Relationship between insulin response to intravenous glucose and plasma lipoproteins in healthy men

In order to evaluate the influence of serum insulin levels on serum lipoprotein composition, 62 randomly selected healthy males were studied. All of them had a normal glucose tolerance. The Insulin Response to a bolus of intravenous glucose (0.50 g/kg) was significantly correlated with VLDL-Triglyceride (p less than 0.01), VLDL-Cholesterol (p less than 0.01) and with the "Atherogenic Index" (Formula: see text) (p less than 0.01). Moreover, stratifing the all population in quartiles according to the Insulin Response distribution, the highest quartile had a significant increase in Total and VLDL-Cholesterol levels (p less than 0.02), as well as in Total (p less than 0.02), VLDL (p less than 0.02) and LDL (p less than 0.01) Triglyceride, in comparison with the lowest quartile. The Atherogenic Index was also significantly elevated in the high Insulin Response group (p less than 0.005). The influence of serum insulin on lipoprotein metabolism was also evaluated by a stepwise multiple regression analysis. Body weight, Insulin Response and Exogenous Triglyceride removal were independently correlated with VLDL-Triglyceride concentration (r = 0.58, p less than 0.001). VLDL cholesterol concentration and fasting serum insulin levels were inversely correlated with HDL-Cholesterol (r = 0.49, p less than 0.001). In conclusion, in absence of any metabolic derangement, high insulin levels are associated with multiple lipoprotein abnormalities. Insulin might act as a risk factor for arterial disease through its influence on serum lipoproteins.     

Very high concentrations of islet amyloid polypeptide are necessary to alter the insulin response to intravenous glucose in man.

Islet amyloid polypeptide (IAPP) is a beta-cell peptide that can oppose insulin action in animal systems, but has not been shown to have any action in man; previously, we failed to show an effect of infused IAPP on iv glucose tolerance in human volunteers. We have reexamined its effects at even higher concentrations in six volunteers who received iv glucose (0.5 g/kg) during infusions of IAPP (25 and 50 pmol/kg.min) or normal saline. IAPP rose from a mean basal of 14.7 +/- 5.3 pmol/L to peak levels of 1,420 +/- 110, 2,240 +/- 140, and 27.7 +/- 9 pmol/L, respectively. IAPP at 25 pmol/kg.min had no effect on the plasma glucose disposal rate or the total incremental insulin response, but, in contrast, at 50 pmol/kg.min decreased the insulin response to glucose compared to the saline infusion (incremental area under the curve, 11,276 +/- 2,353 vs. 17,549 +/- 2,687 U; mean +/- SEM; P less than 0.02). This decrease was observed both during the first phase (0-10 min postglucose) insulin response (3,210 +/- 985 vs. 4,382 +/- 815 U; P less than 0.05) and the second phase response (11-90 min, 8,520 +/- 1,719 vs. 13,679 +/- 2,326 U; P less than 0.03). Glucose disposal rate, however, was unaffected (2.0 +/- 0.2 vs. 1.9 +/- 0.2). Thus, circulating IAPP concentrations greater than 90 times normal postprandial peaks were necessary to affect the insulin response to glucose. IAPP appears unlikely to be a circulating hormone influencing carbohydrate metabolism in man.     

A comparison of serum C-peptide response to intravenous glucagon, and urine C-peptide, as indexes of insulin dependence

Serum C-peptide (SCPR) at fasting and after intravenous injection of glucagon was evaluated in diabetic patients with various degrees of insulin dependence, and compared with 24 h urine C-peptide (UCPR). Fasting SCPR did not differ between healthy subjects and sulfonylurea-treated patients (SU) who were considered to have definite non-insulin-dependent diabetes (NIDDM); but was significantly lower in patients with insulin-dependent diabetes (IDDM) (0.24 +/- 0.10 ng/ml in IDDM vs. 1.43 +/- 0.61 ng/ml in SU, P less than 0.001). SCPR reached a peak at 6 min after glucagon injection, except for the IDDM group. The SCPR response at 6 min after 1 mg glucagon injection was significantly lower in the SU (NIDDM) group than in the normal group (2.86 +/- 1.21 v. 4.69 +/- 1.47 ng/ml, P less than 0.001). In the IDDM group, there was no increase of SCPR after glucagon injection. Among diabetic patients, SCPR response to glucagon correlated positively to the amounts of UCPR (P less than 0.001). By analysis of the distribution patterns of SCPR response to intravenous glucagon, SCPR of 1.0 ng/ml and the increment of SCPR of 0.5 ng/ml at 6 min are to be used as cut-off points to differentiate IDDM and NIDDM. These values correspond roughly to the UCPR values below 20 micrograms/day and above 30 micrograms/day, which we previously proposed as indexes to differentiate insulin-dependent and non-insulin-dependent diabetes.     

