First-phase Insulin Response Research Articles

Insulin secretion decline unrelated to jejunal morphology or exocrine pancreatic function in children with celiac disease.

We describe a prospective 10-year study of insulin secretion and immunologic changes in a group of children with celiac disease (CD) on a gluten-free diet. Thirty CD patients aged 4-16 years and 30 matched controls were examined. They underwent i.v. glucose tolerance test during which glucose disappearance rate (K) and first phase insulin response (FPIR) were measured. Typing for HLA A, B, C, and DR antigens was performed and sera were analyzed for cytoplasmic islet cell antibodies (ICA) on several occasions. Pancreatic isoamylase (PIA) was measured to assess exocrine pancreatic function. In 4/21 CD children, FPIR and K rate were decreased. There was a significant correlation between the two parameters (p < 0.01). The incidence of HLA B8 and DR3 was higher in CD (33% and 60%, respectively) than in healthy individuals (p < 0.001). All patients were found to be ICA negative at the time of the study and at follow-up. There was no correlation between parameters of endocrine (FPIR, K) and exocrine (PIA) pancreatic function. One out of four children with reduced FPIR developed overt DM during the study. In conclusion, the decline of first phase insulin secretion documented in CD patients is unrelated to jejunal morphology or exocrine pancreatic function. This decline may be an expression of a prediabetic phase as observed in one of the subjects who finally developed IDDM. HLA B8 and DR3, which are detected in celiac patients, may indicate a possible common pathogenic mechanism between CD and IDDM.

Transient incidental glucosuria in children.

A consecutive series of 78 children with transient asymptomatic glucosuria was studied and followed up for up to 7.3 years. The age at presentation was 0.9-17.6 (median 4.6) years. One third of the patients had random blood glucose levels of > 10.0 mmol/l (180 mg/dl). Five patients (6.4%) developed insulin-dependent diabetes mellitus within 2.1 years after the first incident of glucosuria. These patients presented with higher levels of glycaemia than others, and three out of five were positive for islet cell antibodies with a first-phase insulin response < 46 mU/l in all four studied. Of the remaining 73 children, 3 were positive for islet cell antibodies and 12/55 had a first-phase insulin response under 46 mU/l. The insulin response deteriorated in 3 but reverted to normal in 7 patients. CONCLUSION. For a child with transient glucosuria and with presence of islet cell antibodies and a subnormal first-phase insulin response, therapeutic attempts to prevent overt insulin-dependent diabetes mellitus should be considered.

Human Leukocyte Antigen Identity and DQ Risk Alleles in Autoantibody-Positive Siblings of Children With IDDM are Associated With Reduced Early Insulin Response

To investigate the relationship between human leukocyte antigen (HLA)-associated genetic factors and the development of β-cell dysfunction, we performed sequential intravenous glucose tolerance tests (IVGTTs) on 81 islet cell antibody (ICA)-positive and/or insulin autoantibody-positive healthy siblings of children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). A lower glucose disappearance rate (Kg) (P &amp;lt; 0.5) and decreased first-phase insulin response (FPIR) (P &amp;lt; 0.05) were observed on multiple occasions in HLA-identical siblings compared with the haploidentical or nonidentical ones. Siblings carrying the DQB1*0302/0201, −0302/x, or −0201/x genotype also had lower FPIRs (P ≤ 0.05) at several time points than those with no DQB1 risk genotype. When all IVGTTs were taken into account, DQB1*0302/0201 heterozygous siblings had an abnormally low FPIR (&amp;lt; 45 mU/I; 3rd percentile) in at least one test more often than did siblings with no DQB1 risk genotype (50.0% vs. 6.1%; P = 0.001). Siblings carrying either the DQB1*0602 or the DQB1*0603 protective allele had lower serum peak ICA and glutamic acid decarboxylase (GAD)65 antibody levels (P = 0.023 and 0.007, respectively) and higher FPIRs on several occasions (P &amp;lt; 0.05) than those with the DQB1 risk genotypes. Progression to IDDM was related to both HLA identity and the presence of the DQB1*0302/0201 genotype. Normal Kg and FPIR levels were observed in siblings who were positive for only insulin autoantibody, and none of them developed IDDM. Serum ICA concentrations were inversely correlated with Kg (rs = −0.41; P &amp;lt; 0.001) and FPIR (rs = −0.52; P &amp;lt; 0.001) in the first IVGTT, suggesting that high serum levels of ICA could to some extent be used as an indicator of impaired insulin-secretory capacity in the β-cells. We conclude that both HLA identity and the presence of DQB1 risk genotype were associated with a decreased early insulin response to intravenous glucose in ICA+ siblings of diabetic children. HLA identity was also associated with impaired glucose tolerance.

