Infusion of synthetic human C-peptide does not affect plasma glucose, serum insulin, or plasma glucagon in healthy subjects

We studied six healthy male subjects to determine whether a four-hour infusion of synthetic human C-peptide sufficient to achieve mean (+/- SD) peripheral plasma concentrations of 1.3 +/- 0.7 pmol/mL affected plasma glucose, serum insulin, or plasma glucagon. Subjects were studied in a fasting state and following an oral glucose load during four-hour 0.9% NaCl (control) and C-peptide (mean dose: 70 nmol) infusions. No differences were observed between saline and C-peptide infusions for mean values of fasting plasma glucose (94 +/- 6 v 87 +/- 5 mg/dL), serum insulin (3 +/- 1 v 2 +/- 1 microU/mL), or plasma glucagon (124 +/- 65 v 112 +/- 70 pg/dL). Following oral glucose ingestion no differences were detected between saline and C-peptide infusions for mean peak values of plasma glucose (168 +/- 18 v 168 +/- 31) and serum insulin (59 +/- 6 v 57 +/- 21) or mean nadir values of plasma glucagon (80 +/- 73 v 75 +/- 70). There was a slight delay in the insulin rise following oral glucose on the C-peptide infusion day, but differences between mean values for individual sampling times were not statistically significantly different.     

Persistence of altered metabolic responses to beta-endorphin after normalization of body weight in human obesity

The responses of plasma glucose, insulin, C-peptide and glucagon to an infusion of human beta-endorphin (0.5 mg/h) were studied in 10 formerly obese subjects who had lost 35 kg by dieting (body mass index less than 25) and compared with those of 10 normal-weight control (body mass index less than 25) and 10 obese (body mass index greater than 30) subjects. The fasting plasma concentrations of beta-endorphin were significantly higher in both the obese and the post-obese group than in the control group. In both obese and post-obese subjects, the infusion of beta-endorphin caused significant increases in peripheral plasma glucose, insulin, C-peptide and glucagon concentrations. In the control group, matched for age, sex and weight with the formerly obese group, there was no appreciable change in plasma insulin and C-peptide concentrations during the infusion of beta-endorphin, but the rise in plasma glucose was more sustained. Thus, 1. the increased plasma beta-endorphin concentrations found in human obesity are not corrected by normalization of body weight; and 2. formerly obese, normal-weight subjects behave as obese subjects in their metabolic and hormonal responses to beta-endorphin infusion. The alteration of the opioid system in human obesity may play some role in the predisposition to weight gain.     

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.     

Physiological elevations of plasma beta-endorphin alter glucose metabolism in obese, but not normal-weight, subjects.

The present study was undertaken to evaluate the metabolic and hormonal responses to physiologic elevations of plasma beta-endorphin concentrations in both normal-weight and obese healthy subjects. The infusion of synthetic human beta-endorphin (4.5 ng/kg/min) produced the following: (1) in normal-weight subjects, no significant change of plasma glucose and pancreatic hormones (insulin, C-peptide, and glucagon), a significant plasma free fatty acids (FFA) increase, and a suppression of glycerol plasma levels; (2) in obese subjects, significant increases of glucose, insulin, C-peptide, and glucagon, a progressive decline of circulating FFA, and no change in glycerol plasma levels. In obese subjects, the intravenous administration of naloxone, given as a bolus (5 mg injected in 5 minutes) before the start of beta-endorphin infusion, reduced the plasma glucose response to the opioid by approximately half, annulled the pancreatic hormonal responses, and also reduced the FFA, but not glycerol, response. In normal-weight subjects, naloxone pretreatment did not induce any change of the flat glucose and hormonal responses to beta-endorphin, but reversed its effects on circulating FFA and glycerol. These data suggest that physiological elevations of plasma beta-endorphin concentrations produce metabolic and hormonal effects in obese subjects significantly different from those occurring in normal-weight subjects; these effects are partially naloxone-sensitive, suggesting the mediation of endogenous opioid receptors.     

Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of somatostatin on epinephrine-stimulated glucose production in the dog

The effects of somatostatin on epinephrine-stimulated hepatic glucose production were assessed in the conscious overnight fasted dog. Glucose production was measured using a primed constant infusion of 3-3H-glucose. Two experiments were performed on each of four animals, each experiment consisting of a tracer equilibration period (80 minutes), a control period (40 minutes), and a test period (180 minutes). In the first experiment, epinephrine was infused at 0.08 microgram/kg/min during the test period so that the plasma concentration rose from 138 +/- 4 to 727 +/- 109 pg/mL. In the second experiment two weeks later, epinephrine was again infused (112 +/- 17 to 727 +/- 148 pg/mL) but with somatostatin (0.8 microgram/kg/min) and intraportal replacement amounts of insulin and glucagon. The pancreatic hormones were administered in such a way as to mimic the insulin and glucagon levels observed during epinephrine infusion in the first experiment. In the first experiment, epinephrine caused changes in insulin and glucagon levels at five minutes of plus 9 +/- 1 microU/mL and minus 1 +/- 3 pg/mL, respectively, and averaged plus 6 +/- 2 microU/mL and minus 9 +/- 5 pg/mL over the first hour. Glucose production peaked at 15 minutes (increment of 0.83 +/- 0.24 mg/kg/min) and increased by an average of 0.38 +/- 0.12 mg/kg/min in the first hour. In the second experiment, intraportal replacement of insulin and glucagon during epinephrine infusion resulted in changes in insulin and glucagon levels at five minutes of plus 8 +/- 3 microU/mL and plus 2 +/- 2 pg/mL, respectively, and averaged plus 4 +/- 2 microU/mL and minus 7 +/- 6 pg/mL over the first hour.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of massive obesity on insulin sensitivity and insulin clearance and the metabolic response to insulin as assessed by the euglycemic clamp technique

Insulin sensitivity was studied in nine nondiabetic massively obese patients (one male and eight females ages 39.0 +/- 2.7 years, body mass index 47.1 +/- 1) by the euglycemic clamp technique (40 microU/m2/min) and compared to seven lean control subjects (three males and three females, ages 34.8 +/- 2.5 years, body mass index 23 +/- 1.1). Fasting plasma glucose, immunoreactive insulin, and C-peptide concentrations were higher in the massively obese patients than in the controls (P less than 0.025). Following exogenous insulin infusion, immunoreactive glucagon and C-peptide concentrations decreased similarly in the massively obese patients and controls, indicating normal sensitivity of the alpha and beta cell to insulin. Glucose uptake (M) expressed either as mg X min-1 of fat free mass was significantly reduced in the massively obese patients compared to the controls (P less than 0.001). Similarly, the M/I ratio (glucose uptake per unit of insulin) was significantly reduced in the massively obese patients (P less than 0.001). Free fatty acids and glycerol concentrations measured in the fasting state were significantly elevated in the massively obese patients (free fatty acids 678 +/- 51 v 467 +/- 55 mumol/L, P less than 0.05; glycerol 97 +/- 9 v 59 +/- 11 mumol/L, P less than 0.02). The effects of insulin on antilipolysis was assessed by measuring the reductions in free fatty acids and glycerol concentration during the glucose clamp study. Although the absolute levels remained higher in the massively obese patients, inhibition of lipolysis was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circulating amino acids and pancreatic endocrine function after ingestion of a protein-rich meal in obese subjects

We measured plasma amino acid together with insulin, glucagon, pancreatic polypeptide (PP), and glucose concentrations after the ingestion of a protein meal in lean and obese subjects. The basal plasma amino acid levels were similar in both groups. The postprandial increase in the plasma amino acid levels in the obese subjects was only 15-50% of that in the lean subjects. The mean basal and peak postprandial plasma insulin levels were significantly higher (72 and 165 pmol/L) in the obese group than in the lean group (36 and 115 pmol/L; P less than 0.05-0.01). The postprandial rise in plasma glucagon was largely attenuated in the obese subjects, and there was no difference in plasma PP and glucose levels in the 2 groups. To further evaluate the role of circulating amino acids on pancreatic endocrine function in obese and lean subjects, an amino acid mixture consisting of 15 amino acids was infused iv. During the infusion the plasma amino acid levels were comparable in both groups. Plasma insulin rose by 36 +/- 7 (+/- SE) pmol/L (5 +/- 1 microU/mL) in the lean and 129 +/- 22 pmol/L (18 +/- 3 microU/mL) in the obese subjects, whereas plasma glucagon, PP, and glucose levels were similar in both groups. In view of the 3.6-fold greater insulin responses in the obese subjects, it is likely that circulating amino acids contribute to their hyperinsulinemia in spite of the reduced postprandial rise of amino acids in this group (50-85%). Thus, under physiological conditions amino acids have to be considered as an important regulatory component of postprandial insulin release in obese subjects.     

