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.     

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.     

Effects of free fatty acids on plasma resistin and insulin resistance in awake rats

Resistin has been postulated to play a role in obesity-related insulin resistance. To explore this possibility, we have investigated effects of acute euglycemic (5.2+/-0.1 mmol/L) hyperinsulinemia (96+/-8 microU/mL) with and without concurrent infusion of lipid plus heparin (to raise or lower plasma free fatty acid [FFA] levels) on glucose turnover and plasma resistin levels in alert rats. Plasma FFA concentrations increased during lipid/heparin (L/H) infusion (from 0.82 to 2.86 mmol/L, P<.001) and decreased (from 0.83 to 0.21 mmol/L, P<.001) in controls who were infused with insulin but not with L/H. L/H infusion reduced insulin suppression of endogenous glucose production by approximately 90% (from 28.9 to 3.1 mg. kg-1 . min-1, P<.001) and insulin-stimulated glucose uptake (glucose rate of disappearance) by 78% (from 30.8% to 6.9%, P<.001). Plasma resistin levels increased by 46% (from 39.9 to 58.4 microg/L, P<.05) during L/H infusion and did not change in controls (39.7 vs 39.3 microg/L). Plasma ghrelin levels decreased by 41% (from 892 to 584 ng/L, P<.05) in response to hyperinsulinemia, whereas concurrent L/H infusion had no additional effect on ghrelin levels (584+/-67 vs 548+/-82 ng/L). In summary, we found that FFA induced hepatic insulin resistance, and to a lesser extent, peripheral insulin resistance was associated with elevated plasma resistin levels. We conclude that FFA-induced release of resistin may contribute to the development of FFA-induced insulin resistance in rats.     

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.     

Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin

We previously demonstrated that supraphysiological insulin concentrations reduced the plasma 34K insulin-like growth factor-binding protein (IGF-BP) concentrations in humans. In this study we examined whether physiological changes in plasma insulin concentrations regulate IGF-BP and, if so, whether the regulation is influenced by race, glucose tolerance, or rate of glucose metabolism. For these purposes we 1) analyzed the relationship between fasting plasma insulin and IGF-BP concentrations in 2 racial groups (23 caucasians and 35 southwestern American Indians), 2) measured the response of plasma IGF-BP to oral glucose in 20 normal subjects, and 3) determined the dose-response characteristics of plasma IGF-BP to glucose and insulin in 23 normal subjects at 4 different insulin and glucose concentrations. The fasting plasma insulin concentration was inversely related to the plasma IGF-BP concentration in both the caucasian and Indian groups (P less than 0.0001). In the caucasian group the mean plasma IGF-BP concentration was higher [15 +/- 4 (+/- SE) micrograms/L] than in the Indian group (8 +/- 2 micrograms/L; P less than 0.05). This difference was independent of race and glucose tolerance, and it could be explained by lower plasma insulin concentrations in the caucasian (387 +/- 50 pmol/L) than in the Indian group (215 +/- 43 pmol/L; P less than 0.001). After oral glucose administration, the insulin concentration (423 +/- 72 pmol/L) was maximal 30 min after glucose treatment, and significant suppression of the IGF-BP concentration occurred at 90 min. Analysis of the dose-response curves revealed maximal suppression of IGF-BP at about 1150 pmol/L insulin, and half-maximal suppression at about 290 pmol/L. The plasma glucose concentration or the rate of glucose metabolism had no effect on the IGF-BP concentration. These data suggest that insulin is a major regulator of plasma IGF-BP concentrations under physiological conditions.     

Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus

The effect of highly purified natural porcine GIP on C-peptide release was examined in six type I (insulin-dependent) diabetics (IDD) with residual beta-cell function, six type II non-insulin-dependent) diabetics (NIDD), and six normal subjects. All subjects were normal weight. From -120 minutes to 180 minutes glucose or insulin was infused IV to achieve a constant plasma glucose level of 8 mmol/L. On two separate days GIP (2 pmol/kg/min) or isotonic NaCl at random were infused from 0 to 30 minutes. After 10 minutes of GIP infusion plasma IR-GIP concentrations were in the physiologic postprandial range. At 30 minutes a further increase in IR-GIP to supraphysiologic levels occurred. In all subjects plasma, C-peptide increased more after 10 minutes of GIP infusion (IDD, 0.48 +/- 0.05; NIDD, 0.79 +/- 0.11; normal subjects, 2.27 +/- 0.29 nmol/L) than on the corresponding day with NaCl infusion (IDD, 0.35 +/- 0.03; NIDD, 0.62 +/- 0.08; normal subjects, 1.22 +/- 0.13 nmol/L, P less than .05 for all). The responses of the diabetics were significantly lower than that of the normal subjects (P less than .001 for both groups). No further increase in C-peptide occurred during the remaining 20 minutes of the GIP infusion in the diabetic subjects (IDD, 0.49 +/- 0.05; NIDD, 0.83 +/- 0.10 nmol/L). In the presence of a plasma glucose concentration of 8 mmol/L, physiologic concentrations of porcine GIP caused an immediate but impaired beta-cell response in IDD and NIDD patients.     

Plasma ghrelin in obesity before and after weight loss after laparoscopical adjustable gastric banding

Weight reduction after gastric bypass surgery has been attributed to a decrease of the orexigenic peptide ghrelin, which may be regulated by insulin and leptin. This study examined effects of long-term weight loss after laparoscopical adjustable gastric banding on plasma ghrelin and leptin concentrations and their relationship with insulin action. Severely obese patients (15 women, three men, 36 +/- 12 yr) underwent clinical examinations every 3 months and modified oral glucose tolerance tests to assess parameters of insulin sensitivity and secretion every 6 months. After surgery, body mass index fell from 45.3 +/- 5.3 to 37.2 +/- 5.3 and 33.6 +/- 5.5 kg/m(2) at 6 and 12 months, respectively (P < 0.0001). This was associated with lower (P < 0.0001) plasma glucose, insulin, insulin resistance, waist circumference, and blood pressure. Plasma leptin decreased from 27.6 +/- 9.5 to 17.7 +/- 9.8 (P = 0.0005) and 12.7 +/- 5.1 ng/ml (P < 0.0001). Plasma ghrelin was comparable before and at 6 months (234 +/- 53; 232 +/- 53 pmol/liter) but increased at 12 months (261 +/- 72 pmol/liter; P = 0.05 vs. 6 months). At 6 and 12 months, ghrelin levels correlated negatively with fasting plasma insulin levels and hepatic insulin extraction but not with body mass or insulin action.In conclusion, prolonged weight loss results in a rise of fasting ghrelin concentrations that correlates with fasting insulin concentrations but not improvement of insulin sensitivity.     

Effects of thorough mastication on postprandial plasma glucose concentrations in nonobese Japanese subjects

Thorough mastication has the potential to affect postprandial plasma glucose concentrations by improving digestibility and absorption of nutrients. To evaluate the effects of mastication on postprandial plasma glucose concentration, we compared usual and thorough mastication in subjects with normal glucose tolerance (NGT group, n = 16) and subjects predisposed to type 2 diabetes (first-degree relatives of type 2 diabetic patients, subjects with impaired glucose tolerance, and type 2 diabetic patients) (predisposed group, n = 10) in a crossover trial of 52 test meals. Plasma glucose and serum insulin concentrations were measured for 3 hours postprandially, and the insulinogenic index (the ratio of incremental serum insulin to plasma glucose concentration during the first 30 minutes after meal) was calculated. In the NGT group, thorough mastication reduced the postprandial plasma glucose concentration at 90 minutes (5.8 +/- 0.3 vs 6.5 +/- 0.4 mmol/L, P < .05) and 120 minutes (5.4 +/- 0.2 vs 6.3 +/- 0.4 mmol/L, P < .05) and the area under the curve (AUC) from -15 to 180 minutes (19.1 +/- 0.6 vs 20.6 +/- 0.8 [mmol . L]/h, P < .05) without an increase in the AUC for insulin. In the predisposed group, thorough mastication significantly augmented plasma glucose and serum insulin concentrations and the AUCs compared with usual mastication. Thorough mastication elicited a significantly higher insulinogenic index than usual mastication in the NGT group (205.0 +/- 27.6 vs 145.6 +/- 17.7 pmol/mmol, P < .05), whereas the predisposed group showed significantly less early-phase insulin secretion than the NGT group. In the NGT group the postprandial plasma glucose concentration upon thorough mastication of meal was significantly lower, most probably because of the potentiation of early-phase insulin secretion. In the subjects predisposed to type 2 diabetes, thorough mastication did not potentiate early-phase insulin secretion and elicited a higher postprandial plasma glucose concentration.     

