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.     

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 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.     

Effects of weight loss and reduced hyperglycemia on the kinetics of insulin secretion in obese non-insulin dependent diabetes mellitus

Impairment in pancreatic production of insulin, a cardinal feature of noninsulin dependent diabetes mellitus (NIDDM), was quantified and the kinetics of insulin secretion characterized in six obese individuals with NIDDM before and after weight loss (18.0 +/- 3.0 kg, mean +/- SEM) using a validated mathematical model that employs C-peptide as a marker of the in vivo rate of insulin secretion. The metabolic clearance of C-peptide, assessed by decay analysis after bolus injection of biosynthetic human C-peptide, was not changed by weight loss (0.143 +/- 0.009 L/min.m2 vs. 0.137 +/- 0.010 L/min.m2). Kinetic parameters from each individual's decay curve before and after weight loss were used to derive accurate rates of secretion during the basal (postabsorptive) state, an oral glucose tolerance test and two hyperglycemic clamps. Basal rates of insulin secretion declined 20 +/- 5 pmol/min.m2 (96 +/- 15 to 76 +/- 15 pmol/min.m2, P less than 0.05) concomitant with decreases of 6.9 +/- 0.9 mmol/L in fasting serum glucose (13.7 +/- 1.0 to 6.8 +/- 0.7 mmol/L, P less than 0.05), 60 +/- 14 pmol/L in serum insulin (134 +/- 30 to 74 +/- 15 pmol/L, P less than 0.05), and 0.15 +/- 0.03 pmol/ml in plasma C-peptide (0.67 +/- 0.11 to 0.52 +/- 0.08 pmol/ml, P less than 0.05) concentrations. As expected, weight loss resulted in improved glucose tolerance as measured by the glycemic profiles during the oral glucose tolerance test (P less than 0.05 analysis of variance). The insulin secretory response before weight loss showed a markedly reduced ability to respond appropriately to an increase in the ambient serum glucose. After weight loss, the pancreatic response was more dynamic (P less than 0.05, analysis of variance) and parralleled the moment-to-moment changes in glycemia. Insulin production above basal doubled (11.2 +/- 3.2 to 24.5 +/- 5.8 nmol/6h.m2, P less than 0.05) and peak rates of insulin secretion above basal tripled (55 +/- 16 to 157 +/- 32 pmol/min/m2, P less than 0.05). To assess the beta-cell response to glucose per se and the changes associated with weight reduction, two hyperglycemic clamps were performed at steady state glucose levels in the range characteristic of individuals with severe NIDDM. At a fixed glycemia of 20 mmol/L, average rates of insulin secretion increased almost 2-fold with treatment (161 +/- 41 to 277 +/- 60 pmol/min.m2, P less than 0.05). At an increment of 6 mmol/L glucose above prevailing fasting glucose levels, the average rate of insulin secretion increased 53% (120 +/- 21 to 183 +/- 39 pmol/min.m2, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes

In Type II, non-insulin-dependent diabetes, insulin secretion is often reduced to the point where oral hypoglycaemic agents fail to control the plasma glucose level. We studied 12 patients (age 41-66 years; 4 lean, 8 obese) with Type II diabetes mellitus for 1-25 years who were uncontrolled despite maximal dose glibenclamide and metformin. After withdrawal of medication, blood glucose control was determined by measuring glucose before and 2 h after each meal for 48 h, and beta-cell function by insulin or C-peptide response to glucagon and to iv glucose. Following these tests, intensive insulin treatment (CSII) was initiated, and near-euglycaemia (mean of 7 daily glucose determinations less than 7.7 mmol/l) was maintained for 16.6 +/- 1.5 days, at which time the tests were repeated. Mean daily insulin requirement was 61 +/- 9 IU (0.81 +/- 0.09 IU/kg). Glucose control was improved after cessation of CSII (mean glucose 12.7 +/- 0.6 mmol/l after vs 20 +/- 1.5 mmol/l before, P less than 0.005). Maximum incremental C-peptide response improved both to glucagon (214 +/- 32 after vs 134 +/- 48 pmol/l before, P = 0.05) and to glucose iv bolus injection (284 +/- 53 vs 113 +/- 32 pmol/l, P less than 0.05). Peak insulin response, measured after iv glucose infusion, also tended to be higher in the post-CSII test (42 +/- 18 vs 22 +/- 5.6 mU/l). Basal and stimulated proinsulin concentrations were high relative to C-peptide levels during the pre-treatment period, but returned to normal after CSII.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastric inhibitory polypeptide in obesity and diabetes mellitus