Peripheral insulin parallels changes in insulin secretion more closely than C-peptide after bolus intravenous glucose administration

The changes in peripheral serum insulin and plasma C-peptide levels and in the insulin secretory rate in response to iv glucose (0.5 g/kg BW) administration were studied in seven normal subjects. Insulin secretory rates were calculated according to a two-compartment model of distribution for C-peptide, using individual C-peptide kinetics calculated from iv bolus injections of biosynthetic human C-peptide. The mean plasma glucose level increased from a fasting level of 5.1 +/- 0.1 (+/- SE) to a peak of 24.0 +/- 1.0 mmol/L at 3 min and reached basal levels 101 +/- 6 min after glucose administration. The mean serum insulin value increased from 50 +/- 12 to a peak of 405 +/- 58 pmol/L at 3 min and then declined to fasting levels 139 +/- 14 min after the stimulus. In contrast, the mean plasma C-peptide level increased from 390 +/- 50 to a peak of 1460 +/- 210 pmol/L at 3 min and only began declining 45 min after glucose administration, reaching fasting levels 191 +/- 15 min after the stimulus. The mean insulin secretory rate increased from 69.8 +/- 19.9 to a peak of 1412.7 +/- 159.1 pmol/min at 3 min (15.3 +/- 2.5-fold elevation over baseline) and reached basal levels 135 +/- 12 min after the stimulus. The clearance of endogenous insulin during the basal period (2.505 +/- 0.365 L/min) and that during the 4 h after the stimulus (2.319 +/- 0.230 L/min) were similar. In conclusion, after bolus iv glucose administration: 1) the insulin secretory rate is more closely represented by changes in peripheral serum insulin than in plasma C-peptide levels; and 2) no change in endogenous insulin clearance occurs.     

Impaired early insulin response to intravenous glucose in alcoholic liver cirrhosis

This study aimed at determining the release and action of insulin in liver cirrhosis. Eight non-diabetic patients with alcoholic liver cirrhosis and eight age-, sex-, and weight-matched controls were investigated. The clearance and hypoglycemic action of insulin were determined after a brief intravenous infusion of insulin (10 mU/kg). Glucose tolerance and insulin response were determined after rapid intravenous infusion of 25 g glucose. In the cirrhotic patients the decrease in glucose tolerance was associated with a) an unchanged insulin clearance, b) a decreased hypoglycemic action of insulin, and c) a marked impairment in the early insulin response and a slight, but not significant, increase in the late insulin response. In the cirrhotic group glucose tolerance varied with the early (and late) insulin response and with the hypoglycemic action of insulin. It is concluded that both insulin action and the early insulin response are impaired in alcoholic liver cirrhosis and that deterioration of the early insulin release plays an important role for deterioration of glucose tolerance.     

Glucose, insulin and C-peptide kinetics during intravenous glucose tolerance test in chronic liver disease

To elucidate the mechanism of glucose intolerance in chronic liver disease (CLD), the kinetics of plasma glucose, insulin and C-peptide were studied after intravenous glucose loading in patients with CLD. Fasting plasma insulin levels were higher in patients with CLD than in normal subjects. This hyperinsulinemia was attributed primarily to an increased pancreatic secretion of insulin. Patients with CLD were divided into two groups, one with normal fasting plasma glucose (FBS less than 100 mg/dl (Group I) and the other with higher FBS (Group II). In Group I, the glucose disappearance rate was normal and a brisk acute insulin response (AIR) to glucose was noted. The glucose disappearance rate in Group II was lower than that in normal subjects, and AIR to glucose was blunted. It is suggested that normal glucose tolerance in Group I patients could be interpreted as a state of compensation by hypersecretion of insulin. On the other hand, the glucose intolerance in Group II patients could be due to inadequate insulin secretion to overcome insulin resistance of CLD.     