Ghrelin secretion in severely obese subjects before and after a 3-week integrated body mass reduction program

Ghrelin, the endogenous ligand of GH-secretagogue receptors, has been implicated in the regulation of feeding behavior and energy balance. Aim of the study was to investigate ghrelin levels in fasting conditions and after a standard meal test in obese subjects before and after a 3-week integrated body weight reduction (BWR) program (consisting of energy-restricted diet, exercise training, psychological counselling and nutritional education). Weight, height, fat mass, fat free mass (by impedentiometry), circulating ghrelin, insulin and leptin levels were evaluated in 10 obese subjects (3 male, 7 female; mean age: 35 +/- 9.3 yr; body mass index BMI: 45.2 +/- 10.6 kg/m2) before and after weight reduction. At baseline, obese subjects showed significantly lower ghrelin levels than controls, which were negatively correlated with BMI, weight, insulin and leptin levels. Fasting ghrelin levels were not modified by standard meal test in obese subjects (from 110.8 +/- 69.7 to 91.8 +/- 70.2 pmol/l p=ns), while a significant reduction was observed in controls (from 352.4 +/- 176.7 to 199.0 +/- 105.2 pmol/l; p<0.01). After a 3-week integrated BWR program obese subjects significantly reduced weight, BMI and leptin levels, while no significant changes were found both in fasting ghrelin and in ghrelin response after the meal. In conclusion, 5% weight loss obtained after a short-term period of integrated BWR program is not sufficient to normalize fasting ghrelin levels nor to restore the normal ghrelin suppression after a meal in severely obese subjects.     

Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?

OBJECTIVE: Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects. SUBJECTS AND MEASUREMENTS: Nine healthy volunteers, mean age 47 years (range 33-58) and body mass index (BMI) 24 kg/m2 (range 20.9-27.6) were recruited and received either 1 mg glucagon (n = 9) or 1 ml saline (n = 6) subcutaneously on separate days between 0800 and 0830 h after an overnight fast. Venous blood was then sampled at 15-min intervals during the first hour, followed by 30-min intervals up to 4 h for glucose, insulin, GH, cortisol, somatostatin and ghrelin. RESULTS: Mean +/- SE basal ghrelin was 213.1 +/- 34.3 pmol/l and decreased significantly by 15 min after glucagon administration to 179.3 +/- 28 pmol/l (P = 0.01), then remaining suppressed relative to the basal value until 240 min after glucagon. Plasma insulin increased from a basal value of 46.7 +/- 7.7 pmol/l to a peak of 327.1 +/- 54.9 pmol/l (P < 0.0001). There was an inverse statistical relationship between the increase in insulin over the first 120 min and the decrease in ghrelin (P = 0.005), while somatostatin, GH and glucose were not significant contributors to the decrease in ghrelin (P > 0.05). Mean +/- SE basal GH was 7.3 +/- 2.9 microg/l and increased by 150 min after glucagon to a peak of 20.5 +/- 6.8 microg/l (P = 0.006). Changes in neither ghrelin nor glucose were related to the increase in GH (P = 0.7). Saline administration did not produce any significant change in ghrelin, insulin or somatostatin although the expected diurnal reduction in cortisol (P < 0.05) was observed. CONCLUSIONS: Our study found no evidence that glucagon stimulates ghrelin secretion in humans and supports the hypothesis that insulin is a negative regulator of ghrelin secretion in the postprandial state. We did not find a negative relationship between endogenous somatostatin and ghrelin despite earlier reports that exogenously administered somatostatin analogues suppress plasma ghrelin. Finally, glucagon-induced GH secretion is not mediated by an increase in plasma ghrelin.     