In vivo β-cell function at the transition to early non-insulin-dependent diabetes mellitus

Impaired insulin secretion occurs at some stage in the development of non-insulin-dependent diabetes mellitus (NIDDM), possibly during impaired glucose tolerance (IGT) or early NIDDM. To assess insulin secretion at these critical stages, we measured the first-phase insulin response (to glucose and arginine), maximal secretory capacity, and glucose potentiation slope for insulin secretion in Pima Indians with normal glucose tolerance (n = 20), IGT (n = 9), and mild (fasting glucose < 7.8 mmol/L) NIDDM (n = 7). We also measured oral glucose tolerance and insulin action. Subjects with IGT were more insulin-resistant ( P < .05) than normals. A wide range of insulin secretion was noted, although as a group, no significant impairment was detected. Subjects with mild NIDDM were similarly insulin-resistant, but they also had impaired insulin secretion. The first-phase response to glucose was markedly reduced in absolute terms ( P < .001), but all secretion indices were impaired relative to the degree of insulin resistance ( P = .05 to P < .0001). These results suggest that in Pima Indians, impairment of insulin secretion, especially the first-phase response to glucose, is associated with mild NIDDM. Insulin secretion in IGT is variable and, overall, seems intact, although a subtle defect in the first-phase insulin response to glucose could not be ruled out in this study. Glucose sensing for first-phase secretion may be one of the early secretory defects in the progression of glucose intolerance and seems to be critical at the transition from IGT to early NIDDM.

Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The Childhood Diabetes in Finland Study Group.

The objective of this study was to test whether levels of proinsulin immunoreactivity (PIM) relative to those of insulin immunoreactivity (IRI) or C-peptide are changed and related to subclinical beta-cell dysfunction in siblings of insulin-dependent diabetes mellitus (IDDM) patients. Twenty-three siblings, previously found positive for islet cell antibodies and/or insulin autoantibodies, were divided into 2 groups according to their first phase insulin response (FPIR) to i.v. glucose tolerance tests (IVGTTs) sequentially performed during an observation period of 2 yr. Eleven siblings had diminished FPIR on at least 1 occasion (group 1), whereas 12 siblings had a normal FPIR on all occasions studied (group 2). All underwent a further IVGTT (0.5 g glucose/kg BW), and serum samples were taken at 0, 1, 3, 6, 10, 20, 30, 40, 50, and 60 min. The 2 groups had comparable median age, female/male ratio, weight, height, fasting blood glucose, immunoreactive insulin, C-peptide, and insulin autoantibodies levels, but group 1 had significantly higher islet cell antibodies levels. Fasting median PIM/IRI and PIM/C-peptide ratios were 2- to 3-fold higher in group 1 [10.5% (range, 1.8-93.8%) vs. 5.2% (range, 1.9-14.3%) and 3.3% (range, 0.4-23.1%) vs. 1.3% (range, 0.7-2.6%; P < 0.05]. Fasting PIM/C-peptide ratios correlated inversely with FPIRs (rs = -0.68; P < 0.01). During glucose stimulation, maximal responses of IRI and C-peptide were 4-fold lower in group 1, and the time of maximal responses of IRI and C-peptide occurred later in group 1 than in group 2. In contrast, no difference in maximal responses of PIM was found, but the time of maximal responses of PIM occurred later in group 1. Nine of 11 siblings in group 1 presented with IDDM 1-28 months after the test, compared to none in group 2. In group 1 a paradoxical inhibitory response of PIM was observed during the first 6 min of the IVGTT. These data indicate that fasting PIM/IRI and/or PIM/C-peptide ratio reflects subclinical beta-cell dysfunction in prediabetic subjects with evidence of immunological beta-cell assault and suggests that an elevated ratio may be an additional marker for later development of IDDM.