Gastric inhibitory polypeptide (GIP) concentrations may be influenced by obesity, diabetes, and glucagon deficiency and be under feedback inhibition by insulin. To assess these factors, insulin-dependent diabetic, totally pancreatectomized diabetic, and lean and obese noninsulin-dependent diabetic patients were studied twice, once during partial insulin withdrawal and again when euglycemia was achieved before and after mixed meal ingestion, using an artificial endocrine pancreas. The results were compared to those from weight-matched lean and obese nondiabetic subjects. No significant differences in postprandial GIP responses were found between lean and obese nondiabetic subjects. Despite basal and postprandial hyperglycemia, the GIP responses to the mixed meal were not significantly different between insulin-deficient (insulin-dependent and totally pancreatectomized) patients and lean nondiabetic subjects. In addition, there were no significant differences in postprandial GIP responses between insulin-dependent and totally pancreatectomized patients. In contrast, lean and obese noninsulin-dependent diabetic patients had reduced GIP responses compared to weight-matched nondiabetic subjects (mean +/- SE, 37.9 +/- 5.4 vs. 67.1 +/- 10.8 ng ml-1 240 min-1, respectively; P less than 0.05). This difference was entirely due to the reduced GIP responses in obese noninsulin-dependent diabetic patients compared to those in obese nondiabetic subjects (32.1 +/- 7.9 vs. 76.9 +/- 18.2 ng ml-1 240 min-1, respectively; P less than 0.05); the postprandial GIP responses were not significantly different between lean noninsulin-dependent diabetic patients and lean nondiabetic subjects. Insulin infusion by an artificial endocrine pancreas resulted in postprandial insulin and glucose profiles that approximated those of nondiabetics, but did not significantly alter GIP responses to the mixed meal (48.2 +/- 5.5 ng ml-1 240 min-1) in the 18 diabetic patients compared to results obtained with sc insulin treatment (42.2 +/- 5.2 ng ml-1 240 min-1). In conclusion, postprandial GIP responses are normal in obese nondiabetic subjects and insulin-deficient diabetic patients and are blunted in obese, but not in lean, noninsulin-dependent diabetic patients. In addition, GIP does not appear to be under feedback inhibition by insulin or influenced by glucagon deficiency in diabetes.     

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.     

Dose-response characteristics for arginine-stimulated insulin secretion in man and influence of hyperglycemia

To test the hypothesis that glucose only affects the responsiveness (maximum velocity) of the beta-cell to arginine without changing the sensitivity (ED50) of the beta-cell to arginine, we investigated the influence of hyperglycemia on the responsiveness and sensitivity of arginine-induced insulin secretion in eight healthy male volunteers. Plasma C-peptide and insulin levels achieved during infusions of five doses of arginine (30 min) with and without a 60-min hyperglycemic clamp (17 mmol/L) were analyzed using a modified Michaelis-Menten equation. At euglycemia, the ED50 (half-maximally stimulating serum arginine concentration) was significantly less for first phase than for second phase plasma C-peptide secretion (0.7 +/- 0.1 vs. 2.7 +/- 0.4 mmol/L; P less than 0.002). Hyperglycemia significantly increased arginine-induced insulin secretion at all arginine infusion rates (P less than 0.01) without significantly altering the ED50 for either phase. We conclude 1) that the regulation of arginine-induced insulin secretion differs between both phases of insulin secretion, and 2) that a 1-h infusion with glucose significantly potentiates arginine-induced insulin secretion without influencing the difference in regulation of both phases of arginine-induced insulin secretion, supporting the validity of the use of arginine as a secretagogue in studies involving hyperglycemia.     