Somatostatin, insulin and glucagon after arginine stimulation in active and treated acromegaly

Ten acromegalic patients, 28-71 years old, were compared with 10 normal controls, 21-39 years old. In another study, 7 patients with active acromegaly, 19-70 years old, were investigated before and 4-9 months following transsphenoidal adenectomy and radiation. They were all investigated following an arginine infusion (0.5 g/kg/20 min). Although the mean plasma somatostatin (somatotrophin release inhibiting factor (SRIF] was somewhat higher in acromegalic patients compared to normal controls (mean basal values 21 +/- 3.8 and 16.6 +/- 2.1 pmol/l, respectively), the difference was not significant. The patients had higher serum insulin (peak values 118 +/- 23.9 and 63 +/- 11.8 mU/l, respectively) and lower plasma glucagon (peak values 171 +/- 29.0 and 310 +/- 52.7 pmol/l, respectively). Plasma SRIF increased during arginine infusion, but the concentrations were similar before and following the operation (mean basal values 18.2 +/- 2.6 and 15.2 +/- 2.3 pmol/l, respectively). Serum insulin was significantly higher before the operation (peak values 154 +/- 38.8 and 91 +/- 24.9 mU/l, respectively). Plasma glucagon was similar before and after the operation (peak values 143 +/- 23.4 and 127 +/- 22.7 pmol/l, respectively). Plasma SRIF is similar in active acromegaly and normal controls, and in acromegaly before and following treatment, despite differences in serum growth hormone (GH), serum insulin and plasma glucagon. This points towards a modulating role for GH on plasma SRIF, possibly by affecting the other islet cell hormones.     

BASAL AND SALINE-STIMULATED LEVELS OF PLASMA ATRIAL NATRIURETIC FACTOR IN ACROMEGALY

We have studied plasma ANF before and after a 4-h intravenous infusion of normal saline in eight subjects with active acromegaly and in eight age and sex-matched control subjects. Plasma ANF, serum aldosterone and blood pressure were measured basally and after 2 and 4 h and plasma renin activity basally and after 4 h. Basal plasma ANF was similar in each group (4.4 +/- 1.5 pmol/l (mean +/- SEM) in acromegalic subjects and 5.3 +/- 0.7 pmol/l in controls NS). Plasma ANF did not rise significantly after saline in the acromegalic group (2-h value, 5.9 +/- 0.9; 4-h value, 5.1 +/- 0.9 pmol/l) but did rise significantly in the control group (2-h value, 8.9 +/- 1.9; 4-h value 9.5 +/- 1.3 pmol/l, both values P less than 0.05 vs basal level). The 4-h ANF value was significantly higher in the control group than in the acromegalic group (P less than 0.05). Basal and stimulated serum aldosterone values were similar in the two groups. Plasma renin activity suppressed to a lesser extent in the acromegalic group after 4 h. The facts that basal plasma ANF was not raised in acromegalic subjects and did not respond to saline stimulation demonstrate that an abnormality of ANF control may be an important factor in the aetiology of the expanded sodium status of patients with acromegaly and hence may contribute to the hypertension seen in patients with growth hormone excess.     

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)     

Diazoxide infusion at excess but not at basal hyperglycemia enhances beta-cell sensitivity to glucose in vitro in neonatally streptozotocin-diabetic rats.

The influence of chronic and moderate hyperglycemia vis-à-vis a 48-hour further elevation of blood glucose on beta-cell sensitivity to glucose was compared in an animal model of non-insulin-dependent diabetes. Neonatally streptozotocin-diabetic (n-STZ) rats infused with saline for 48 hours displayed moderate nonfasting hyperglycemia (mean, 11.5 +/- 1.5 mmol/L/48 h) and plasma insulin levels similar to those seen in normoglycemic, nondiabetic rats. In perfused pancreas, the insulin response to 27 mmol/L glucose was severely reduced to 1.60 +/- 0.45 pmol/min, ie, approximately 15% of the response in nondiabetic rats. A continuous infusion of diazoxide (5 mg/kg/h), which normally blocks glucose-induced insulin secretion, did not affect glucose and insulin levels in vivo, nor did it significantly affect the insulin response to glucose in vitro. In other experiments, "basal" hyperglycemia in n-STZ rats was doubled by glucose infusions for 48 hours to reach a mean of 23.8 +/- 0.6 mmol/L. Plasma insulin increased 3.2-fold. The in vitro insulin response to 27 mmol/L glucose was totally abolished, and the pancreatic insulin content was decreased by 81% relative to the content after saline. Addition of a diazoxide infusion inhibited the increase in plasma insulin by 93%. After the combined glucose and diazoxide infusion, the subsequent in vitro response to 27 mmol/L glucose was dramatically enhanced to 9.55 +/- 3.25 pmol/min, ie, the response was sixfold higher than after saline alone. This aftereffect of the diazoxide infusion was not significantly altered by an insulin infusion (2 U/d) added to the hyperglycemia plus diazoxide protocol to compensate for the insulin-lowering effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of subcutaneously administered U40 and U100 formulations of regular human insulin.