Glucosamine Inhibits Glucokinase In Vitro and Produces a Glucose-Specific Impairment of In Vivo Insulin Secretion in Rats

A characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) is the lack of an acute insulin response to intravenous glucose with maintenance of the response to other secretagogues. It has been hypothesized that impaired glucose sensing stems from defective beta-cell glucokinase. It remains unclear whether decreased pancreatic glucokinase activity will produce defects of insulin secretion similar to those observed in NIDDM. In this study, the effects of glucosamine on glucokinase activity and on islet function were assessed in vitro and in vivo. Glucosamine (5 mmol/l) reduced glucokinase activity in islet homogenate and diminished the insulin response to glucose (200 mg/dl) by isolated islets, whereas the response to arginine (20 mmol/l at 100 mg/dl glucose) was unaffected. In conscious normal rats, glucosamine lowered plasma insulin, followed by an increase in blood glucose. Administration of glucosamine 10 min before an infusion of glucose (10 mg.min-1. 15 min) reduced the insulin response. The primary effect was an attenuation of the first-phase insulin response relative to the decreased basal insulin levels. Arginine (10 mg.min-1.15 min) induced biphasic insulin release in both groups. Although glucosamine slightly reduced the absolute insulin response, it was normal relative to preinfusion levels. In all experiments, glucagon secretion was unaffected by glucosamine. The results indicate that glucosamine inhibits beta-cell glucokinase activity in vitro. In addition, glucosamine impairs glucose- but not arginine-induced insulin secretion. We conclude that glucosamine, probably via a reduction of glucokinase activity, impairs insulin secretion in a manner comparable to that seen in NIDDM.

Hyperinsulinemia Decreases Second-Phase But Not First-Phase Arginine-Induced Insulin Release in Humans

The aim of this study was to investigate the effect of hyperinsulinemia on the first and second phase of arginine-induced insulin release in humans. Seven healthy subjects underwent three studies (lasting 360 min): a control study using saline infusion and two euglycemic clamps using a low-dose (0.33 mU.kg-1.min-1) and a high-dose (1.20 mU.kg-1.min-1) insulin infusion. After a 3-h equilibration period, arginine (25 g) was infused for 30 min, and insulin and C-peptide responses to arginine were followed for 180 min. At the end of the equilibration period, before arginine administration, steady-state insulin levels were (means +/- SE) 60.0 +/- 2.4, 165.6 +/- 1.8, and 455.4 +/- 7.8 pmol/l during saline, low-dose, and high-dose insulin infusions, respectively. The time course of insulin release during the arginine test was calculated from C-peptide concentrations by using C-peptide kinetic modeling and deconvolution. In particular, first-phase and second-phase insulin response was obtained by integrating the time course of the insulin release during either the first 5 min or the following 40 min of the arginine test, respectively. Whereas first-phase insulin release was independent of any effect induced by either insulin infusion, second-phase insulin release was reduced in a similar degree by both insulin infusion doses. First phase was 75.5 +/- 10.1, 73.7 +/- 12.8, and 73.4 +/- 10.3 pmol/kg, whereas second phase was 266.1 +/- 46.0, 143.1 +/- 33.5, and 133.0 +/- 30.2 pmol/kg for saline, low-dose, and high-dose insulin infusions, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