Altered metabolic and hormonal responses to epinephrine and beta-endorphin in human obesity

Catecholamines and endogenous opioid peptides are released in response to stress. Exogenous infusions of epinephrine and beta-endorphin (both in doses of 15, 50, and 80 ng/kg.min sequentially, each dose lasting 30 min) were used to mimic short term stress in both normal weight (body mass index, less than 25 kg/m2) and obese (body mass index, greater than 30 kg/m2) subjects. Fasting plasma insulin, C-peptide, and beta-endorphin concentrations were significantly higher in the obese than in the normal subjects (P less than 0.01-0.005). In lean subjects epinephrine produced significant increases in plasma glucose levels, but no appreciable changes in plasma insulin, C-peptide, or glucagon. Infusion of beta-endorphin in the same subjects caused plasma glucose and glucagon to rise, but insulin and C-peptide levels did not change. The simultaneous infusion of epinephrine and beta-endorphin produced a glycemic response which, although greater, was not significantly different than the sum of the responses to the individual hormone infusions. However, the two hormones had a synergistic interaction on plasma glucagon levels [total glucagon response, 2275 +/- 370 pg/min.mL (ng/min.L); sum of single effects, 750 +/- 152 (+/- SE) pg/min.mL (ng/min.L); P less than 0.01]. The plasma epinephrine [207 +/- 21, 607 +/- 70, and 1205 +/- 134 pg/mL (1130 +/- 115, 3640 +/- 382, and 6577 +/- 691 pmol/L] and beta-endorphin [875 +/- 88, 1250 +/- 137, and 1562 +/- 165 pg/mL (250 +/- 25, 358 +/- 39, and 447 +/- 47 pmol/L] concentrations attained during the infusions of each single hormone were not different from those recorded during the combined hormonal infusion. In obese subjects epinephrine raised plasma glucose levels and caused dose-related increments of plasma glucagon concentrations. Plasma insulin and C-peptide concentrations remained low and rebounded at the end of the infusions. In the same subjects, beta-endorphin produced elevations of plasma glucose, insulin, C-peptide, and glucagon. When the combined hormonal infusion was given to obese subjects, the plasma epinephrine and beta-endorphin concentrations rose to values not significantly different from those in normal weight subjects. However, there was a dramatic increase in plasma glucose exceeding 200 mg/dL (11.1 mmol/L), which remained elevated 30 min after the infusion. The glucagon response was not greater than the sum of the single effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Twenty-four-hour profile of plasma glucose and glucoregulatory hormones during normal living conditions in trained and untrained men

Compared with untrained (UT) subjects, in trained (T) subjects the increased insulin sensitivity and decreased glucose induced insulin secretion would tend to promote health by decreasing glucose levels and insulin secretion whereas the increased food intake would tend to increase these variables. To study the net effect of training, blood was sampled from seven T and eight UT young men [VO2max: 76 +/- 2 (T) vs. 48 +/- 1 (UT) mL.kg-1.min-1] for 24 h during ordinary living conditions. Athletes exercised 204 +/- 20 min and ate 50% more calories and 130% more carbohydrate than UT subjects (P less than 0.05). However, 24-h integrated plasma concentrations of glucose, C-peptide, glucagon, free fatty acids, and glycerol as well as glycosylated hemoglobin levels were identical in T and UT subjects. Mean insulin concentration was 41% lower in T than in UT but levels differed significantly (P less than 0.05) only late during the night. Urinary excretion of pancreatic peptides paralleled plasma concentrations. In conclusion, during training adaptations in pancreas- and insulin-sensitive tissues allow the necessary increase in food intake without harmful hyperglycemia and overloading of beta-cells, but sparing of insulin secretion and reductions in glucose levels are only relative to food intake. However, training may be wholesome by increasing hepatic insulin extraction and thereby decreasing arterial insulin levels. Training-induced beta-cell adaptation is not caused by diminished average glucose levels. Finally, renal handling of insulin, C-peptide, and glucagon is not influenced by training.     