The glucoregulatory response to intravenous glucose infusion in normal man: Roles of insulin and glucose

In order to differentiate the roles of hyperinsulinemia and hyperglycemia per se in the homeostatic response to i.v. glucose administration, two groups of normal subjects were given either glucose alone (3.5 mg kg^?1 min^?1) or glucose (3 mg kg^?1 min^?1) in conjunction with somatostatin (500 μg hr^?1), insulin (0.15 mU kg^?1 min^?1) and glucagon (1 ng kg^?1 min^?1). Glucose kinetics were measured by the primed-constant infusion of 3-³H-glucose. During the infusion of glucose alone, plasma glucose stabilized at levels 45–50 mg/dl above the fasting values. Endogenous glucose output was markedly suppressed by 85%–90% while glucose uptake rose to values very close to the infusion rate of exogenous glucose. Glucose clearance remained unchanged. Plasma insulin rose three-fourfold while plasma glucagon fell by 25%–30%. When glucose was infused with somatostatin, insulin, and glucagon, plasma insulin was maintained at levels 50% above baseline while glucagon remained at preinfusion levels. Under these conditions, the infusion of exogenous glucose resulted in a progressive increase of plasma glucose which did not stabilize until the end of the study period (190 mg/dl at 120 min). Endogenous glucose production was consistently suppressed (52%) but significantly less than observed with the infusion of glucose alone (p < 0.01). Glucose uptake increased to the same extent as with glucose alone, despite the more pronounced hyperglycemia. Thus, glucose clearance fell significantly below baseline (25%–30%; p < 0.01). These data demonstrate that hyperglycemia per se (fixed, near basal levels of insulin and glucagon) certainly contributes to the glucoregulatory response to i.v. glucose administration by both inhibiting endogenous glucose output and increasing tissue glucose uptake. However, the extra-insulin evoked by hyperglycemia is necessary for the glucoregulatory system to respond to the glucose load with maximal effectiveness.     

The first phase insulin response to intravenous glucose is highly reproducible

Summary To determine the reproducibility of the first phase insulin response to intravenous glucose, ten normal subjects underwent two intravenous glucose tolerance tests separated by at least two weeks. Intravenous dextrose (0.3 g/kg) was administered over 2 min by continuous infusion and arterialised-venous samples were taken from a retrogradely cannulated hand vein in the opposite arm. Within subjects, median coefficient of variation for the 3 min insulin was 4.0% (range 1.2–24.3%) and median coefficient of variation for the 0–10 min area was 6.7% (range 1.7–18.8%). These coefficients of variation are close to those of the assay itself (< 10%). Despite this, between subject responses varied by greater than sixfold. In conclusion, contrary to previous reports the intravenous glucose tolerance test is highly reproducible. This makes it a very valuable tool for further studies of the pathogenesis of diabetes.     

First-phase insulin response to glucose in nonobese or obese subjects with glucose intolerance: analysis by C-peptide secretion rate

This study was proposed to clarify the impairment of first-phase insulin response to glucose in subjects with glucose intolerance by analysis of C-peptide secretion rate after glucose or glucagon injection. The rate was calculated from kinetic analysis of peripheral C-peptide behavior. The rate reached the peak two minutes after glucose injection and then rapidly declined (first-phase secretion) in control subjects. In nonobese subjects with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM), the rate promptly increased in response to glucose and was followed by a second phase increase. The time course of the rate in the subjects was slightly different from that in control subjects. There was a progressively greater deficit in the first-phase increase with increasing severity of glucose intolerance. The time course of the rate in the obese subjects with NIDDM was different from that in control subjects. The first-phase increase was reduced in the obese subjects with NIDDM. The glucose disappearance rate was correlated with the first-phase increase. Since the time course of the rate after glucagon injection in all subjects did correspond well with that in the control subjects, variation of metabolic clearance rate of endogenous C-peptide among the subjects may be negligible for this study. This study provides the precise time course of first- and second-phase insulin response to glucose injection in nonobese and obese subjects with IGT or NIDDM as well as convincing evidence of the progressive reduction of first-phase insulin response with increasing severity of glucose intolerance. First-phase insulin response to glucose might be slightly delayed in some obese subjects with NIDDM.     

Plasma C-peptide response to oral glucose load in hyperthyroidism

Aim of the present study was to evaluate the pancreatic beta cell response to oral glucose load in a group of patients with hyperthyroidism. For this purpose plasma C-peptide at fasting and after a 100 g oral glucose load was measured in 8 newly-diagnosed untreated hyperthyroid patients with fasting normoglycemia, and 8 sex-, age-, and weight-matched healthy controls. As compared to healthy subjects, patients with hyperthyroidism showed higher plasma glucose levels (incremental area 5405 +/- 742 vs 2729 +/- 539 mg/dl x 180 min, p less than 0.05), and slightly reduced plasma C-peptide concentrations (incremental area 166 +/- 12 vs 182 +/- 36 pmol/ml x 180 min, p = NS) following oral glucose load. The ratios between plasma C-peptide and plasma glucose incremental areas were lower in hyperthyroid patients than in controls (3.66 +/- 0.85 vs 10.41 +/- 3.08, p less than 0.05). These data suggest that hyperthyroidism is characterized by a decreased pancreatic beta cell response to oral glucose load.     