RAT ISLET ISOGRAFT FUNCTION

Islet isograft function was analyzed after transplantation of 4 well-defined endocrine volumes (12.5%, 25%, 50%, and 100% of the endocrine volume in the normal adult rat pancreas) to 3 different sites (kidney, liver, and spleen). Graft function was tested in unanesthetized, unstressed rats by the responses to glucose infusion and to a meal. All animals with grafts > or = 25% of the endocrine volume of the rat pancreas returned to normoglycemia after transplantation. The minimal graft volume for restoring normoglycemia is probably between 12.5% and 25%, since also a small number of grafts of 12.5% were successful. At 1 month, basal glucose and insulin levels were similar to those of controls in rats with grafts to the spleen, but higher in rats with grafts to the kidney or liver. Irrespective of the transplantation site, recipients had higher glucose and lower insulin levels than controls in response to glucose infusion. In response to a meal, however, only the first-phase insulin response was reduced, but the total insulin output during the entire test was similar to that of controls. Graft performance was found to be graft-size dependent. Results of tests performed at 2 months showed a tendency of increasing responsiveness compared with the results of tests at 1 month.

Carbohydrate metabolism and gestational diabetes.

There are significant alterations in glucose metabolism during pregnancy. In women with normal glucose tolerance, there is a significant (30%) increase in basal hepatic glucose production, a progressive (60%) decrease in insulin sensitivity, and an associated 3.0-3.5-fold increase in insulin response by 34-36 weeks' gestation. In contrast, women with normal glucose tolerance before conception who develop gestational diabetes have significant decreased insulin sensitivity relative to women in a control group. This decrease in insulin sensitivity is most apparent before conception and becomes less significant with advancing gestation. Decreased first-phase insulin response and impaired suppression of hepatic glucose production with insulin infusion develop only in late pregnancy, resulting in clinically abnormal glucose tolerance. These results are consistent with the findings of DeFronzo and Bogardus, who showed that decreased insulin sensitivity preceded the development of decreased insulin response in subjects with impaired glucose tolerance and noninsulin-dependent diabetes. Because of the relatively small number of subjects in our study population and the fact that they were not obese, our results must be interpreted with care. Additional longitudinal studies in obese subjects using comparable methods should improve our understanding of the alterations in carbohydrate metabolism in gestation in women with normal and abnormal glucose tolerance.

First-phase insulin response to intravenous glucose in cystic fibrosis patients with different degrees of glucose tolerance.

The aim of our study was to determine whether first-phase insulin response to intravenous (i.v.) glucose could be used as a simple and rapid test to identify cystic fibrosis (CF) patients at risk to develop diabetes mellitus. Forty consecutive CF patients with normal fasting blood glucose values but with different degrees of glucose tolerance on the standard oral glucose tolerance test (22 with normal glucose tolerance, 16 with impaired glucose tolerance, 2 with diabetes mellitus) and 12 normal subjects, matched for age and body mass index, underwent an i.v. glucose bolus to evaluate early phase insulin release. When compared to the normal subjects, CF patients had significantly reduced basal (76 +/- 50 vs 108 +/- 30 pM/l, 2 p < 0.02) and glucose stimulated insulin levels (1 + 3 min insulin = 456 +/- 275 vs 951 +/- 170 pM/l, 2 p < 0.01). Early phase insulin release, however, did not differentiate between CF patients with normal and impaired glucose tolerance; also in the two diabetic patients insulin levels did not clearly differ from those observed in the other groups of CF subjects. In conclusion, first-phase insulin response may identify an impairment of B-cell function in CF subjects; however, it does not discriminate between different degrees of glucose tolerance, as determined by the oral glucose tolerance test and, therefore, it does not reliably identify those patients who will eventually develop overt diabetes mellitus.

Quantification of the Relationship Between Insulin Sensitivity and β-Cell Function in Human Subjects: Evidence for a Hyperbolic Function

To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with fasting glucose levels < 6.4 mM. SI was compared with measures of body adiposity and beta-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the beta-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and beta-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the beta-cell measures could not be distinguished from a hyperbola, i.e., SI x beta-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, beta-cell function varies quantitatively with differences in insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in glucose metabolism in the elderly patient with diabetes.