Impaired insulin response to glucose but not to arginine in heroin addicts

Plasma glucose, insulin, glucagon and growth hormone responses to both oral glucose and iv arginine were evaluated in 15 heroin addicts and 15 control subjects matched for age, sex and weight. The heroin users had an exaggerated rise in plasma glucose concentrations following oral sugar, which persisted until the end of the study (102 +/- 5 mg/dl in addicts vs 72 +/- 3 mg/dl in controls at 240 min, p less than 0.01) and significantly lower insulin responses (insulin peak 28 +/- 4 microU/ml in addicts vs 67 +/- 8 microU/ml in controls, p less than 0.01). The inhibitory effect of glucose on glucagon concentrations was less evident in addicts than in controls. The responses of plasma glucose, insulin and glucagon to arginine were not significantly different between addicts and controls, while the growth hormone rise was significantly greater in addicts. These results demonstrate that heroin users have impaired insulin secretion to oral glucose but not to arginine and suggest that: the impaired insulin secretion in heroin addicts is not dependent on beta-cell exhaustion, and a selective inhibition of glucose-induced insulin secretion is operative in these subjects, as it happens in patients with noninsulin-dependent diabetes mellitus.     

The effect of various blood glucose levels on post-glucagon C-peptide secretion in type 2 (non insulin-dependent) diabetes.

We investigated how different plasma glucose concentrations could significantly modify the C-peptide response to glucagon. Twenty poorly-controlled (HbA1c 10.2 +/- 1.5%) non insulin-dependent (NIDDM) subjects (body mass index 27 +/- 1.8), 2 treated with diet alone and 18 with oral hypoglycemic agents were studied. The first day glucagon (1 mg iv) was injected, patients being fasting and untreated. Mean plasma glucose levels were 11.4 +/- 1.2 mM. On a second non consecutive day, after an overnight fast, the same patients were connected to a closed-loop insulin infusion system (Betalike, Genoa), their blood glucose concentrations were stabilized within a normoglycemic range (5-5.5 mM) for 2 h and insulin infusion was stopped. The glucagon test was repeated 30 min later. Blood samples were taken 0, 6, 10, 20 min after glucagon injection. In the second test, basal, and 6, 10 and 20 min post-glucagon glucose levels were significantly lower (p less than 0.001); similarly C-peptide concentrations were significantly reduced both in basal conditions (0.55 +/- 0.04 vs 0.37 +/- 0.04 nM; p less than 0.001) and 6 (0.92 +/- 0.06 vs 0.6 +/- 0.06; p less than 0.001), 10 (0.79 +/- 0.06 vs 0.56 +/- 0.06; p less than 0.001) and 20 min (0.64 +/- 0.05 vs 0.44 +/- 0.04; p less than 0.001) after stimulation. The C-peptide secretion area showed the same trend (49.5 +/- 4.8 vs 32.1 +/- 5.8; p less than 0.001). In conclusion, our data confirms that blood glucose levels modulate the pancreatic insulin secretion; glycemic normalization significantly reduced both basal and post-glucagon C-peptide release.     

Nocturnal elevation of glucose levels during fasting in noninsulin-dependent diabetes

To define the spontaneous diurnal variations in glucose regulation during fasting in noninsulin-dependent diabetes (NIDDM), we measured circulating levels of glucose, insulin, C-peptide, GH, cortisol, and glucagon at 15-min intervals in 11 patients with untreated diabetes and 7 matched control subjects studied during a 24-h period. The rates of insulin secretion were derived from the concentrations of C-peptide by deconvolution using a two-compartment mathematical model for C-peptide distribution and metabolism. In both groups of subjects, despite continued fasting, glucose levels stopped declining in the evening and subsequently rose throughout the night to reach a morning maximum. Elevated levels persisted until noon. The morning glucose maximum corresponded to a relative increase of 23.8 +/- 5.5% above the evening nadir in NIDDM patients and 13.2 +/- 4.6% in nondiabetic subjects (P less than 0.05). In NIDDM patients, insulin levels and insulin secretion rates did not parallel the nocturnal glucose changes. In contrast, in control subjects, this nocturnal glucose rise coincided with a similar increase in insulin secretion rates. Cortisol concentrations in patients with NIDDM were higher than those in control subjects throughout the study period (P less than 0.001) and rose earlier in the evening than in control subjects, thus failing to demonstrate the normal nocturnal suppression. In both groups of subjects, the nighttime glucose elevation was temporally and quantitatively correlated with the circadian cortisol rise. GH secretion was increased in the evening and nighttime periods compared to the daytime values, and in NIDDM patients, but not in control subjects, the size of the morning glucose elevation was directly related to the magnitude of this increase in GH secretion (r = 0.88; P less than 0.01). Glucagon concentrations were similar in both groups of subjects and remained essentially constant throughout the study period. We hypothesize that the nocturnal glucose rise that occurs during fasting represents a normal diurnal variation in the set-point of glucose regulation amplified by counterregulatory mechanisms activated by the fasting condition.     

Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 +/- 1.2 vs 11.4 +/- 1.2 mmol/l, P less than 0.01) without enhancing mean day-time plasma insulin (43 +/- 4 vs 50 +/- 7 mU/l, NS) or C-peptide levels (1.26 +/- 0.12 vs 1.38 +/- 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 +/- 0.16 vs 1.44 +/- 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 +/- 0.11 vs 1.38 +/- 0.11 mmol/l, P less than 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 +/- 38 vs 313 +/- 33 mg.m-2.min-1, P less than 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 +/- 5.8 vs 50.6 +/- 2.8 ml.m-2.min-1, P less than 0.05), whereas basal hepatic glucose production was unchanged (81 +/- 6 vs 77 +/- 4 mg.m-2.min-1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Suppression of glucagon secretion during a tolbutamide infusion in normal and noninsulin-dependent diabetic subjects

To determine the effect of tolbutamide on glucagon release in noninsulin-dependent diabetic and normal subjects and how plasma glucose levels may modulate this effect, the acute glucagon response (AGR) to a 5-g iv arginine pulse was determined before and during a tolbutamide infusion. There was a decrease in plasma glucose concentration in both normal and diabetic subjects (both P less than 0.001); there tended to be a suppression of the AGR (4 of 6 normals and 8 of 11 diabetics), but this suppression was not statistically significant. In separate studies, when the plasma glucose level was clamped at baseline values by a variable rate of glucose infusion, the AGR was suppressed during the tolbutamide infusion in all 7 normal [change in AGR (delta AGR) = -35 +/- 12 pg/ml; P less than 0.05] and all 6 noninsulin-dependent diabetic subjects (delta AGR = -14 +/- 5 pg/ml, p less than .05). In 6 insulin-dependent diabetic subjects, there was no evidence of glucagon suppression by tolbutamide (delta AGR = +2 +/- 2 pg/ml). These results are consistent with the hypothesis that sulfonylureas suppress glucagon secretion by augmenting insulin secretion, an effect that falling glucose levels can mask. Consideration of this observation is necessary when interpreting the effects of a sulfonylurea on islet cell responses.     

Lack of effect of high-dose biosynthetic human C-peptide on pancreatic hormone release in normal subjects

We studied the effect of high doses of biosynthetic human C-peptide on pancreatic hormone secretion in response to oral (75 g) and intravenous [( IV] 0.33 g/kg of D50%) glucose on normal volunteers. The infusion of human C-peptide at a rate of 360 ng/kg/min body weight, increased the plasma C-peptide concentration from a basal level of 0.32 +/- 0.04 pmol/mL to 38.5 +/- 1.8 pmol/ml. Overall, C-peptide had no significant effect on the serum levels of glucose, insulin, proinsulin, glucagon, and pancreatic polypeptide, either under basal conditions or following IV and oral glucose administration. However, small decreases in glucose and insulin concentrations that were not statistically significant were seen during the first hour after C-peptide infusion. The results of the present studies are therefore consistent with the conclusion that even supraphysiologic plasma concentrations of infused C-peptide do not affect basal insulin secretion or overall insulin secretory responses to oral or IV glucose. However, we cannot definitively exclude a small reduction in insulin secretion in the first hour after oral glucose ingestion.     

