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.     

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.     

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.     

Compared to glibenclamide, repaglinide treatment results in a more rapid fall in glucose level and beta-cell secretion after glucose stimulation

BACKGROUND: The more rapid onset of action and the shorter half-life of repaglinide may reduce the post-load glucose excursion and limit sustained insulin secretion compared to sulphonylurea (SU) derivatives. METHODS: We studied 12 patients with type 2 diabetes (age 62 +/- 2 years, BMI 28.3 +/- 1.3 kg m(-2), HbA1c 6.7 +/- 0.2%) on SU monotherapy at submaximal dose. Patients were treated for 3 weeks with repaglinide or glibenclamide in a randomized, crossover trial. At the end of each treatment period, patients underwent a 60-min hyperglycaemic clamp (glucose 12 mmol L(-1)) followed by 4-h observation (60-300 min) with frequent blood sampling for determination of glucose, insulin, proinsulin and C-peptide levels. Before the clamp (5 min for repaglinide, 30 min for glibenclamide), patients ingested their usual morning drug dose. RESULTS: After the end of the hyperglycaemic clamp, mean plasma glucose fell to a level of 5 mmol L(-1) after approximately 150 min with repaglinide, and after approximately 190 min with glibenclamide. While initially quite similar, in the period from 240 to 300 min, insulin, proinsulin and C-peptide levels were lower during repaglinide treatment (insulin 133 +/- 20 vs 153 +/- 25 pmol L(-1) (P < 0.05), proinsulin 14 +/- 3 vs 19 +/- 4 pmol L(-1) (P = 0.06) and C-peptide 0.81 +/- 0.19 vs 1.14 +/- 0.18 nmol L(-1) (P = 0.05) for repaglinide vs glibenclamide, respectively). CONCLUSIONS: Following glucose stimulation, plasma glucose levels, and insulin concentration decrease more rapidly after repaglinide treatment than after glibenclamide. Proinsulin and C-peptide secretion tended to fall more rapidly as well. These findings are consistent with a more rapid onset and shorter duration of beta-cell stimulation associated with repaglinide.     

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.     

Glyburide enhances the responsiveness of the beta-cell to glucose but does not correct the abnormal patterns of insulin secretion in noninsulin-dependent diabetes mellitus

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated. In response to glyburide, the fasting plasma glucose level decreased from 12.3 +/- 1.2 to 6.8 +/- 0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7 +/- 1.4 to 10.8 +/- 1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152 +/- 48 pmol/L, 0.82 +/- 0.16 pmol/mL, and 196 +/- 34 pmol/min, respectively) and after (186 +/- 28 pmol/L, 0.91 +/- 0.11 pmol/mL, and 216 +/- 23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366 +/- 97 pmol/L and 1.35 +/- 0.19 pmol/mL to 434 +/- 76 pmol/L and 1.65 +/- 0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447 +/- 58 nmol before therapy to 561 +/- 55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses. In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47 +/- 9 nmol over the 3-h period before treatment to 103 +/- 21 nmol after glyburide therapy. We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)     

Lipolysis and gluconeogenesis from glycerol are increased in patients with noninsulin-dependent diabetes mellitus.

