Proinsulin Concentrations Research Articles

Intra-individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in a general Caucasian population: the Hoorn Study

Intra-individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in a general Caucasian population: the Hoorn Study

Hyperproinsulinemia is associated with increased beta cell demand after hemipancreatectomy in humans.

The cause of disproportionate hyperproinsulinemia in patients with type II diabetes is controversial. To examine whether increased beta cell demand might contribute, we measured proinsulin and insulin concentrations in clinically healthy humans who had undergone hemipancreatectomy for the purpose of organ donation, a procedure previously demonstrated to increase beta cell demand and diminish insulin secretory reserve capacity. Subjects were studied at least 1 yr after hemipancreatectomy. Seven donors were followed prospectively and serves as their own controls. Nine additional donors were matched with normal controls (cross-sectional group). Fasting serum concentrations of intact proinsulin and conversion intermediates (total) were measured by a two-step radioimmunoassay; independent determinations of intact proinsulin and 32,33 split proinsulin were performed using an immunoradiometric assay. Serum total proinsulin values were significantly greater in hemipancreatectomized groups than controls (prospective group: predonation = 6.24 +/- 1.14 pM, postdonation = 34.63 +/- 17.47 pM, P < 0.005; cross-sectional group: controls = 5.78 +/- 1.12 pM, donors = 15.22 +/- 5.20 pM, P < 0.025). The ratio of total proinsulin to immunoreactive insulin was directly correlated with fasting plasma glucose and showed a significant inverse relationship to secretory reserve capacity. Both absolute and relative hyperproinsulinemia is found in hemipancreatectomized donors. These data demonstrate that partial pancreatectomy with its associated increase in beta cell demand raises measures of proinsulin in humans.

Plasminogen Activator Inhibitor (PAI-1) and Non-insulin-dependent Diabetes in Pima Indians, South Asians and Europeans

Activity of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of fibrinolysis, is raised in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to excess macrovascular disease. We investigated the association of PAI-1 activity with NIDDM in Pima Indians, a racial group with low risk of coronary artery disease, but in whom the impact of NIDDM on the occurrence of coronary artery disease is similar to other racial groups. We studied 308 (136 non-diabetic, 172 diabetic) Pima Indians from Arizona, and 138 (98 non-diabetic, 40 diabetic) South Asians and 129 (80 non-diabetic, 49 diabetic) Europeans living in North London. PAI-1 activity was measured by a spectrophotometric assay, and insulin, intact proinsulin and des 31,32 proinsulin concentrations were measured employing highly specific monoclonal antibody-based assays. Compared with non-diabetic subjects, PAI-1 activity was significantly higher in subjects with NIDDM among South Asians (22.8 +/- 7.3 vs. 17.4 +/- 6.9 AU/ml, p < 0.001) and Europeans (23.1 +/- 6.6 vs. 16.5 +/- 6.1 AU/ml, p < 0.001) but not among Pima Indians (19.5 +/- 9.6 vs. 18.5 +/- 8.6 AU/ml, ns). The association of PAI-1 activity with diabetes remained statistically significant when controlled for age, sex, body mass index and waist-hip ratio, serum triglyceride and fasting insulin concentrations in South Asians (p < 0.001) and Europeans (p < 0.001). The relationships of PAI-1 activity with clinical and biochemical variables were similar in the three racial groups other than for fasting and 2 h plasma glucose concentrations which were significantly associated with PAI-1 activity in South Asians (partial r = 0.32 and 0.31) and Europeans (partial r = 0.44 and 0.50) but not in Pima Indians (partial r = 0.11 and 0.15). In Pima Indians with NIDDM, PAI-1 activity was similar in those treated with sulphonylureas, insulin, or no drugs for diabetes. In conclusion, the association of PAI-1 with diabetes differs in racial groups who are at different risk of NIDDM and ischaemic heart disease. Previously reported differences in the prevalence of ischaemic heart disease between diabetic and non-diabetic Pima Indians, and between non-diabetic subjects from the three racial groups, are unlikely to be due to differences in PAI-1 activity.

Correlations of Plasma Concentrations of β-Cell Polypeptides with pathologic features of Insulinomas

To assess the correlations between plasma concentrations of b-cell polypeptides (insulin, C peptide) and size, multiplicity, and malignancy of insulinomas. We retrospectively reviewed the medical records of 55 consecutively treated patients at our institution with surgically confirmed insulinoma. The 29 female and 26 male patients ranged from 13 to 77 years of age (median, 46). Plasma insulin, C peptide, proinsulin, and glucose concentrations were analyzed statistically in patients with benign and those with malignant insulinomas. Significant correlations were observed between plasma insulin and tumor size (r = 0.45; P = 0.001) and tumor volume (r = 0.41; P = 0.007) and between plasma C peptide and tumor size (r = 0.38; P = 0.004) and tumor volume (r = 0.33; P = 0.025). No differences between benign and malignant tumors were noted for plasma insulin, C peptide, glucose, nor tumor size or volume. No correlations were found between plasma insulin, C peptide, or glucose and number of tumors. The plasma levels of insulin and C peptide provide qualitative indications about the size of insulinomas.

