C-peptide concentration more than the low-rate insulin infusion (P < .05). Independent of the rate of insulin infusion, the decrease in C-peptide was distinctly more pronounced during hypoglycemia versus euglycemia (P < .001). These data indicate that insulin inhibits insulin/C-peptide secretion in a dose-dependent manner. Hypoglycemia is a much stronger inhibitor of insulin secretion than insulin itself.     

Modulation of insulin secretion by insulin and glucose in type II diabetes mellitus

We studied the dose-response characteristics of insulin's ability to modulate its own secretion in normal and type II diabetic (NIDDM) subjects by measuring suppression of serum C-peptide levels during insulin infusions with the plasma glucose level held constant. In normal subjects at euglycemia, primed continuous insulin infusion rates of 15, 40, 120, and 240 mU/M2 X min acutely raised serum insulin to steady state levels of 37 +/- 2 (+/- SE), 96 +/- 6, 286 +/- 17, and 871 +/- 93 microU/ml, respectively. During each infusion, maximal suppression of C-peptide to 30% of basal levels occurred by 130 min. At the higher insulin levels (greater than or equal to 100 microU/ml), C-peptide levels fell rapidly, with an apparent t1/2 of 13 min, which approximates estimates for the t1/2 of circulating C-peptide in man. This is consistent with an immediate 70% inhibition of the basal rate of insulin secretion. At the lower insulin level (37 +/- 2 microU/ml), C-peptide levels fell to 30% of basal values less rapidly (apparent t1/2, 33 min), suggesting that 70% inhibition of basal insulin secretion rates was achieved more slowly. In NIDDM subjects, primed continuous insulin infusion rates of 15, 40, 120, and 1200 mU/M2 X min acutely raised serum insulin to steady state levels of 49 +/- 7, 93 +/- 11,364 +/- 31, and 10,003 +/- 988 microU/ml. During studies at basal hyperglycemia, only minimal C-peptide suppression was found, even at pharmacological insulin levels (10,003 +/- 988 microU/ml). However, if plasma glucose was allowed to fall during the insulin infusions, there was a rapid decrease in serum C-peptide to 30% of basal levels, analogous to that in normal subjects. Three weeks of intensive insulin therapy did not alter C-peptide suppression under conditions of hyperinsulinemia and falling plasma glucose. The following conclusions were reached. 1) In normal subjects, insulin (40-1000 microU/ml) inhibits its own secretion in a dose-responsive manner; more time is required to achieve maximal 70% suppression at the lower insulin level (40 microU/ml). 2) In NIDDM studied at basal hyperglycemia, insulin has minimal ability to suppress its own secretion. Thus, impaired feedback inhibition could contribute to basal hyperinsulinemia. 3) Under conditions of hyperinsulinemia and falling plasma glucose, insulin secretion is rapidly suppressed in NIDDM (analogous to that in normal subjects studied during euglycemia.     

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.     

Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers

Glucagon-like peptide 1 (GLP-1) and analogues are being evaluated as a new therapeutic principle for the treatment of type 2 diabetes. GLP-1 suppresses glucagon secretion, which could lead to disturbances of hypoglycemia counterregulation. This has, however, not been tested. Nine healthy volunteers with normal oral glucose tolerance received infusions of regular insulin (1 mU x kg(-1) x min(-1)) over 360 min on two occasions in the fasting state. Capillary glucose concentrations were clamped at plateaus of 4.3, 3.7, 3.0, and 2.3 mmol/liter for 90 min each (stepwise hypoglycemic clamp); on one occasion, GLP-1 (1.2 pmol x kg(-1) x min(-1)) was administered i.v. (steady-state concentration, approximately 125 pmol/liter); on the other occasion, NaCl was administered as placebo. Glucagon, cortisol, GH (immunoassays), and catecholamines (radioenzymatic assay) were determined, autonomous and neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of C-peptide kinetics). At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P = 0.26). Only during the euglycemic plateau (4.3 mmol/liter), GLP-1 suppressed glucagon concentrations (4.1 +/- 0.4 vs. 6.5 +/- 0.7 pmol/liter; P = 0.012); at all hypoglycemic plateaus, glucagon increased similarly with GLP-1 or placebo, to maximum values greater than 20 pmol/liter (P = 0.97). The other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses during hypoglycemia with GLP-1 (P = 0.04). GLP-1 stimulated insulin secretion only at plasma glucose concentrations of at least 4.3 mmol/liter. In conclusion, the suppression of glucagon by GLP-1 does occur at euglycemia, but not at hypoglycemic plasma glucose concentrations (< or = 3.7 mmol/liter). GLP-1 does not impair overall hypoglycemia counterregulation except for a reduction in GH responses, which is in line with other findings demonstrating pituitary actions of GLP-1. Below plasma glucose concentrations of 4.3 mmol/liter, the insulinotropic action of GLP-1 is negligible.     