The effects of epinephrine on ketogenesis in the dog after a prolonged fast

The effects of a selective increase in epinephrine on ketogenesis and lipolysis were determined in the conscious dog following a prolonged fast (7 days). Plasma insulin and glucagon were fixed at basal levels by infusion of somatostatin (0.8 micrograms/kg/min) and basal intraportal replacement amounts of insulin (210 +/- 20 microU/kg/min) and glucagon (0.65 ng/kg/min). Following a 40-minute control period, saline or epinephrine (0.04 microgram/kg/min) was infused for 3 hours. Plasma insulin, glucagon, and norepinephrine levels did not change during saline (6 +/- 1 microU/mL, 83 +/- 17 pg/mL, and 137 +/- 38 pg/mL, respectively) or epinephrine (10 +/- 1 microU/mL, 73 +/- 18 pg/ml, 98 +/- 13 pg/mL, respectively) infusion. Plasma epinephrine levels increased from 80 +/- 26 to 440 +/- 47 pg/mL in response to infusion of the catecholamine, but remained unchanged during saline infusion. Glycerol levels (93 +/- 10 mumol/L) remained unchanged during saline infusion, but increased in response to epinephrine (108 +/- 9 to 170 +/- 18 mumol/L by 30 minutes). The glycerol level had returned to baseline and to the value apparent in saline controls by 60 minutes. The nonesterified fatty acid (NEFA) level declined slowly during the 3-hour saline infusion, but was elevated in response to epinephrine infusion (1.27 +/- 0.16 to 1.97 +/- 0.25 mmol/L at 30 minutes). After the initial epinephrine-induced increase, the NEFA level declined so that by 3 hours it was not significantly different from the basal or saline values.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency

The physiological significance of the hyperglucagonemia that occurs in patients with many catabolic conditions is unclear. The effect of hyperglucagonemia on resting metabolic rate (RMR) was studied in six normal subjects. Infusion of somatostatin (SRIH; 500 micrograms/h for 210 min) resulted in a 5-fold decrease in plasma C-peptide and a 2-fold decrease in plasma insulin and glucagon concentrations, but did not change RMR significantly. When glucagon (0.2 micrograms/kg X h), was infused with SRIH (500 micrograms/h for 210 min), the decreases in plasma C-peptide and insulin were similar to that during the infusion of SRIH alone, but plasma glucagon increased from 160 +/- 24 (+/- SEM) to 560 +/- 80 pg/mL (P less than 0.001). There was a significant increase in RMR during the entire period (210 min) of glucagon infusion (P less than 0.01). During the last hour of the glucagon plus SRIH infusion, the RMR was 1.38 +/- 0.10 Cal/min, which was 15% higher than the preinfusion RMR (1.19 +/- 0.10 Cal/min; P less than 0.01) and 14% higher than the RMR during the same period when SRIH alone was infused (1.21 +/- 0.11 Cal/min; P less than 0.01). When SRIH and glucagon were infused, protein oxidation (calculated from urinary nitrogen loss) was 52 +/- 5 mg/min, 29% higher than when SRIH alone was infused (40 +/- 5 mg/min; P less than 0.05). These results indicate that hyperglucagonemia during insulin deficiency results in an increase in energy expenditure, which may contribute to the catabolic state in many conditions.     

How does glucose regulate the human pancreatic A cell in vivo?