Use of specific immunoradiometric assay to determine preterm neonatal insulin-glucose relations.

Highly specific immunoradiometric assays were used to measure plasma concentrations of insulin, proinsulin, and 32-33 split proinsulin in neonates (n = 16). Neonatal plasma insulin concentrations were high relative to blood glucose concentrations and compared with adult insulin-glucose relations. Concentrations of proinsulin and 32-33 split proinsulin together accounted for 34-70% of the total concentration of insulin and pro-peptides. This study confirms the need to use a specific assay and neonatal reference data in the diagnosis of neonatal hyperinsulinism, and shows that neonatal pancreatic beta cell function may differ from that of older subjects.

A preponderance of small dense LDL is associated with specific insulin, proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects.

Recently, the presence of small dense low density lipoprotein (LDL) has been postulated to be a stronger risk factor for coronary heart disease than large LDL. While small dense LDL has been associated with individual components of the insulin resistance syndrome such as hypertension, high triglyceride level, low high density (HDL) cholesterol, and diabetes mellitus, there has been little work exploring whether LDL size is decreased in subjects with multiple metabolic disorders. We examined the association of LDL size and pattern to specific insulin (which does not cross-react with proinsulin), proinsulin, increased triglyceride, decreased HDL, hypertension and impaired glucose tolerance in 488 non-diabetic subjects from the San Antonio Heart Study. LDL size was significantly related to specific insulin, proinsulin and the fasting proinsulin/insulin ratio. Small dense LDL was significantly associated with high triglyceride level, decreased HDL cholesterol, hypertension and impaired glucose tolerance. LDL size (A) decreased in a stepwise fashion with increasing number of the metabolic disorders described above (zero 262.6 +/- 9.4; one 257.0 +/- 9.3; two 256.4 +/- 9.4; three 249.0 +/- 9.1; and four 244.9 +/- 9.0). These results were similar in men and women and in non-Hispanic whites and Mexican Americans. The association between LDL size and the number of metabolic disorders remained statistically significant even after adjustment for obesity, body fat distribution, gender, ethnicity, proinsulin and insulin concentrations. Furthermore, decreases in LDL size are also significantly associated with both a selective beta-cell defect (as estimated by the fasting proinsulin/insulin ratio) and insulin resistance (as estimated by the fasting insulin concentrations) although the association was somewhat stronger for the latter. We conclude that small dense LDL may form part of the insulin resistance syndrome in non-diabetic subjects.

Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects

Insulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Disproportionately increased proinsulin relative to insulin levels are suggested to be an early indicator of a failing pancreas. We examined the relationship of fasting specific insulin, proinsulin, and 32, 33 split proinsulin concentrations, and the proinsulin: insulin ration to the risk of developing NIDDM 3.5 years later in 65-74-year-old non-diabetic Finnish subjects participating in a population-based study (n=892) on diabetes and heart disease. Altogether 69 subjects developed NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender, glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in insulin concentrations between cases and random or matched control subjects [median and interquartile range: 123 (77-154), 108 (74-143), 118 (83-145) pmol/l, p=0.271]. Random control subjects had lower proinsulin and 32, 33 split proinsulin concentrations and split proinsulin: insulin ratios compared to cases [5.7 (3.8-9.0) vs 7.3 (4.8-10.0) pmol/l, p=0.005; 7.3 (4.5-13.0 vs 10.4 (7.1-18.0) pmol/l, p=0.002; 0.073 (0.057-0.110) vs 0.097 (0.060- 0.135), p=0.003]. Matched control subjects had lower proinsulin concentrations and proinsulin: insulin ratios compared to cases [5.9 (4.0-7.7) vs 7.3 (4.8-10.0) pmol/l, p=0.019; 0.048 (0.035-0.071) vs 0.064 (0.045-0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline proinsulin: insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased proinsulin concentration, an indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period.

Association of proinsulin-like molecules with lipids and fibrinogen in non-diabetic subjects--evidence against a modulating role for insulin.