Beta-cell insulin secretory response to oral hypoglycemic agents is blunted in humans in vivo during moderate hypoglycemia

Oral hypoglycemic agents bind to the ATP-sensitive potassium channel and lower glucose levels effectively in individuals with diabetes. Although the principle mechanism of action can also promote hypoglycemia, clinically profound hypoglycemia is rare. Decreased stimulation of insulin secretion by these agents at mild hypoglycemia could provide protection from more profound hypoglycemia. Sulfonylureas and meglitinides bind to both shared and unique sites on the ATP-sensitive potassium receptor/channel complex but have different pharmacokinetic profiles. To evaluate the differential ability of both sulfonylureas and meglitinides to stimulate insulin release at modest hypoglycemia, we evaluated dextrose infusion rates necessary to maintain plasma glucose after oral administration of repaglinide (1 mg) or glipizide (5 mg) at euglycemia and again at modest hypoglycemia. Healthy subjects with no family history of diabetes underwent four clamp studies, two performed while maintaining isoglycemia (glucose levels at the fasted value) and two while maintaining modest hypoglycemia of 2.78 mmol/liter (50 mg/dl) induced by low-dose insulin infusion (3.6 pmol/kg.min). There was a marked decrease in the dextrose infusion rate with administration of either repaglinide or glipizide at hypoglycemia compared with drug administration at euglycemia (P 相似文献   

Idiopathic reactive hypoglycemia: a role for glucagon?

We previously reported that patients with idiopathic reactive hypoglycemia (plasma glucose concentration lower than 2.5 mmol/L 2-4 h after the ingestion of 75 g of glucose) display reduced or absent counterregulatory response of the glucagon secretion and increased insulin sensitivity. In order to examine the effect of glucagon on the increased insulin sensitivity in these patients, 12 subjects with idiopathic reactive hypoglycemia underwent a two-step hyperinsulinemic (1 mU/kg.min) euglycemic glucose clamp and were compared with 12 normal control subjects matched for age, weight and sex. During the first step of the glucose clamp (only insulin + glucose infusion) the patients with Idiopathic Reactive Hypoglycemia required higher glucose infusion rates to maintain euglycemia than normal subjects (9.09 +/- 0.29 mg/kg. min vs 7.61 mg/kg.min). When basal glucagon secretion was replaced (+ somatostatin and glucagon, second step of the clamp) the glucose infusion rates required to maintain euglycemia in patients with Idiopathic Reactive Hypoglycemia significantly decreased (to 7.17 +/- 0.40 mg/kg.min) and resulted similar to normal subjects (7.64 +/- 0.41 mg/kg.min). Thus, in patients affected by Idiopathic Reactive Hypoglycemia, glucagon secretion may play an important role in the pathogenesis of the increased insulin sensitivity and hypoglycemia.     