Summary To investigate the mechanism whereby changes in plasma glucose level alter human pancreatic A-cell activity in vivo, A-cell activity was determined during manipulation of plasma glucose and pancreatic B-cell activity by insulin and glucose infusions. A-cell activity (the acute immunoreactive glucagon response to intravenous arginine, 0–10 min) rose from 482±125 to 968±191 pg · ml^-1 · 10 min^-1 (mean±SEM) when the plasma C-peptide level (a measure of B-cell activity) was suppressed from 2164±365 to 872±162 pg/ml by an insulin infusion at euglycaemia (employing the glucose clamp technique) in six normal subjects. Raising plasma glucose to 6.7 mmol/l during the same insulin infusion returned mean C-peptide (2688±581 pg/ml) and the acute glucagon response to arginine (447±146 pg · ml^-1 · 10 min^-1) close to basal levels. Individual changes in the acute glucagon response to arginine followed the C-peptide changes. The mean change in the acute glucagon response to arginine per unit change in plasma glucose (-191±36) was similar to that seen when plasma glucose was raised to twice basal levels in six different subjects without an insulin infusion (-159±45). This suggests that, when plasma glucose is raised to about twice basal level in vivo, the major factor in suppressing A-cell activity is the concurrent change in B-cell activity rather than direct effects of glucose or circulating insulin on the A cell.     

Secretion and hepatic extraction of insulin after weight loss in obese noninsulin-dependent diabetes mellitus

We assessed the effects of weight loss on pancreatic secretion and hepatic extraction of insulin in 11 obese subjects with noninsulin-dependent diabetes mellitus. Weight loss of 15.4 +/- 2.0 kg (mean +/- SE) resulted in decreased fasting insulin [20.2 +/- 2.5 to 9.8 +/- 2.5 microU/mL (145 +/- 18 to 70 +/- 18 pmol/L); P less than 0.02] and C-peptide (850 +/- 80 to 630 +/- 110 pmol/L; P less than 0.05) levels. The plasma glucose response to oral glucose and iv glucagon was improved with unchanged peripheral insulin levels. When plasma glucose levels were matched to those before weight loss, peripheral serum insulin and plasma C-peptide responses to iv glucagon were increased and similar to those in obese nondiabetic subjects studied at euglycemia. The total insulin response (area under the curve) to iv glucagon was reduced 30% (P less than 0.005), while the total C-peptide response area did not change after weight loss. At matched hyperglycemia, the total response area was enhanced 72% for insulin (P less than 0.002) and 64% for C-peptide (P less than 0.001). Incremental (above basal) response areas after weight loss did not change for insulin, but increased 66% for C-peptide (P less than 0.05). The incremental areas were augmented nearly 2-fold (196%) for insulin (P less than 0.01) and 1.7-fold (173%) for C-peptide (P less than 0.01) when assessed at matched hyperglycemia. Both basal (7.3 +/- 0.5 to 14.1 +/- 1.8; P less than 0.01) and total stimulated (6.1 +/- 0.4 to 8.8 +/- 1.4; P less than 0.05) C-peptide to insulin molar ratios increased after weight loss. We conclude that after weight loss in noninsulin-dependent diabetes mellitus, 1) insulin secretion is decreased in the basal state but increased after stimulation; 2) changes in insulin secretion are reflected by peripheral levels of C-peptide but not insulin, due in part to enhanced hepatic insulin extraction; and 3) at matched levels of hyperglycemia insulin secretion is markedly increased and similar to that in obese nondiabetic subjects studied at euglycemia.     

Effects of ketone bodies on carbohydrate metabolism in non-insulin-dependent (type II) diabetes mellitus

The ability of ketone bodies to suppress elevated hepatic glucose output was investigated in eight postabsorptive subjects with non-insulin-dependent diabetes mellitus (NIDDM). Infusion of sodium acetoacetate alone (20 mumols/kg/min) for 3 hours increased total serum ketones (beta-hydroxybutyrate and acetoacetate) to approximately 6 mmol/L, but did not reduce plasma glucose (14.0 +/- 0.8 to 12.3 +/- 0.9 mmol/L) or isotopically determined hepatic glucose output (17.5 +/- 1.4 to 12.7 +/- 1.0 mumols/kg/min) more than saline alone. Plasma C-peptide concentrations were unchanged, while serum glucagon increased from 131 +/- 13 to 169 +/- 24 ng/mL (P less than .015) and free fatty acids were suppressed by 43% (0.35 +/- 0.08 to 0.20 +/- 0.06 mmol/L, P less than .025). When sodium acetoacetate was infused with somatostatin (0.10 micrograms/kg/min) to suppress glucagon and insulin secretion, the decrease in both plasma glucose (13.3 +/- 0.9 to 10.2 +/- 0.7 mmol/L) and hepatic glucose output (17.2 +/- 1.6 to 9.4 +/- 0.6 mumols/kg/min) was greater than either acetoacetate or somatostatin infusion alone. Infusion of equimolar amounts of sodium bicarbonate had no effect on glucose metabolism. In conclusion, these results demonstrate that ketone bodies can directly suppress elevated hepatic glucose output in NIDDM independent of changes in insulin secretion, but only when the concomitant stimulation of glucagon secretion is prevented. Ketone bodies also suppress adipose tissue lipolysis in the absence of changes in plasma insulin and may serve to regulate their own production.     