The relationship between first-phase insulin secretion and glucose metabolism.

A possible pathogenetic link between absence of first-phase insulin secretion and development of impaired glucose metabolism has been suggested by the results of several cross-sectional studies. First-phase insulin secretion measured during a +7 mmol/l hyperglycemic glucose clamp correlated with total glucose disposal during the clamp (r = 0.65, p < 0.001, N = 59). To examine whether restoration of first-phase insulin secretion improves peripheral glucose uptake in subjects with impaired glucose utilization, seven insulin-resistant subjects (age 54 (38-62) years: BMI 29.3 (21.7-35.8); fasting plasma glucose 5.5 (4.8-7.2) mmol/l; fasting insulin 57 (37-105) pmol/l with impaired first-phase (148 (29-587) vs controls 485 (326-1086) pmol/l x 10 min; p < 0.05) and normal second-phase (1604 (777-4480) vs controls (1799 (763-2771) pmol/l x 110 min) insulin secretion were restudied. The impaired first-phase insulin secretion was restored by an iv insulin bolus at the start of the hyperglycemic clamp. Substrate oxidation rates and hepatic glucose production were determined by indirect calorimetry and [3-3H]glucose infusion. Total glucose uptake was impaired in the insulin-resistant subjects with impaired first-phase insulin secretion compared to controls (18.8 (13.2-22.2) vs 34.8 (24.3-62.1) mumol.kg-1 x min-1; p < 0.01). Restoration of first-phase insulin secretion (1467 (746-2440) pmol/l x 10 min) did not affect glucose uptake (20.2 (9.9-23.8) mumol.kg-1.min-1), with no difference in oxidative and non-oxidative glucose metabolism between the experiments. Second-phase insulin secretion was similar during both experiments.(ABSTRACT TRUNCATED AT 250 WORDS)     

C-peptide response to oral glucose and its clinical role in elderly people.

C-Peptide response to oral glucose was measured in 45 elderly diabetics, in whom final treatment was established on clinical grounds during a 16-18 months follow-up. The diabetic patients comprised 19 ultimately classified as insulin-dependent (IDD) (group 1) and 26 regarded as non-insulin-dependent (NIDD) (group 2). Fifteen matched controls (group 3) and 15 young controls (group 4) were similarly studied. Fasting C-peptide values were lower in groups 1 and 2 (1.48 +/- 0.39 and 2.14 +/- 0.22 ng/ml; mean +/- SEM, respectively) compared with groups 3 and 4 (2.51 +/- 0.16 and 2.71 +/- 0.20 ng/ml, respectively) (p less than 0.001). Peak C-peptide levels were reached at 30 min in healthy young and at 60 min in healthy elderly. All non-diabetic control subjects showed a peak of at least 6.5 ng/ml and an increment of at least 4 ng/ml. The ratio of C-peptide increment/blood glucose increment (100 delta CP/delta BG) at 60 min derived to assess beta-cell function was at least 90 in all healthy subjects. The ratio was less than 10 in 68% of IDD but in only 27% of NIDD patients (p less than 0.01). The 100 delta CP/delta BG was inversely related to the prevailing fasting blood glucose (FBG) (p less than 0.001). These findings suggest that C-peptide response to oral glucose may be a useful test in certain elderly diabetic patients whose insulin dependence is in question.     

The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers

This study was initiated to see if defects in the ability of physiological hyperinsulinemia (approximately 60 microU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (approximately 10 microU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean +/- SEM) body mass index of 24.8 +/- 0.5 kg/m2. Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m2 x min) and insulin (32 mU/m2 x min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m2 x min) and insulin (6 mU/m2 x min). The SSPI concentration (mean +/- SEM) during physiological hyperinsulinemia was 64 +/- 3 microU/mL), in contrast to 12 +/- 0.4 microU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG60) and SSPG(Basal) (r = 0.57, P < 0.01) and FFA(Basal) (r = 0.73, P < 0.001). Furthermore, FFA(Basal) and SSPG(Basal) were significantly correlated (r = 0.47, P < 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG60 values of 209 +/- 16 vs. 64 +/- 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPG(Basal) (105 +/- 5 vs. 78 +/- 7 mg/dL, P < 0.01) and FFA(Basal) (394 +/- 91 vs. 104 +/- 41, P < 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.