The rate of lipolysis (glycerol Ra), gluconeogenesis from glycerol, and its contribution to overall hepatic glucose production (glucose Ra) were determined in 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) [body mass index (BMI) 27.2 +/- 1.0 kg/m2, fasting plasma glucose 10.3 +/- 1.2 mmol/L], and in 6 matched control subjects (BMI 27.3 +/- 1.1 kg/m2, fasting plasma glucose 5.3 +/- 0.3 mmol/L) using infusions of [3-3H]glucose (0-600 min) and [U-14C]glycerol (360-600 min). Glycerol Ra was increased in the patients with NIDDM (120 +/- 16 mumol/m2.min) compared to the normal subjects (84 +/- 9 mumol/m2.min, P less than 0.05). Gluconeogenesis from glycerol was 1.7-fold higher in the patients (96 +/- 16 mumol/m2.min) than in the normal subjects (56 +/- 10 mumol/m2.min, P less than 0.05), and explained 9 +/- 1% and 7 +/- 1% (NS) of total glucose Ra in patients with NIDDM and normal subjects, respectively. To determine whether these abnormalities are more pronounced in overweight patients with NIDDM, glucose and glycerol Ra were also determined in 5 obese patients with NIDDM (BMI 36.4 +/- 1.0 kg/m2, fasting plasma glucose 11.3 +/- 1.3 mmol/L). Glycerol Ra (154 +/- 26 mumol/m2.min) was again higher than in the normal subjects (P less than 0.05) but not different from that in the less obese patients with NIDDM. The rate of gluconeogenesis from glycerol (159 +/- 20 mumol/m2.min) was significantly higher in the obese than in the less obese patients with NIDDM (P less than 0.05) but its contribution to total glucose Ra (10 +/- 1%) was similar to that in the less obese patients with NIDDM. When all data were analyzed together, gluconeogenesis from glycerol (r = 0.57, P less than 0.01) but not lipolysis (r = 0.02, NS) correlated with the percentage of lipolysis diverted toward gluconeogenesis suggesting that the rate of gluconeogenesis from glycerol is regulated by intrahepatic mechanisms rather than by glycerol availability. Neither the rate of lipolysis nor the rate of glycerol gluconeogenesis correlated with BMI, serum triglyceride, or insulin concentrations. We conclude that gluconeogenesis from glycerol is increased in patients with NIDDM. This increase appears to be the consequence of both accelerated lipolysis and increased intrahepatic conversion of glycerol to glucose.     

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)     

Influence of gliclazide on glucose-stimulated insulin release in man

Although sulfonylureas (SU) are widely used in the management of patients with non-insulin-dependent diabetes mellitus (NIDDM), there is still debate about their mechanism of action on the pancreatic beta cell. It is unclear whether the effect of SU on insulin release is additive to the effect of glucose, or whether SU act by increasing pancreatic beta-cell sensitivity to glucose (a shift in the dose-response curve of glucose-stimulated insulin release without a change in maximum release). To address this issue, we assessed the influence of the SU gliclazide on glucose-stimulated insulin release in eight healthy male volunteers. Sixty-minute hyperglycemic glucose clamps (blood glucose levels: 8 mmol/L, a submaximal stimulus; and 32 mmol/L, a maximally stimulating concentration) were performed with and without prior oral administration of gliclazide (80 mg) 30 minutes before the glucose clamp. Mean plasma C-peptide increment at 5 minutes (first-phase secretion) obtained during the 8-mmol/L hyperglycemic clamp, was higher on the gliclazide study day than on the control day (1.07 +/- 0.10 v 0.88 +/- 0.10 mmol/L, P less than .05), whereas no difference in plasma C-peptide response was observed during the 32-mmol/L hyperglycemic clamp. Mean plasma C-peptide increment obtained at the end 60 minutes; (second-phase secretion) of the 8-mmol/L hyperglycemic clamps was higher on the gliclazide study day than on the control day (1.36 +/- 0.13 v 1.09 +/- 0.09 mmol/L, P less than .02). No difference was observed in plasma C-peptide response at the end of the 32-mmol/L hyperglycemic glucose clamps.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Effect of gemfibrozil treatment in sulfonylurea-treated patients with noninsulin-dependent diabetes mellitus