Feedback inhibition of insulin secretion is altered in cirrhosis

Hyperinsulinemia in human cirrhosis is generally considered an expression of reduced hepatic insulin degradation. To determine whether hyperinsulinemia may also depend on an altered feedback inhibition of insulin secretion, we performed euglycemic hyperinsulinemic clamp studies, infusing 40, 372, or 1280 mU/m2 X min biosynthetic human insulin in 30 compensated cirrhotic patients with portal hypertension and impaired glucose tolerance and 25 normal subjects, matched for age, sex, and weight. Mean fasting plasma insulin was significantly higher in cirrhotic patients [26.1 +/- 2.3 vs. 12.4 +/- 0.6 (+/- SE) microU/ml; P less than 0.001], while fasting plasma glucose levels were similar in the 2 groups. The mean plasma C-peptide level was significantly higher in cirrhotic patients, both basally (2.7 +/- 0.1 vs. 1.7 +/- 0.1 ng/ml; P less than 0.001) and during the clamp studies. Suppression of C-peptide at 120 min of the clamp was significantly less in cirrhotic patients (37 +/- 7% vs. 79 +/- 4%, 52 +/- 9% vs. approximately 100%, and 54 +/- 4% vs. approximately 100% during the 40, 372, and 1280 mU/m2 X min insulin infusions, respectively). The fasting C-peptide to insulin molar ratio was significantly lower in cirrhotic patients (5.4 +/- 0.3 vs. 6.4 +/- 0.3; P less than 0.005). The MCR of insulin at the three steady states was not significantly different between the 2 groups, whereas the basal systemic delivery rate of insulin was significantly higher in cirrhotic patients (14.7 +/- 1.7 vs. 6.5 +/- 0.4 mU/m2 X min; P less than 0.001). These results suggest that reduced feedback inhibition of insulin secretion may contribute to the hyperinsulinemia associated with cirrhosis.     

Lack of effect of a physiological elevation of plasma non-esterified fatty acid levels on insulin secretion

Elevated plasma non-esterified fatty acid (NEFA) levels in obese subjects may contribute to their higher insulin secretory rates by direct effects on the islet B-cells. This may involve short-term metabolic effects, or long-term effects on islet B-cell mass, which is characteristically increased in obesity. We examined the effects of elevating plasma NEFA levels for 5.5 to 7 h on insulin secretion after an overnight fast and during a 90 min 12 mmol/l hyperglycemic clamp in 9 normal women (40.1 +/- 9.5 years [mean +/- SD]; BMI: 25.2 +/- 3.72 kg/m(2) ). Subjects were studied twice. In one study plasma NEFA levels were increased approximately 2-fold by infusion of 20% Intralipid (60 ml/h) and heparin (900 U/h) for 5.5 h before and throughout the glucose clamp. Elevated NEFA levels were associated with a small increase in fasting plasma glucose (5.0 +/- 0.1 vs 4.7 +/- 0.1 mmol/l, P <0.05) and C-peptide levels (0.54 +/- 0.09 vs 0.41 +/- 0.06 nmol/l, P <0.05). The increase in fasting insulin levels did not, however, reach statistical significance (9.0 +/- 2.5 vs 5.3 +/- 1.4 mU/l, NS). During the glucose clamp, plasma NEFA levels were suppressed to very low levels in the saline control study. Although plasma NEFA levels also fell in the lipid/heparin study, they remained significantly higher than on the control day, and somewhat higher than might be expected postprandially in obese subjects. During the glucose clamps, plasma glucose, insulin, and C-peptide profiles were similar on the two study days. No difference in either first or second phase insulin secretion was observed between the two studies. In conclusion, our findings do not support the idea that the exaggerated insulin secretion in obesity is mediated by short-term effects of plasma NEFA levels on islet B-cell metabolism, independent of plasma glucose levels.     

Acute changes of bone turnover and PTH induced by insulin and glucose: euglycemic and hypoglycemic hyperinsulinemic clamp studies