Action profiles of 12 U of regular human insulin (Actrapid HM) administered subcutaneously as a U40 or U100 formulation were studied. Euglycaemic glucose clamps were performed on two separate days in 8 healthy subjects (basal i.v. insulin infusion 0.1 mU/kg/min, plasma glucose 5.0 mmol/l, mean +/- SD age 25 +/- 2 years, BMI 22.7 +/- 1.4 kg/m2). Serum insulin concentrations increased after injection of U40 or U100 from similar baseline values to maximal individual concentrations of 305 +/- 79 vs. 285 +/- 62 pmol/l (NS) after 90 +/- 33 vs. 114 +/- 58 min (NS). Ten, 15, and 20 min post injection insulin concentrations were significantly higher by an average of 30 pmol/l after U40 insulin vs. U100 insulin (p less than 0.05). Glucose infusion rates increased from comparable baseline rates to maximal individual glucose infusion rates of 10.7 +/- 2.4 vs. 10.9 +/- 3.0 mg/kg/min (NS) after 172 +/- 51 vs. 169 +/- (39) min (NS). At the three time points when significantly different serum insulin concentrations occurred soon after insulin injection, glucose infusion rates were not significantly different between U40 and U100. Although small differences in insulin pharmacokinetics were detected early after s.c. insulin injection (U40 was absorbed faster than U100 insulin) the pharmacodynamics of the U40 and U100 formulation of regular human insulin appear to be comparable in healthy subjects.     

Peripheral and hepatic insulin antagonism in hyperthyroidism

Eight hyperthyroid and eight normal subjects underwent 2-h oral glucose tolerance tests (OGTT) and euglycemic clamp studies to assess the presence of peripheral and hepatic insulin antagonism in hyperthyroidism. Although the mean total glucose area during the OGTT was similar in the hyperthyroid patients and normal subjects [16.4 +/- 0.8 (+/- SE) vs. 15.8 +/- 0.7 mmol/L.h], the mean insulin area was significantly elevated in the hyperthyroid group (1413 +/- 136 vs. 1004 +/- 122 pmol/L.h; P less than 0.05). Basal hepatic glucose production was measured during the second hour of a primed [3-3H]glucose infusion. A two-insulin dose euglycemic clamp study with [3-3H]glucose and somatostatin (500 micrograms/h) was carried out during the next 6 h. The insulin infusion rate was 0.05 mU/kg.min during the third, fourth, and fifth hours and 0.60 mU/kg.min during the sixth, seventh, and eighth hours. Hepatic glucose production and glucose utilization were measured during the final 0.5 h of each clamp period. Serum C-peptide concentrations were measured in the initial sample and in the last sample of each clamp period. The mean equilibrium serum insulin concentrations were similar in both groups during the final 0.5 h of the low (90 +/- 8 vs. 79 +/- 6 pmol/L) and high (367 +/- 11 vs. 367 +/- 15 pmol/L) insulin infusion rates. Basal serum C-peptide levels were significantly increased in the hyperthyroid patients (596 +/- 17 vs. 487 +/- 43 pmol/L; P less than 0.05) but were suppressed equally in both groups at the end of both clamp periods. The MCRs of insulin were similar in the hyperthyroid and normal subjects during the low (6.7 +/- 1.1 vs. 5.6 +/- 0.5 mL/kg.min) and high (11.9 +/- 0.4 vs. 12.1 +/- 0.5 mL/kg.mm) insulin infusion rates. Glucose production was significantly increased in the hyperthyroid patients during the basal state (17.6 +/- 0.9 vs. 11.5 +/- 0.5 mumol/kg.min; P less than 0.001) and remained elevated during the final 0.5 h of the low (12.1 +/- 1.1 vs. 5.9 +/- 1.7; P less than 0.01) and high (3.2 +/- 1.2 vs. 0.5 +/- 0.3; P less than 0.05) insulin infusion rates. Peripheral insulin action, assessed by Bergman's sensitivity index, was significantly decreased in the hyperthyroid patients (7.4 +/- 2.2 vs. 15.6 +/- 2.1 L/kg min-1/pmol/L; P less than 0.02). In conclusion, hyperthyroidism is characterized by 1) hyperinsulinemia after oral glucose loading, 2) increased basal hepatic glucose production, 3) impairment of insulin-mediated suppression of hepatic glucose production, and 4) antagonism to insulin-stimulated peripheral glucose utilization.     