This study was initiated to 1) assess gemfibrozil's ability to lower plasma triglyceride (TG) concentration in patients with NIDDM, and 2) determine whether this effect was associated with any changes in glycemic control. Measurements were made of mean hourly plasma glucose, insulin, TG, and FFA concentrations from 1200-1600 h in response to a test meal; hepatic glucose production (HGP); insulin-stimulated glucose uptake during a hyperinsulinemic glucose clamp study (MCR); and fasting plasma lipoprotein TG and cholesterol concentrations in 12 patients with NIDDM before and 3 months after gemfibrozil treatment. Although ambient plasma TG and FFA concentrations fell significantly, plasma glucose, insulin, HGP, concentrations fell significantly, plasma glucose, insulin, HGP, and glucose MCR did not change. However, when patients were divided into two groups, those with fasting plasma glucose levels above 9 mmol/L (fair control) and those with levels below 9 mmol/L (good control), a different phenomenon was observed. Patients in fair control had significant decreases in mean hourly plasma concentrations of glucose (15.1 +/- 1.7 to 12.6 +/- 0.9 mmol/L; P less than 0.001), insulin (523 +/- 59 to 471 +/- 75 pmol/L; P less than 0.001), FFA (652 +/- 150 to 504 +/- 76 mumol/L), and HGP (9.5 0.4 to 8.1 +/- 0.4 mumol/kg.min; P less than 0.005), and an increase in glucose MCR (2.63 +/- 0.49 to 3.72 +/- 0.54 mL/kg.min; P less than 0.07) in association with a fall in TG from 6.9 +/- 1.3 to 3.5 +/- 0.9 mmol/L (P less than 0.001). Although fasting low density lipoprotein cholesterol increased (1.8 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.05), the ratio of total to high density lipoprotein cholesterol decreased (6.84 +/- 0.88 to 5.80 +/- 1.05; P less than 0.02). Despite a significant fall in mean hourly TG concentration (4.6 +/- 0.7 to 3.8 +/- 0.7 mmol/L; P less than 0.001), neither insulin, FFA, HGP, nor glucose MCR changed in patients in good control. Furthermore, the mean hourly plasma glucose concentration increased from 9.2 +/- 0.7 to 11.7 +/- 1.4 mmol/L (P less than 0.001). Low density lipoprotein cholesterol also increased in this group (1.9 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.02), but, as before, the ratio of total to high density lipoprotein cholesterol decreased (8.15 +/- 1.93 to 6.36 +/- 1.03; P less than 0.02).     

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)     

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.     

Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8

The quantitative contribution of glucose-dependent insulinotropic polypeptide [gastric inhibitory polypeptide (GIP)] to the incretin effect after oral glucose (augmentation of insulin secretion over the degree that is explained by the glycemic rise) is not known. Therefore, hyperglycemic clamp experiments (8 mmol/L, corresponding to postprandial glucose concentrations) were performed in healthy volunteers, and synthetic human GIP was infused for 60 min at a rate (approximately 1.3 pmol/kg.min) that results in plasma GIP concentrations similar to those occurring after oral glucose loads of 75 g. The MCR for exogenous GIP was approximately 6 mL/kg.min; the decay after ceasing infusion was exponential with a t1/2 of about 18 min, and the resulting volume of distribution was about 140 mL/kg. At euglycemic (basal) plasma glucose concentrations (5.0 mmol/L) similar values were found. Insulin secretion was stimulated by hyperglycemia alone, but was greatly (2.3-fold based on C-peptide) potentiated by GIP infusions (P less than or equal to 0.001 for integrated incremental values). When integrated incremental responses over 120 min of GIP, immunoreactive insulin, and immunoreactive C-peptide were compared after oral glucose and during GIP infusions, no significant differences were found. Peak glucose concentrations after oral glucose (7.6 +/- 0.6 mmol/L) were similar to mean plasma glucose values during clamp experiments (8.2 +/- 0.1 mmol/L; P = 0.124). However, mean glucose concentrations after oral glucose were lower (6.0 +/- 0.3 mmol/L; P = 0.0004). Additional infusion of sulfated cholecystokinin-8 (25 pmol/kg.h) or the amino acid phenylalanine (1.7 mumol/kg.min) did not further stimulate insulin secretion and had no influence on the pharmacokinetics of exogenous GIP. It is concluded that human synthetic GIP is insulinotropic in man and that this activity may well explain a substantial part of the incretin effect after oral glucose. There is no interaction with cholecystokinin or phenylalanine in concentrations found after mixed meals.     

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

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

Insulin and C-peptide plasma levels in patients with severe chronic pancreatitis and fasting normoglycemia

The aim of the present study was to evaluate insulin secretion by the pancreatic B cell in a group of patients with severe chronic pancreatitis and without overt diabetes. For this purpose we have measured plasma insulin and C-peptide peripheral levels in the fasting state and after a 100-g oral glucose load in 10 patients with severe chronic pancreatitis and fasting normoglycemia, and in 10 sex-, age-, and weight-matched healthy controls. As compared to normal subjects, patients with chronic pancreatitis showed: (1) significantly higher plasma glucose levels after oral glucose load (area under the plasma glucose curve 1708 +/- 142 vs 1208 +/- 47 mmol/liter X 240 min, P less than 0.005); (2) plasma insulin levels significantly higher at fasting (0.11 +/- 0.008 vs 0.08 +/- 0.005 nmol/liter, P less than 0.01) but not after oral glucose administration (area under the plasma insulin curve 79 +/- 12 vs 88 +/- 16 nmol/liter X 240 min); (3) significantly lower plasma C-peptide concentrations both in the fasting state (0.15 +/- 0.01 vs 0.54 +/- 0.05 nmol/liter, P less than 0.001) and after oral glucose load (area under the plasma C-peptide curve 211 +/- 30 vs 325 +/- 37 nmol/liter X 240 min, P less than 0.05). The finding of diminished plasma C-peptide levels suggests that chronic pancreatitis is associated with an impaired B-cell function even in the absence of overt diabetes. The increased or unchanged plasma insulin levels in spite of decreased plasma C-peptide concentrations indicate that in chronic pancreatitis insulin metabolism is reduced, most likely within the liver.     