Bone turnover is acutely suppressed after feeding or oral glucose. Insulin infusion suppresses bone turnover and might mediate this effect, but this is confounded by a possible direct effect of hypoglycemia. We examined the effect of euglycemic hyperinsulinemia and hypoglycemic hyperinsulinemia on bone turnover using an insulin clamp. Sixteen men participated in this double-blind crossover study. Clamp induction involved infusion of insulin (80 mU/m(2).min) while maintaining euglycemia (5 mmol/liter) for 40 min with a variable rate dextrose infusion. Glucose was lowered to 2.5 mmol/liter (hypoglycemic clamp) or maintained at 5 mmol/liter (euglycemic clamp) for a further 105 min. Nine controls received a matched saline infusion. Measurements included serum C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide, osteocalcin, and PTH. Induction of hyperinsulinemia resulted in a reduction in PTH (27% +/- 5; P < 0.01), but no significant change in bone turnover from baseline. Hypoglycemic clamp resulted in suppression of serum C-terminal telopeptide of type I collagen by 34% +/- 3, procollagen type I N-terminal propeptide by 15% +/- 1, osteocalcin by 5% +/- 1, and PTH by a further 12% +/- 5 (all P < 0.05). By contrast, there was no significant change in any marker of bone turnover during euglycemic clamp. Postprandial hyperinsulinemia is unlikely to explain the acute suppression of bone turnover with feeding. The reduction in bone turnover during hypoglycemia may be related to hypoglycemia itself, acute changes in PTH, or other hormones released in response to hypoglycemia.     

Modeling beta-cell insulin secretion--implications for closed-loop glucose homeostasis

Glucose sensing and insulin delivery technology can potentially be linked to form a closed-loop insulin delivery system. Ideally, such a system would establish normal physiologic glucose profiles. To this end, a model of beta-cell secretion can potentially provide insight into the preferred structure of the insulin delivery algorithm. Two secretion models were evaluated for their ability to describe plasma insulin dynamics during hyperglycemic clamps (humans; n=7), and for their ability to establish and maintain fasting euglycemia under conditions simulated by the minimal model. The first beta-cell model (SD) characterized insulin secretion as a static component that had a delayed response to glucose, and a dynamic component that responded to the rate of increase of glucose. The second model (PID) described the response in terms of a proportional component without delay, an integral component that adjusted basal delivery in proportion to hyper/hypoglycemia, and a derivative component that responded to the rate of glucose change. Both models fit the beta-cell response during the clamp, and established fasting euglycemia under simulated closed-loop conditions; however, the SD model did not maintain euglycemia following simulated changes in insulin sensitivity or glucose appearance, whereas the PID model did. The PID model was more stable under the simulated closed-loop conditions. Both the SD and PID models described beta-cell secretion in response to a rapid increase in glucose. However, the PID model could maintain fasting euglycemia and was more stable under closed-loop conditions, and thus is more suited for such conditions.     

Effects of insulin on fasting and meal-stimulated somatostatin-like immunoreactivity in noninsulin-dependent diabetes mellitus: evidence for more than one mechanism of action

We assessed the effects of insulin and normalization of blood glucose on plasma levels of somatostatin-like immunoreactivity (SLI) in patients with noninsulin-dependent diabetes mellitus (NIDDM). In one series of experiments, normalization of blood glucose was achieved by Biostator-controlled feedback infusion of insulin. This procedure reduced plasma SLI levels by 34% [from 17.1 +/- 2.1 (+/- SEM) to 11.3 +/- 1.9 pg/ml; P less than 0.05], concomitant with a significant reduction in plasma glucagon and C-peptide and an evanescent decrease in plasma gastric inhibitory peptide (GIP) levels. An ensuing mixed meal elicited a rise in SLI that reached the same levels during infusion of insulin as during uncontrolled hyperglycemia; the incremental increase was, however, 45% higher (P less than 0.005) during insulin infusion. Furthermore feedback insulin infusion enhanced GIP and decreased C-peptide responses, but did not affect the glucagon response to the meal. To further evaluate the influence of insulin of SLI levels, we compared the effects of normo- and hyperglycemia during constant hyperinsulinemia by varying the rate of glucose infusion (glucose clamping). Basal SLI levels decreased significantly only during the normoglycemic clamp. The SLI response to a meal was more pronounced during the normoglycemic than the hyperglycemic clamp. The patterns of glucagon and GIP were similar during the two clamp conditions, while both basal and stimulated C-peptide levels were lower during the normoglycemic clamp. To investigate the temporal relationship between changes in blood glucose and SLI levels, patients were studied during a prolonged (270-min) period of normoglycemic clamp and fasting. After attaining normoglycemia, SLI levels continued to decline for 150 min, whereas glucagon and GIP levels did not change. We conclude that in patients with NIDDM, insulin significantly lowers basal SLI levels if normoglycemia is concomitantly attained; this action of insulin was partially dissociated from its hypoglycemic action; hyperglycemia per se inhibits a meal-induced SLI response, and insulin effects on SLI are not secondary to changes in glucagon or GIP levels.     