Effects of aging on plasma islet amyloid polypeptide basal level and response to oral glucose load.

To delineate the effects of aging on basal and glucose-stimulated secretion of islet amyloid polypeptide (IAPP), we compared the basal level of plasma IAPP and its response to an oral glucose load in elderly subjects with those of young subjects. Plasma IAPP level was determined by radioimmunoassay. Basal level of plasma IAPP in 20 elderly subjects (mean age 63 yr) was 5.3 +/- 0.4 pmol/l, which was not significantly different from 5.0 +/- 0.3 pmol/l in 22 young subjects (mean age 26 yr). Plasma glucose levels after an oral glucose load in elderly subjects (n = 8, mean age 67 yr) and young subjects (n = 8, mean age 29 yr) were within normal limits. However, the plasma glucose response in the aged group was significantly higher than that in the young group. The plasma insulin response to a glucose load in elderly subjects was not different from that in young subjects. The plasma IAPP level in the aged group significantly increased from 5.3 +/- 0.5 to 16.4 +/- 2.3 pmol/l 120 min after the oral glucose load. This result was quite similar to that in the young group whose plasma IAPP level increased from 4.9 +/- 0.5 to 14.1 +/- 1.5 pmol/l 120 min after the glucose load. We concluded that the basal level of plasma IAPP and its response to glucose were not affected by aging.     

Altered ghrelin and peptide YY responses to meals in bulimia nervosa

OBJECTIVE: In recent years great advances have been made in our understanding of the peripheral signals produced within the gastrointestinal tract that regulate appetite, such as ghrelin and peptide YY (PYY). While ghrelin elicites hunger signals, PYY elicites satiety. Therefore, alterations in hormone physiology may play a role in the pathogenesis of bulimia nervosa (BN). In this study, we investigated the postprandial profile of ghrelin and PYY levels in patients with BN. DESIGN AND PATIENTS: Postprandial plasma ghrelin and PYY levels and insulin and glucose responses were measured in 10 patients with BN and 12 control patients in response to a standard 400 kcal meal. RESULTS: Basal ghrelin levels present in BN subjects (265.0 +/- 25.5 pmol/l) were significantly higher than those in healthy controls (199.3 +/- 18.4 pmol/l, P < 0.05), while basal PYY levels were equivalent in BN (14.6 +/- 1.3 pmol/l) and control (12.8 +/- 1.1 pmol/l, P = 0.30) subjects. Postprandial ghrelin suppression (decremental ghrelin area under the curve) was significantly attenuated in BN patients, compared to controls (-96.3 +/- 26.8 pmol/l x 3 h vs. -178.2 +/- 25.7 pmol/l x 3 h, P < 0.05). After a meal, the incremental PYY area under the curve in BN patients was significantly blunted from that observed in controls (9.2 +/- 2.6 pmol/l x 3 h vs. 26.8 +/- 3.2 pmol/l x 3 h, P < 0.01).Glucose and insulin responses to meals were similar between the two groups. CONCLUSIONS: BN patients exhibit elevated ghrelin levels before meals with reduced ghrelin suppression after eating. In bulimia nervosa subjects, the rise in PYY levels after meals is also blunted. A gut-hypothalamic pathway involving peripheral signals, such as ghrelin and PYY, may be involved in the pathophysiology of BN.     