Dose-response characteristics for glucose-stimulated insulin release in man and assessment of influence of glucose on arginine-stimulated insulin release

Glucose potentiates arginine-induced insulin release. We investigated the dose-response characteristics for both phases of glucose-induced insulin release in normal man, and studied the influence of hyperglycemia on arginine-induced insulin secretion. Dose-response curves of plasma C-peptide increments achieved during 60-minute hyperglycemia clamps (7, 11, 17, 24, and 32 mmol/L) with and without a primed continuous infusion of arginine (infusion rate, 15 mg/kg/min) were analyzed with a modified Michaelis-Menten equation. The ED50 (half-maximally stimulating blood glucose concentration) of first-phase insulin release (determined from plasma C-peptide increments at 5 minutes) was significantly lower than the ED50 for the second phase (60 minutes; 8.4 +/- 0.8 v 14.3 +/- 1.3 mmol/L, respectively, P less than .002). Combined glucose-arginine stimulation significantly increased insulin release. Vmax of both phases of glucose-arginine-stimulated insulin release were positively correlated (r = .75, P less than .05). The ED50 of the influence of glucose on first-phase arginine-induced insulin release was significantly lower than the ED50 for the second phase (9.0 +/- 1.1 v 12.7 +/- 1.0 mmol/L, respectively, P less than .02). For each insulin secretion phase separately, the ED50 for the influence of hyperglycemia on arginine-induced insulin release were not significantly different from the ED50 for glucose-induced insulin secretion (without arginine). When dose-response curves of plasma insulin increments were analyzed with the same equation, the ED50 of second-phase glucose-induced plasma insulin increments was significantly higher than the ED50 assessed from the plasma C-peptide increments (21.6 +/- 2.8 v 14.3 +/- 1.3 mmol/L, respectively, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control.

The effect of metformin treatment was studied in 13 patients with noninsulin-dependent diabetes mellitus (NIDDM), whose fasting plasma glucose concentration was greater than 10 mmol/L with maximal sulfonylurea doses. Patients were studied before and 3 months after receiving 2.5 g/day metformin. The fasting plasma glucose concentration (12.4 +/- 0.8 vs. 8.8 +/- 0.7 mmol/L), mean hourly postprandial plasma glucose concentration from 0800-1600 h (14.0 +/- 1 vs. 9.4 +/- 0.9 mmol/L), and glycosylated hemoglobin level (12.3 +/- 0.6% vs. 9.0 +/- 0.6%) were all significantly (P less than 0.005-0.001) lower after the administration of metformin. The improvement in glycemic control was associated with a 24% increase (P less than 0.05) in insulin-stimulated glucose uptake during glucose clamp studies and a 16% decrease in basal hepatic glucose production (P less than 0.05). Mean hourly concentrations of plasma insulin (411 +/- 73 vs. 364 +/- 73 pmol/L) and FFA concentrations (440 +/- 31 vs. 390 +/- 40 mumol/L) were also lower after 3 months of metformin treatment. However, neither insulin binding nor insulin internalization by isolated monocytes changed in response to metformin. Finally, plasma triglyceride, very low density lipoprotein triglyceride, and very low density lipoprotein cholesterol were significantly decreased (P less than 0.01-0.001), and high density lipoprotein cholesterol was significantly increased (P less than 0.001) after metformin treatment. Thus, the addition of metformin to sulfonylurea-treated patients with NIDDM not in good glycemic control significantly lowered fasting and postprandial plasma glucose concentrations, presumably due to the combination of enhanced glucose uptake and decreased hepatic glucose production. Since the dyslipidemia present in these patients also improved, the results suggest that metformin may be of significant clinical utility in patients with NIDDM not well controlled with sulfonylurea compounds.     