To determine the alterations in glucose metabolism in elderly patients with NIDDM. We studied 9 healthy elderly control subjects (73 +/- 1 yr of age; body mass index 25.7 +/- 0.4 kg/m2) and 9 untreated elderly NIDDM patients (72 +/- 2 yr of age; BMI 25.9 +/- 0.5 kg/m2). Each subject underwent a 3-h oral glucose tolerance test (40 g/m2); a 2-h hyperglycemic glucose clamp study (glucose 5.4 mM above basal); and a 4-h euglycemic insulin clamp (40 mM.m2.min-1). Tritiated glucose methodology was used to measure glucose production and disposal rates during the euglycemic clamp. Patients with NIDDM had a higher fasting glucose (9.3 +/- 0.3 vs. 5.1 +/- 0.1 mM in control subjects vs. NIDDM patients, respectively, P < 0.001) and a greater area under the curve for glucose during the OGTT (16.0 +/- 0.6 vs. 6.7 +/- 0.3 mM in control subjects vs. NIDDM patients, respectively, P < 0.01) than the healthy control subjects. During the hyperglycemic clamp, patients with NIDDM had an absent first-phase insulin response (112 +/- 6 vs. 250 +/- 31 pM in control subjects vs. NIDDM patients, respectively, P < 0.01), and a blunted second-phase insulin response (159 +/- 11 vs. 337 +/- 46 pM in control subjects vs. NIDDM patients, respectively, P < 0.01). Before the euglycemic clamp, fasting insulin (99 +/- 5 vs. 111 +/- 10 pM in control subjects vs. NIDDM patients, respectively) and hepatic glucose production (11.8 +/- 0.7 vs. 11.5 +/- 0.5 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively) were similar. Steady-state (180-240 min) glucose disposal rates during the euglycemic clamp were slightly, but not significantly, higher in the normal control subjects (36.5 +/- 1.1 vs. 33.1 +/- 1.9 mumol.kg-1-min-1 in control subjects vs. NIDDM patients, respectively, NS). We conclude that NIDDM in nonobese elderly subjects is characterized by a marked impairment in insulin release. This may be attributable to the toxic effects of chronic hyperglycemia on the beta-cell. When compared with age-matched control subjects, the NIDDM patients showed no increase in fasting insulin or hepatic glucose production, and insulin resistance was mild.

Insulin responses following glucose administration in menstruating women

OBJECTIVE: The aim of the study was to investigate changes in insulin sensitivity during the menstrual cycle, in a group of regularly menstruating black African women. METHOD: Insulin responses to intravenous glucose (300 mg/kg) were assessed, for up to 3 h, in 3 groups of age- and body mass-matched nonobese sedentary Nigerian women: Group A, 7 women in the menstrual follicular phase; Group B, 7 women in the menstrual luteal phase; C, 7 men. RESULT: Women in the menstrual luteal phase had the greatest integrated firstphase insulin response and insulin/glucose ratios, much higher than the similar values for these variables obtained in other groups. This suggests that the menstrual luteal phase is associated with relative insulin resistance. CONCLUSION: Black African women in the menstrual luteal phase demonstrate an exaggerated insulin response to an acute glucose load and are thus relatively insulin-insensitive. This confirms previous observations in Caucasians.

The Magnitude, the Kinetics and the Metabolic Efficiency of First-Phase Insulin Response to Intravenous Glucose are Related

We investigated the relationship between the kinetics, the magnitude and the metabolic efficiency of first-phase insulin response (FPIR) to intravenous glucose. Twenty healthy control subjects and fifty first degree relatives of Type 1 diabetic patients were studied using a standardized protocol for the intravenous glucose tolerance test (IVGTT). The first significant increase in plasma insulin concentrations above baseline appeared as early as the 2nd min (1 min before the end of glucose injection, fast response) in 80% of controls and 70% of relatives, and at the 3rd min or later (delayed response) in the remaining subjects. The greatest delay in insulin release (5th min) was observed in 4 of 6 relatives of Type 1 diabetic patients with impaired FPIR. In the controls and the relatives, the subjects with a fast insulin response had a significantly higher FPIR (controls 215.4 +/- 93.5 vs 59.7 +/- 5.6 microU/ml, p < 0.001 and relatives 143.5 +/- 61.8 vs 55.9 +/- 27.7 microU/ml, p < 0.001) and showed better glucose assimilation (controls 3.05 +/- 1.05 vs 1.64 +/- 0.16%/min, p < 0.05 and relatives 2.6 +/- 0.96 vs 1.6 +/- 0.85%/min, p < 0.01) during IVGTT than the subjects with a delayed response. Moreover, for normal FPIR values in the group of relatives of Type 1 diabetic patients, a fast response was associated with a significantly better glucose assimilation as assessed by the incremental area under the glucose curve (358.6 +/- 64.7 vs 539.2 +/- 67.7 mmol/l per 90 min, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance and compensatory insulin secretion in middle-aged persons with hypertriglyceridemia.