Eating pattern and the effect of oral glucose on ghrelin and insulin secretion in patients with anorexia nervosa

OBJECTIVE: Ghrelin is thought to be involved in the regulation of eating behaviour and energy metabolism in acute and chronic feeding states. Circulating plasma ghrelin levels in healthy humans have been found to decrease significantly after oral glucose administration. Because it is suggested that eating behaviour may influence the secretion of ghrelin and insulin in anorexia nervosa (AN), we examined the effect of oral glucose on ghrelin and insulin secretion in subtypes of AN patients. DESIGN AND PATIENTS: Twenty female AN patients and 10 age-matched female controls were subjects. The patients were subdivided into two subtypes based on eating behaviour as follows: 11 restricting type (AN-R), nine binge-eating and purging type (AN-BP). Subjects underwent an oral glucose tolerance test at 08.00 h. Blood was collected 0, 30, 60, 120 and 180 min after the glucose load. RESULTS: Both AN-R and AN-BP had a significant increased basal ghrelin level (P < 0.01) and a significantly decreased basal insulin level (P < 0.05) as compared to controls. The time of the nadir of mean ghrelin in AN-BP (120 min, 58.1% of basal level, 204.9 +/- 34.3 pmol/l, mean +/- SEM) was delayed compared to controls (60 min, 60.2%, 74.3 +/- 7.9 pmol/l), and in the AN-R group it kept decreasing for 180 min (80.0%, 182.4 +/- 31.5 pmol/l). The peaks insulin levels in AN-BP (120 min, 319.3 +/- 88.8 pmol/l) and AN-R (180 min, 418.9 +/- 68.4 pmol/l) were also delayed as compared to controls (60 min, 509.2 +/- 88.8 pmol/l). The glucose level at 180 min in AN-R was significantly (P < 0.05) higher than in controls. CONCLUSIONS: These findings suggest that differences in eating behaviour in AN may induce alterations in both ghrelin and insulin metabolism in the acute feeding state. Furthermore, metabolic changes in the restrictive eating pattern may be related to the pathophysiology of small quantitative meal intake in AN-R patients.     

Comparison of insulinotrophic actions of nateglinide with glibenclamide dissociated from absorption in conscious dogs

Nateglinide is more rapidly absorbed than glibenclamide. Therefore, the different absorption kinetics of both drugs were eliminated by intraportal administration in conscious fasted dogs. The plasma insulin profiles were compared under similar kinetic changes in plasma drug concentrations. After a priming dose of nateglinide (1 mg/kg. 5 min) or glibenclamide (40 microg/kg. 5 min), plasma drug concentrations reached a peak at 4 minutes (nateglinide, 80 +/- 5 micromol/L, n = 6 and glibenclamide, 263 +/- 60 nmol/L, n = 6) followed by a sustained level at approximately 30% of the peak concentration at 30 minutes. Nateglinide led to a rapid and constant reduction in arterial glucose of approximately 30% basal, while glibenclamide promoted a gradual decrease to approximately 50% basal at 120 minutes. An increase in plasma insulin level by nateglinide of 4 times basal (218 +/- 58 pmol/L v 47 +/- 3 pmol/L, P <.05, n = 6) occurred at 6 to 10 minutes followed by sustained release of 1.4 times basal (67 +/- 15 pmol/L, n = 6). The insulin surge was more than doubled (484 +/- 209 pmol/L, n = 6) under a euglycemic clamp. Insulin release by glibenclamide increased gradually reaching 10-fold basal (449 +/- 166 pmol/L, n = 6) at 60 minutes. This was not enhanced during a euglycemic clamp. Lowering the primed doses of nateglinide resulted in a diminished peak plasma insulin concentration. In contrast, glibenclamide caused only a slower increase, but eventually reaching a similar peak. By increasing the continuous infusion of nateglinide, the sustained insulin release was not altered. Glibenclamide, but not nateglinide, evoked prompt and sustained insulin release in the continuing presence of the other. These results are consistent with the concept that nateglinide produces a quick, but very short-lived, interaction with sulfonylurea (SU)-receptors on plasma membrane by free access of the drug from the cell exterior. In contrast, glibenclamide promotes a slow and longer interaction with the receptor by distribution of the drug into the cell inferior. We conclude, therefore, that not only the different kinetics of gastrointestinal (GI) absorption, but also the inherent difference in the interaction with beta cells is attributed to the different insulin release characteristics between nateglinide and glibenclamide in vivo.