Hyperglycemia per se (insulin and glucagon withdrawn) can inhibit hepatic glucose production in man.

We examined the effect of hyperglycemia per se on net splanchnic glucose balance. In 2 groups of normal postabsorptive men who had undergone hepatic vein catheterization, somatostatin was administered to block endogenous insulin and glucagon secretion. Exogenous glucose was infused in both groups to maintain euglycemia for 2 h in one group (n = 7) and to induce hyperglycemia of 220-240 mg/dl after 30 minutes of euglycemia in the second group (n = 4). In both groups the induction of insulinopenia and glucagonopenia with euglycemia maintained resulted in an initial 75% fall in net splanchnic glucose production (NSGP). In the group in which euglycemia was maintained NSGP returned to basal rates (157 +/- 31 mg/min) within 2 h. However, in the group in which hyperglycemia was induced, NSGP did not return to basal rates but remained suppressed (28 +/- 4 mg/min) for the duration of the study. These data in normal man indicate that hyperglycemia per se with insulin and glucagon acutely withdrawn can suppress splanchnic glucose production but does not induce net splanchnic glucose storage.     

The effects of epinephrine on islet hormone secretion in the dog

We investigated the direct effects of physiological levels of epinephrine on the basal and arginine-stimulated secretion of insulin, glucagon, and somatostatin from the in situ pancreas in halothane-anaesthetized dogs. An IV infusion of 20 ng/kg/min of epinephrine increased plasma epinephrine levels to 918 +/- 103 pg/ml (P less than 0.001), and increased the baseline pancreatic output of insulin (P less than 0.05), glucagon (P less than 0.05) and somatostatin (P less than 0.05). The acute insulin response (AIR) to 2.5 g of arginine during this infusion of epinephrine was significantly higher (P less than 0.05) than in controls as were the acute glucagon response (AGR) (P less than 0.05) and the acute somatostatin response (ASLIR) (P less than 0.05). Plasma glucose levels increased slightly and transiently during infusion of epinephrine from 99 +/- 2 mg/dl to a maximum of 110 +/- 3 mg/dl (P less than 0.05). An IV infusion of 80 ng/kg/min of epinephrine produced plasma epinephrine levels of 2,948 +/- 281 pg/ml, and increased the baseline pancreatic output of insulin (P less than 0.05) and glucagon (P less than 0.05). In contrast, baseline somatostatin output decreased transiently during this high dose infusion of epinephrine. The AIR and ASLIR to arginine were both significantly lower (P less than 0.05) than those during the infusion of epinephrine at the low dose. The AGR to arginine remained potentiated (P less than 0.05). Plasma glucose levels increased from 99 +/- 3 mg/dl to 119 +/- 4 mg/dl (P less than 0.01). We conclude that the effect of epinephrine on islet hormone secretion is dependent on the plasma level of epinephrine. At stress levels of 900-1000 pg/ml, both insulin and somatostatin secretion are stimulated; only at near pharmacologic, or extreme stress levels, does epinephrine produce net inhibition.     

Amylase/Creatinine Clearance Ratio Response to Hyperglucagonemia in Diabetes and Obesity

Hyperglucagonemia accompanies several disorders such as acute pancreatitis and diabetic ketoacidosis characterized by increased amylase/creatinine clearance ratio (ACCR). We tested the hypothesis that glucagon may be responsible for the augmental ACCR among diabetic and/or obese subjects. A constant glucagon infusion (15 ng/kg/min) was given to eight noninsulin-dependent diabetics and to eight obese subjects to attain glucagon levels comparable with those obtained during acute pancreatitis. The ACCR significantly increased from 0.9 +/- 0.1 to 1.5 +/- 0.1% (p less than 0.005) in both noninsulin-dependent diabetics and obese subjects, whereas among normal control subjects the ACCR increased from 0.84 +/- 0.8 to 1.3 +/- 0.14% (p less than 0.001). Because the increased values observed in either noninsulin-dependent diabetics or obese subjects are less than the ACCR values observed in acute pancreatitis or in diabetic ketoacidosis, the elevated ACCR in those conditions is only partially explained by the hyperglucagonemia.