Elevated concentrations of proinsulin-like molecules, other than insulin, may be associated with abnormalities of cardiovascular risk factors, promoting atherogenesis and thrombosis. Using specific assays we examined the relationship of levels of insulin, intact proinsulin and des-31,32 proinsulin to blood pressure, lipids, fibrinogen, factor VII and albumin excretion rate in 270 europids with normal glucose tolerance. After correcting for age and body mass index, fasting and 2-h insulin concentrations were significantly associated with those of total and LDL-cholesterol (r = 0.18-0.22), HDL-cholesterol (both r = -0.20) and triglycerides (r = 0.21 and 0.18), but not with blood pressure. Concentrations of intact and des-31,32 proinsulin showed significant associations with those of total and LDL-cholesterol (r = 0.20-0.23), HDL-cholesterol (r = -0.31 and -0.32) and triglycerides (r = 0.22 and 0.26). Fasting insulin and intact proinsulin concentrations were significantly associated with fibrinogen (r = -0.15 and 0.18). Concentrations of proinsulin-like molecules comprised less than 10% of all insulin-like molecules, and so were calculated not to influence previously described relationships between insulin concentrations and cardiovascular risk factors measured using non-specific assays. In multiple regression analyses des-31,32 proinsulin concentration was more strongly associated with those of HDL-cholesterol (negatively), LDL-cholesterol and triglycerides than fasting insulin concentrations, while intact proinsulin replaced insulin concentrations in their relationships with fibrinogen. Our results show correlations between dyslipidaemia and proinsulin-like molecules at concentrations at which biological, insulin-like, activity appears unlikely. We also show relationships between LDL-cholesterol and fibrinogen and the proinsulin-like molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

The serum concentration of insulin, C-peptide, and proinsulin in patients with acute pancreatitis

In 14 patients with acute pancreatitis during 16 episodes of the disease the concentrations of blood glucose, serum insulin (IRI), C-peptide (CP), and proinsulin (Pro) were determined in the fasting state on d 1, 2, 3, 5, and 10 after the attack. The peptides were measured using RIAs, and for determination of CP two antibodies: Byk-Mallinckrodt's and more specific M-1221 Novo antibodies were used. Apart from sporadic rises in the initial period of the disease, the blood glucose level did not change significantly and had a decreasing trend. On d 1 the mean serum IRI level was 0.17 +/- 0.04 (SD) nM, and it decreased on d 5 to 0.06 +/- 0.04 nM, rising again to 0.11 +/- 0.15 nM on d 10. The serum Pro concentration was on the same days: 11.1 +/- 12.6, 4.2 +/- 2.4 and 7.5 +/- 10.8 pM, whereas the serum CP values determined with M-1221 antibodies were 0.48 +/- 0.50, 0.34 +/- 0.19, and 0.52 +/- 0.25 nM, respectively. However, when serum CP was determined using Byk-Mallinckrodt kits, the concentration on d 1 was 1.90 +/- 1.12 nM and over the following days it decreased to 1.08 +/- 0.98 nM on d 5 and on d 10 it was 1.11 +/- 0.46 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance

We have studied low density lipoprotein (LDL) subclass distribution in a group of male patients with non-insulin-dependent diabetes mellitus (NIDDM) and investigated its relationships to fasting and postprandial triglyceride (TG)-rich lipoproteins, insulin resistance, lipoprotein lipase (EC 3.1.1.3; LPL), hepatic lipase (EC 3.1.1.34; HL), lecithin:cholesterol acyl transferase (EC 2.3.1.43; LCAT) and cholesteryl ester transfer protein (CETP) activities. LDL was subfractionated by density gradient ultracentrifugation. Postprandial lipoproteins were measured after an oral fat load using retinyl palmitate as a marker for intestinal TG-rich lipoproteins. Hypertriglyceridaemic NIDDMs (HTG) had a preponderance of small dense LDL particles present in the plasma and reduced amounts of large buoyant species when compared to normotriglyceridaemic patients (NTG) and controls. Both groups of diabetics were more insulin resistant than the controls ( P < 0.05) and had raised concentrations of proinsulin ( P < 0.05), although insulin content did not differ significantly. 32–33 split proinsulin (SPI) was the major insulin-like molecule present in HTG and was present in significantly higher amounts in these patients ( P < 0.05) than either NTG or control subjects and correlated significantly with the presence of small dense LDL particles. After a test meal, the postprandial chylomicron response was greater in HTG than either NTG diabetics or controls ( P < 0.05). Chylomicron remnants were present to a greater extent in HTG than in NTG and controls ( P < 0.05), although in this case NTG also contained more chylomicron remnants than control subjects ( P < 0.05). There was no difference in the LPL activity, CETP and LCAT between diabetics and controls, whereas an increase in hepatic lipase activity was seen in the HTG diabetics ( P < 0.05). Both CETP and LCAT activities increased postprandially. Multivariate analysis showed that TG, HDL content and HL activity were the most important determinants of small dense LDL concentration in the fasting state ( R 2 = 67%). Postprandially, chylomicron remnant clearance, HL and insulin resistance were the major determinants ( R 2 = 61%) of LDL-III.

Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo.