Preferential release of proinsulin relative to insulin in non-insulin-dependent diabetes mellitus

A radioimmunoassay, using an antiserum that is specific for human proinsulin, has been used to study the response of serum proinsulin to low (25 g) and high (75 g) oral glucose loads in non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Diabetic patients were treated by diet only (N = 8) or were receiving oral anti-hyperglycemic agents (N = 8) and therapy was not interrupted during the study. In the fasted state, proinsulin concentrations were higher (P less than 0.05) in the drug-treated patients (31 +/- 3 pmol/l (SEM)) compared with age- and weight-matched healthy subjects (22 +/- 2 pmol/l; N = 10), but concentrations in the diet-treated patients 25 +/- 3 pmol/l) were not significantly different. Following 25 g and 75 g glucose loads, the rises in serum immunoreactive insulin and C-peptide concentrations in both groups of diabetic patients were impaired and delayed relative to those in the control subjects. The responses of serum proinsulin, however, were not significantly different in the NIDDM patients compared with controls at any time point up to 180 min except in the case of drug-treated patients receiving 25 g of glucose who had elevated (P less than 0.05) proinsulin concentrations at 150 min and 180 min after ingestion. It is concluded that NIDDM is not associated with an exaggerated release of proinsulin in response to glucose compared with healthy subjects, but the islets have maintained the ability to release proinsulin better than the ability to release insulin.     

The effects of superphysiologic hyperinsulinemia on glucose and lipid metabolism in glucose-tolerant offspring of patients with non-insulin-dependent diabetes mellitus (NIDDM).

First-degree relatives of patients with NIDDM manifest severe insulin resistance despite normal glucose tolerance test. To examine the mechanisms underlying the normal glucose tolerance, we evaluated the serum glucose/C-peptide/insulin dynamics and free fatty acid (FFA) as well as substrate oxidation rates and energy expenditure (EE) (indirect calorimetry) in nine young offspring of NIDDM patients (mean +/- SEM age 30 +/- 2.3 years, body mass index 24.2 +/- 1.2 kg/m2). Nine age-, sex- and weight-matched, normal subjects with no family history of diabetes served as the controls. Metabolic parameters were measured before, during and after a two-step glucose infusion (2 and 4 mg/kg.min) for 120 min. Mean basal serum glucose, insulin and C-peptide levels were similar in both groups. During 2 mg/kg.min glucose infusion, mean serum insulin and C-peptide rose to significantly (P less than 0.05-0.02) greater levels in the offspring vs. controls, while serum glucose levels were similar. With the 4 mg/kg.min glucose infusion, mean serum glucose, insulin and C-peptide levels were significantly (P less than 0.02-0.001) greater in the offspring at 100-120 min. Isotopically-derived (D[3-3H]glucose), basal hepatic glucose output (HGO) was not significantly different between the offspring vs. controls (1.86 +/- 0.30 vs. 1.78 +/- 0.06 mg/kg.min). During glucose infusion, basal HGO was partially suppressed by 66% at 60 min and by 100% at 120 min in the offspring. In contrast, HGO was completely (100%) suppressed at both times in the controls. Following cessation of glucose infusion, HGO rose to 1.64 +/- 0.12 mg/kg.min in the offspring and 1.46 +/- 0.05 mg/kg.min in the controls (P less than 0.05) between 200 and 240 min. These were 88% and 82% of the respective basal HGO values. At low glucose infusion (t = 0-60 min), the mean absolute, non-oxidative glucose disposal remained 1.5-fold greater in the offspring while at higher glucose infusion, nonoxidative glucose metabolism was not different in both groups. Throughout the study period, oxidative glucose disposal rate was not significantly different in both groups. The mean basal FFA was significantly greater in the offspring vs. controls (865 +/- 57 vs. 642 +/- 45 microEq/l). It was appropriately suppressed during glucose infusion to a similar nadir in both groups (395 +/- 24 vs. 375 +/- 33 microEq/l). The mean basal lipid oxidation was also significantly greater in the offspring than controls (1.06 +/- 0.05 vs. 0.75 +/- 0.04 mg/kg.min, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)