Insulin secretion and insulin sensitivity were measured in hypertriglyceridemic patients using the frequently sampled intravenous glucose tolerance test. Three groups of men who were matched for age and body mass index were studied: eight healthy control subjects (C), seven patients with mild hypertriglyceridemia and normal glucose tolerance (TG), and seven with well-controlled type 2 diabetes with hypertriglyceridemia (TG-DM). The first-phase insulin response was increased by 116% in the TG group and decreased by 59% in the TG-DM group. The second phase of insulin secretion was increased in both TG groups (TG by 310% and TG-DM by 250%). The mean insulin sensitivity index (SI) was reduced by 50% in the TG group and by 60% in the TG-DM group. Glucose effectiveness (SG) was reduced by 30% in the TG-DM group compared with the control subjects.

Glucose and insulin responses to intravenous glucose challenge in relatives of Nigerian patients with non-insulin-dependent diabetes mellitus

We analysed blood insulin and glucose concentrations before and during frequently sampled intravenous glucose tolerance tests (FSIGT) in 2 groups of Nigerian subjects: (A) Control group ( n = 18), without a positive family history of diabetes mellitus, and (B) Experimental group ( n = 16), comprising age-, sex- and body mass-matched first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM). In comparison with Group A subjects, those in Group B had: (i) higher fasting plasma glucose level (mean ± S.E.M., 4.1 ± 0.1 vs. 3.8 ± 0.11 mmol/l, P < 0.05); (ii) similar fasting serum insulin levels (6.7 ± 5.0 vs. 5.8 ± 5.6 mU/l, P = NS); (iii) lower mean incremental area under the first-phase ( t = 0–10 min) post-glucose challenge insulin curve (376.9 ± 8.8 vs. 435.6 ± 5.6 mU/min l −1, P < 0.05); (iv) increased incremental area under the second-phase ( t = 10–182 min) post-glucose challenge insulin curve (432.9 ± 11.5 vs. 161.3 ± 8.7 mU/min l −1, P < 0.05); (v) reduced K G rate constant of glucose elimination (0.97 ± 0.12 vs. 1.41 ± 0.12%/min, P < 0.05). These results suggest that the subjects with a positive family history of NIDDM have a reduced beta-cell insulin secretory reserve (from reduced first-phase insulin response), tendency to rebound hyperinsulinemia during the latter phase of the insulin secretory response, a degree of tissue insulin insensitivity (as evident from high fasting plasma glucose despite similar insulin levels) and a diminished glucose disposal rate, in comparison with subjects without a family history of NIDDM. These features predict subsequent development of diabetes and suggest that as in Caucasians, first-degree relatives of Nigerian patients with NIDDM are at greater risk for future development of the disease.

Carbohydrate metabolism during pregnancy in control subjects and women with gestational diabetes.