Direct effect of insulin on secretion of insulin, glucagon, gastric inhibitory polypeptide, and gastrin during maintenance of normoglycemia.

The direct effect of insulin on the secretion of insulin (as measured by C-peptide), glucagon, gastric inhibitory polypeptide, and gastrin was studied in normal subjects by infusing insulin while the plasma level of glucose was maintained in the normal fasting range (euglycemic clamp). Insulin-induced hypoglycemia resulted in increases in circulating glucagon and gastric inhibitory polypeptide, a decrease in C-peptide, and no change in gastrin levels. In contrast, during the euglycemic clamp, insulin was found to behave a direct suppressive effect on the secretion of glucagon, C-peptide, and gastrin, but no effect on levels of gastric inhibitory polypeptide.     

Insulin sensitivity in newly diagnosed type 1 diabetics after ketoacidosis and after three months of insulin therapy

Tissue sensitivity to insulin (euglycemic insulin clamp technique), hepatic glucose production (3-[3H]glucose infusion) and insulin binding to erythrocyte receptors were studied in 14 newly diagnosed type 1 diabetic patients after the disappearance of ketosis and after 3 months of insulin therapy. The control group consisted of 14 normal subjects. During the two insulin clamp studies, plasma glucose in the diabetic patients was maintained at 5.0 +/- 0.04 (SEM) mmol/liter and 4.9 +/- 0.05 mmol/liter, with corresponding steady state free insulin levels of 90 +/- 4 mU/liter, and 67 +/- 6 mU/liter (P less than 0.02) during the first and second study, respectively. The decline in free insulin levels was due to the development of insulin antibodies during insulin therapy (10 +/- 0.1% vs. 18 +/- 2%, P less than 0.001, serum insulin-binding capacity during the first and second study, respectively). In the normal subjects, steady state plasma glucose and insulin levels were 4.9 +/- 0.1 mmol/liter and 89 +/- 4 mU/liter, respectively. The rate of glucose metabolism (M) in the diabetic patients during the first study (5.13 +/- 0.65 mg/kg X min) was 35% lower than that in the normal subjects (7.94 +/- 0.50 mg/kg X min, P less than 0.005). After 3 months of insulin therapy, M increased by 35% to 6.92 +/- 0.58 mg/kg X min, which was comparable to that in the normal subjects. To compensate for the difference in plasma free insulin levels, we calculated an index for insulin sensitivity by dividing M by the ambient insulin concentration (I). During the 3 months of insulin therapy, M/I rose 2-fold to 11.63 +/- 1.10 mg/kg X min per mU insulin/liter X 100, which was similar to that in normal subjects (9.16 +/- 0.67 mg/kg X min per mU insulin/liter X 100). Five diabetic patients had a partial clinical remission, as determined by normal fasting C-peptide levels. In these patients, insulin sensitivity was 35-50% greater than in those who failed to have a remission (P less than 0.05). Basal hepatic glucose production in the diabetic patients during the first study (2.78 +/- 0.14 mg/kg X min) was 56% higher than in the normal subjects (1.78 +/- 0.04 mg/kg X min, P less than 0.001), and remained unchanged during insulin therapy. During the hyperinsulinemia induced by the clamp, hepatic glucose production was totally suppressed in both the diabetic and control subjects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Failure of human insulin to influence endogenous basal insulin secretion in mild diabetics