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.     

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 morbid obesity on insulin clearance and insulin sensitivity in several aspects of metabolism as assessed by low-dose insulin infusion.

Obesity is associated with impaired insulin action in glucose disposal, but not necessarily in other aspects of intermediary metabolism or insulin clearance. Sixteen morbidly obese and 14 normal-weight subjects (body mass index, 51.2 +/- 11.5 v 22.1 +/- 2.2 kg.m-2; mean +/- SD) were studied with sequential, low-dose, incremental insulin infusion with estimation of glucose turnover. In obese patients, basal plasma insulin was higher (10.5 +/- 3.8 v 2.4 +/- 3.0 mU.L-1, P less than .001) and remained elevated throughout infusion (F = 492, P less than .001), as did C-peptide (F = 22.7, P less than .001). Metabolic clearance rate for insulin (MCRI) at the highest infusion rate was similar (1,048 +/- 425 v 1,018 +/- 357 mL.m-2.min-1, NS). Basal hepatic glucose production in obese subjects was less than in normal-weight subjects (270 +/- 108 v 444 +/- 68 mumol.m-2.min-1, P less than .01), as was the basal metabolic clearance rate for glucose (MCRG, 77 +/- 26 v 108 +/- 31 mL.m-2.min-1, P less than .05). Insulin infusion caused blood glucose to decrease less in the obese patients (1.4 +/- 0.5 v 1.9 +/- 0.5 mmol.L-1, P less than .05); hepatic glucose production was appropriately suppressed in them by hyperinsulinemia, but their insulin-mediated glucose disposal was reduced (1.67 [0.79] v 4.45 [2.13] mL.m-2.min-1/mU.L-1, P less than .01). Concentrations of nonesterified fatty acids (NEFA), glycerol, and ketones were elevated throughout the insulin infusions in obese patients, despite the higher insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans

After a meal, hormones released from the gut potentiate insulin release. This study was undertaken to determine if physiological concentrations of plasma cholecystokinin (CCK) stimulate insulin secretion in man. Employing a specific CCK bioassay, postprandial CCK levels were determined in normal subjects. Ingestion of a mixed liquid meal stimulated an increase in circulating CCK from a mean fasting level of 0.9 +/- 0.2 (SEM) pmol/L to a mean peak level of 7.1 +/- 1.1 pmol/L within 10 min of feeding. After 30 min the mean CCK level fell to 3.5 pmol/L and remained elevated for the remainder of the 90-min experiment. Eight subjects underwent 40-min infusions of either arginine (15 g), mixed amino acids (15 g), or glucose (30 g) with or without the simultaneous infusion of CCK-8. Since CCK-8 has full biological potency, this form was chosen for infusion to reproduce total CCK bioactivity in plasma. CCK-8 was infused at rates of 12 or 24 pmol/kg X h, producing steady state plasma CCK levels of 4.5 +/- 0.7 and 8.2 +/- 1.1 pmol/L, respectively, spanning the range of normal postprandial levels. CCK alone had no effect on insulin, glucose, or glucagon levels. Administration of arginine alone stimulated insulin from a mean basal level of 12.8 +/- 1.3 microU/mL to a peak level of 41.3 +/- 5.4 microU/mL. Infusion of CCK at 12 and 24 pmol/kg X h augmented arginine-stimulated insulin levels to peaks of 62.5 +/- 13.9 and 63.0 +/- 4.0 microU/mL, respectively. Moreover, CCK nearly doubled the total amount of insulin secreted during the arginine infusion. A similar potentiation of glucagon release was found with both doses of CCK. In addition, infusion of a mixture of amino acids with and without concomitant CCK infusions revealed that CCK potentiated the insulin release induced by mixed amino acids. In contrast to the potent effect of CCK on amino acid-induced insulin release, infusions of CCK together with glucose caused no enhancement of glucose-stimulated insulin release. These results demonstrate that physiological concentrations of CCK potentiate amino acid (but not glucose)-induced insulin secretion in man. These data suggest, therefore, that CCK may have a role in man as a modulator of insulin release.     

Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations

BACKGROUND: Growing evidence indicates that the administration of large amounts of ghrelin to humans increases circulating concentrations of several pituitary and adrenal hormones, induces hyperglycemia and reduces serum insulin concentrations. At present, it is not known whether physiological increments in plasma ghrelin concentrations affect glucose kinetics or hormone concentrations in humans. METHODS AND RESULTS: We compared the effects of two- and three-fold increments in plasma ghrelin concentrations in eight healthy subjects during a 2 h intravenous infusion of 7.5 (GHRE7.5), 15 (GHRE15) pmol kg(-1) min(-1) acylated human ghrelin or placebo (PL), in a randomized double-blind study. Compared with PL (146 +/- 24 pM) plasma ghrelin concentrations increased at 120 min (p<0.001) about two-fold after GHRE7.5 (300 +/- 35 pM) and three-fold after GHRE15 (494 +/- 30 pM). GHRE15 significantly increased circulating concentrations of NEFA, GH, ACTH, epinephrine, and prolactin (p<0.01). GHRELIN7.5 significantly (p<0.01) increased only serum GH concentrations. Neither ghrelin infusions changed glucose flux or circulating concentrations of glucose, insulin, C-peptide, glucagon, IGF-1, cortisol and norepinephrine. CONCLUSIONS: GH secretion is the only response that is stimulated by physiological increments in plasma ghrelin concentrations; about three-fold increases in plasma ghrelin concentrations are required to elicit the responses of epinephrine, prolactin, ACTH and NEFA.     

Oscillations in insulin secretion during constant glucose infusion in normal man: relationship to changes in plasma glucose

Peripheral plasma or serum concentrations of glucose, insulin, C-peptide, glucagon, and cortisol and insulin secretory rates (ISR) were determined at 15-min intervals in eight normal subjects during a constant iv infusion of 4.5 mg glucose/kg.min for a 24-h period. During each sampling interval, the secretory rate of insulin was calculated by deconvolution of the peripheral plasma C-peptide concentration using C-peptide kinetic parameters derived after bolus injections of C-peptide in individual subjects. Periodogram analysis of the individual glucose curves demonstrated a circadian rhythm in all subjects, with a major nocturnal acrophase occurring at an average clock time of 0228 h (range, 0045-0350 h). In five of the eight subjects, a minor acrophase occurred at an average time of 1774 h (range, 1530-2045 h). This diurnal variation in plasma glucose levels was not paralleled by a similar pattern in insulin secretion. Although glucose was infused at a constant rate, significant pulses were found in glucose, insulin, and C-peptide levels and ISR; the pulse durations of these parameters were 182 +/- 30 (+/- SE), 89 +/- 5, 100 +/- 8, and 85 +/- 5 min, respectively, and their periodicities were 208 +/- 33, 106 +/- 7, 114 +/- 10, and 106 +/- 7 min. The durations and frequencies for pulses of insulin, C-peptide, and ISR were not significantly different, whereas glucose pulses had a longer duration and were less frequent (P less than 0.05, by analysis of variance). On the average, 54 +/- 9% of the C-peptide pulses and 47 +/- 8% of the ISR pulses were concomitant with a pulse in glucose levels. Moreover, approximately half of the C-peptide and ISR pulses that were not concomitant with a glucose pulse occurred in synchrony with a shoulder on the up-stroke or down-stroke of glucose pulses. Analysis of glucagon and cortisol profiles revealed no significant associations with the insulin and glucose oscillations. In conclusion, during a constant glucose infusion in normal subjects, regular oscillations of insulin secretion occur at 80- to 120-min intervals. Their tight coupling with glucose oscillations and the lack of association with fluctuations of glucagon and cortisol suggest that these oscillations represent a dynamic property of the insulin-glucose feedback loop.