The purpose of this study was to characterize carbohydrate metabolism associated with the development of gestational diabetes. Six control (Ctl) and ten women with gestational diabetes mellitus (GDM) were evaluated using an intravenous glucose tolerance test and hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose prior to conception (P) and at 12-14 (E), and 34-36 wk of gestation (L). There was an increase (P = 0.0001) in first-phase insulin response in Ctl (P 174 +/- 133, E 388 +/- 120, and L 587 +/- 303 microU/ml) and GDM (P 197 +/- 94, E 267 +/- 77, and L 376 +/- 162 microU/ml) but a significant (P = 0.02) lag in change in GDM with advancing gestation. Basal endogenous glucose production increased during gestation [Ctl: P 2.74 +/- 0.23, E 2.62 +/- 0.38, and L 3.14 +/- 0.36; GDM: P 2.68 +/- 0.51, E 2.78 +/- 0.45, and L 2.98 +/- 0.48 mg.kg fat-free mass (FFM)-1 x min-1; P = 0.02], but there was resistance to suppression by insulin infusion (P = 0.03) in late gestation (GDM: 0.61 +/- 0.44 vs. Ctl: 0.16 +/- 0.17 mg.kg FFM-1 x min-1). Insulin sensitivity decreased during gestation (Ctl: P 10.78 +/- 2.78, E 8.34 +/- 2.36, and L 4.75 +/- 1.22; GDM: P 7.49 +/- 2.13, E 7.40 +/- 1.45, and L 4.21 +/- 1.01 mg.kg FFM-1 x min-1; P = 0.0001) and was primarily decreased (P = 0.04) in GDM compared with Ctl from P through E. These findings closely resemble those of non-insulin-dependent, predominantly insulin-resistant diabetes, which is often a sequel of GDM.

Inverse relationship between serum Lp(a) levels and first-phase insulin secretion.

Relationships between serum Lp(a) levels and insulin metabolism were investigated in 147 healthy nonobese men attending an executive health-screening program. Each subject received an IVGTT with measurement of plasma levels of glucose, insulin, and C-peptide. An inverse relationship was seen with the first-phase plasma insulin response when subjects were stratified into quartile ranges of the serum Lp(a) distribution. This relationship was supported by mathematical modeling analyses of these data, which revealed an inverse relationship between serum Lp(a) levels and first-phase pancreatic insulin secretion and plasma insulin responsiveness to glucose.

Standardization of IVGTT to predict IDDM.

To review current practice in centers that use the IVGTT for prediction of IDDM. To establish consensus protocol for performance of the test. Postal questionnaires were delivered to 12 centers. Eleven centers used a glucose dose of 0.5 g/kg and 1 used 0.3 g/kg; the dosage in adults was limited to a maximum of 25-50 g in some centers but others applied no upper limit. The glucose concentration of the infusate varied between 20 and 66%. Eight centers injected glucose manually, two used a syringe pump, and two used gravity infusion. The period of infusion ranged from 30 +/- 10 s to 4 +/- 2 min, and time zero was taken as the start (1 center), middle (1 center), or end (10 centers) of the infusion. The potential range in timing of the +1-min sample varied between 1 and 7 min from the start of the infusion. Quality-assurance standards for the insulin assays used were not always appropriate for the fasting and low stimulated range of insulin levels. The first-phase insulin response to the IVGTT is widely measured as an index of risk of progression to IDDM. We established that methodology varies widely. Because of this, a new standard protocol for use in prediction of IDDM was agreed by an ICARUS working group and is described herein.

The ranges of insulin response and glucose tolerance in lean, normal, and obese women during pregnancy

We characterized insulin secretion and glucose disposal in a large unselected group of women, encompassing the full spectrum of glucose tolerance in pregnancy, and related the findings to maternal obesity. Intravenous glucose tolerance and first-phase insulin response were measured at about 32 weeks' gestation in 690 unselected pregnancies. The women were designated as "lean," "normal," or "obese" on weight-for-height criteria. The distribution of insulin response was bimodal, but there was no corresponding dichotomy in maternal glucose disposal rate. Insulin response was greatest and glucose disposal rate slowest in obese women. In general, "poor" glucose tolerance was associated with relatively low insulin output. It was not possible to identify any cluster of women, obese or otherwise, in whom poor glucose tolerance was specifically associated with an unusually high insulin response. The data indicate that the distribution of glucose tolerance in pregnancy is a continuum. Glucose intolerance represents one end of that spectrum and is attributable to insufficient insulin secretion. This relative insufficiency is most frequent with maternal obesity.