In evaluating the possibility of self-regulation of insulin secretion in man, human insulin may be more appropriate as an inhibitor to be considered than insulins from other species because the differences in the structure of the hormones might play some part in this conflicting proposal. The present study was carried out to examine whether human insulin per se can exert a feedback effect on the insulin secretion of B-cell in mild diabetics under physiologic condition. Fifteen mild diabetics were given a two-hour infusion of human insulin at a constant rate of 40 mU/m/min after a priming dose of 160 mU/m/min for the first two minutes. The plasma glucose in nine of these patients were maintained at their basal level of 92.8 +/- 3.7 mg/dL (Group A) with a glucose clamp technique (the coefficient of variation = 5.0 +/- 0.8% during the clamp), while that in the remaining six patients were intentionally altered, within physiologic range, from 114.5 +/- 8.4 mg/dL to 83.8 +/- 4.9 mg/dL (Group B). During insulin infusion the plasma immunoreactive insulin (IRI) level were well-maintained at about 50 microU/mL level in both groups, whereas the C-peptide reactivity (CPR) in group B decreased from 1.28 +/- 0.15 ng/mL to 0.59 +/- 0.14 ng/mL in parallel to the change of plasma glucose, in contrast to the relatively stable CPR level of 0.92 +/- 0.08 ng/mL in group A.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hormonal and metabolic rhythms in Cushing's syndrome

Hormone and metabolite profiles were investigated over a 12-hr period in six patients with Cushing's syndrome, ten age- and sex-matched normal controls, and six moderately obese subjects matched for weight with the patient group. Mean diurnal plasma cortisol levels were 563 ± 74 nmole/liter in the patients, 275 ± 22 nmole/liter in normal controls and 241 ± 32 nmole/liter in obese subjects, with total loss of diurnal changes in Cushing's syndrome. Fasting blood glucose concentration was similar in all groups although mild hyperglycemia occurred after meals in the Cushing's patients compared with normal and obese subjects (mean 12-hr blood glucose: Cushing's 6.31 ± 0.39 mmole/liter; normal controls, 5.32 ± 0.14 mmole/liter, p < 0.01; obese subjects, 5.41 ± 0.18 mmole/liter, p < 0.05) despite marked hyperinsulinemia (mean 12-hr serum insulin: Cushing's 57.3 ± 18.2 mU/liter; normal controls, 19.7 ± 2.5 mU/liter, p < 0.02; obese subjects, 18.1 ± 4.0 mU/liter, p < 0.05). Concentrations of the gluconeogenic precursors lactate, pyruvate, and alanine were raised in Cushing's syndrome, particularly postprandially. Plasma nonesterified fatty acids (NEFA), blood glycerol, and blood ketone body concentrations were comparable in all three groups although the normal diurnal variation in circulating NEFA and ketone body levels was lost in Cushing's syndrome. Serum triglyceride (TG) concentrations were grossly elevated in the Cushing's patients (mean 12-hr serum TG: Cushing's 3.51 ± 1.23 mmole/liter; normal controls 0.89 ± 0.19 mmole/liter, p < 0.02; obese subjects, 0.93 ± 0.23 mmole/liter, p < 0.05) and correlated positively with serum insulin levels. Plasma glucagon concentrations were raised in Cushing's syndrome (mean 12-hr plasma glucagon: Cushing's 23.2 ± 3.7 pmole/liter; normal controls 12.3 ± 1.5 pmole/liter p < 0.01; obese subjects 12.2 ± 2.0 pmole/liter, p < 0.02) and correlated positively with the serum cortisol but not with blood alanine, suggesting that some stimulatory factor other than alanine was responsible. The metabolic effects of chronic glucocorticoid excess thus may not be explained on the basis of obesity alone. Compensatory hyperinsulinemia limits the disturbance of carbohydrate and lipid metabolism in Cushing's syndrome but may be important in production of the hypertriglyceridemia observed.     

Acute cortisol excess results in unimpaired insulin action on lipolysis and branched chain amino acids, but not on glucose kinetics and C-peptide concentrations in man

To assess whether acute cortisol excess impairs insulin action on lipolysis, plasma amino acids, endogenous insulin secretion, and glucose kinetics, nine normal subjects were studied after acute cortisol excess (80 mg hydrocortisone by mouth) and after placebo. Insulin sensitivity was assessed 6 hours after hydrocortisone using the glucose clamp technique (insulin infusion of 20 mU/m2 X minute for 120 minutes, plasma insulin levels of approximately equal to 50 mU/L). Hyperinsulinemia suppressed plasma free fatty acids (FFA) similarly by 75 and 76%, respectively. Most plasma amino acid concentrations were increased after hydrocortisone; however, the insulin-induced decrease of branched chain amino acids, serine, threonine, and tyrosine was unimpaired after hydrocortisone. Plasma C-peptide concentrations were less suppressed during hyperinsulinemia after hydrocortisone than after placebo (by 0.15 +/- 0.03 v 0.25 +/- 0.02 nmol/L, P less than 0.01), suggesting diminished insulin-induced suppression of insulin secretion. The glucose infusion rates required to maintain euglycemia were 35% lower (P less than 0.01) after hydrocortisone due to decreased insulin effects on metabolic clearance rate of glucose and diminished suppression of hepatic glucose production (0.4 +/- 0.1 v -0.1 +/- 0.1 mg/kg X minute, p less than 0.05, 3-3H-glucose infusion method). The data demonstrate that acute elevation of plasma cortisol to levels near those observed in severe stress results in insulin resistance of peripheral and hepatic glucose metabolism but in unimpaired insulin effects on plasma FFA and branched chain amino acids, suggesting that cortisol's lipolytic and proteolytic effects are antagonized by elevated plasma insulin levels.     

Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: Studies with somatostatin

To study the role of glucagon in human glucose homeostasis, experimental glucagon deficiency was produced by infusing somatostatin (i.v. 250 μg bolus, followed by infusion of 500 μg/hr) in six normal subjects and in two hypophysectomized patients—an insulin-dependent diabetic and a nondiabetic. In normal subjects, somatostatin lowered plasma glucagon from a mean (± SE) basal level of 85 ± 15 to 33 ± 10 pg/ml, p < 0.001. Concurrently, plasma glucose fell from $\text{90 ± 2 to 73 ± 3 mg}\text{100 ml}$, p < 0.001. Serum insulin and growth hormone fell slightly during somatostatin infusion, while plasma free fatty acids rose. In both hypophysectomized patients, somatostatin lowered plasma glucagon and glucose levels. In all subjects, after stopping somatostatin infusions, plasma glucagon and glucose returned promptly to control values, while serum growth hormone did not change. In additional in vitro studies, somatostatin (1 μg/ml) had no effect on muscle glucose uptake. Since it is known that somatostatin has no direct effect on hepatic glucose production, these results suggest that the fall in plasma glucose during somatostatin infusion resulted from inhibition of glucagon secretion, thus providing evidence that this hormone plays a physiologic role in the maintenance of fasting euglycemia in man.     

Increased insulin sensitivity is associated with reduced insulin and glucagon secretion and increased insulin clearance in man

Insulin secretion is increased in insulin resistance. In this study, we examined whether high insulin sensitivity results in low insulin secretion. Twelve male master athletes [age 25.6 +/- 4.1 (mean +/- SD) yr] and seven male sedentary students (age 25.0 +/- 2.0 yr) underwent a hyperinsulinemic, euglycemic clamp and a glucose-dependent arginine stimulation test. Athletes had high insulin sensitivity [230 +/- 18 vs. 92 +/- 12 (nmol glucose/kg.min)/(pmol insulin/liter), P < 0.001] and low insulin response to arginine (at fasting glucose 135 +/- 22 vs. 394 +/- 60 pmol/liter, P < 0.001), which resulted in unaltered disposition index (32.8 +/- 3.8 vs. 33.5 +/- 3.3 micro mol glucose/kg.min, NS). Also, the C-peptide response to arginine was reduced (at fasting glucose 0.71 +/- 0.09 vs. 0.89 +/- 0.09 nmol/liter, P = 0.034). However, the C-peptide reduction was not as large as the insulin reduction yielding increased disposition index in athletes when calculated from C-peptide data (184 +/- 9 vs. 76 +/- 11 micro mol glucose/kg.min, P < 0.001). This difference is explained by increased insulin clearance among the athletes during the first 5 min after arginine (81.1% +/- 1.8% vs. 53.6% +/- 4.7%, P < 0.001). Also, the glucagon response to arginine was reduced in the athletes (58.8 +/- 6.7 vs. 90.1 +/- 9.9 ng/liter at fasting glucose, P = 0.009). We conclude that high insulin sensitivity results in low islet hormone secretion and increased insulin clearance.