Fasting hyperinsulinemia (reflected by elevations in immunoreactive "insulin") is typical of patients with non-insulin-dependent diabetes mellitus (NIDDM) and is often associated with obesity and hypertension. The elevated concentrations detected are indicative not only of insulin but also of its immunologically cross-reactive precursors, including proinsulin. Fasting hyperinsulinemia appears to be associated with decreased fibrinolytic activity in blood, which results from increased activity of plasminogen activator inhibitor type-1 (PAI-1), a potential independent risk factor for coronary artery disease. Patients who were given proinsulin in a previous clinical study by others exhibited an increased incidence of cardiovascular events. Thus, a "proinsulin-PAI-1 axis" may predispose to coronary thrombosis. To define the possible presence of such an axis, this study was designed to determine whether insulin, its precursors, or both increase the concentrations of PAI-1 in rabbits in vivo. Equimolar proinsulin (n = 10), insulin (n = 11), C-peptide (n = 4), or vehicle alone (n = 10) was administered intravenously over 1 hour to euglycemic, conscious rabbits. Plasma PAI-1 activity increased 3.8-fold with proinsulin (P = .002) and 3.6-fold with insulin (P = .002). By contrast, no increase occurred after C-peptide or vehicle was administered. The increased PAI-1 activity was shown to be attributable to PAI-1 protein by reverse fibrin autography. As judged from changes in mRNA in tissues, proinsulin and insulin increased PAI-1 gene expression within 3 hours by 2.1- and 2.1-fold, respectively, in aorta (P = .025 each) and by 1.9- and 2.4-fold in liver (P = .015 and P = .001), with return of values to baseline within 24 hours (n = 4 experiments in each case). These results extend our previous observations from studies in vitro and suggest that hyperinsulinemia attributable to augmented concentrations of proinsulin and insulin in plasma increase plasma PAI-1 activity and may contribute to acceleration of atherosclerosis and impairment of coronary thrombolysis in patients with NIDDM.

Proinsulin and specific insulin concentration in high- and low-risk populations for NIDDM.

Hyperinsulinemia and insulin resistance have been implicated as risk factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). Recent data suggest that proinsulin may comprise a large proportion of immunoreactive insulin in subjects with NIDDM and possibly in those with impaired glucose tolerance (IGT) as well. Increased proinsulin concentrations are thought to be an early indicator of a failing pancreas. We examined proinsulin, insulin (using an assay that does not display appreciable cross-reactivity with proinsulin), and the fasting proinsulin:insulin ratio in 206 nondiabetic Mexican-American (a high-risk population for NIDDM) and 123 nondiabetic non-Hispanic white (a low-risk population for NIDDM) participants in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Mexican-Americans had significantly higher fasting and 2-h proinsulin and insulin levels but similar fasting proinsulin:insulin ratios compared with non-Hispanic whites. After statistical adjustment for age, body mass index, waist-to-hip ratio, and glucose tolerance status, Mexican-Americans continued to have higher fasting and 2-h insulin and fasting and 2-h proinsulin concentrations but similar proinsulin:insulin ratios compared with non-Hispanic whites. The fasting proinsulin:insulin ratio was higher in 85 subjects with NIDDM compared with subjects with IGT or normal glucose tolerance (0.31, 0.09, and 0.07, respectively). Thus, nondiabetic subjects from a high-risk population for NIDDM are hyperinsulinemic (using an assay that does not cross-react with proinsulin) and, further, do not secrete more proinsulin relative to insulin itself than do nondiabetic subjects from a low-risk population.

Proinsulin and specific insulin concentration in high- and low-risk populations for NIDDM

Proinsulin and specific insulin concentration in high- and low-risk populations for NIDDM

Effects of changes in acid base and calcium concentration on fasting serum insulin, proinsulin, and glucose concentrations.

To test the hypothesis that alterations in acid base or calcium concentration may affect proinsulin processing or the insulin secretion mechanism. Changes in proinsulin secretion or cleavage were assessed by measuring serum intact proinsulin and immunoreactive insulin concentrations in three models of acid base and calcium disturbance: (1) subacute changes in acid base status in six volunteers who received oral placebo, ammonium chloride, or sodium bicarbonate for three five day periods; (2) acute changes in calcium concentration in eight subjects who received 25 mmol oral calcium; (3) chronic changes in calcium concentration in seven patients with primary hyperparathyroidism and five with pseudohypoparathyroidism. Acid base changes were confirmed by rises in serum bicarbonate concentrations (p < 0.01). No changes in serum insulin, intact proinsulin, or the proinsulin:insulin molar ratio were found. Serum calcium concentrations increased (2.49 v 2.38 mmol/l; p < 0.05) and parathyroid hormone concentrations decreased (1.1 v 1.9 pmol/l; p < 0.01) two hours after acute calcium loading. There were no significant differences in serum glucose, insulin, or intact proinsulin concentrations. Fasting proinsulin concentrations were significantly lower in the hyperparathyroid group (1.1 v 2.1 pmol/l; p < 0.05) and increased significantly after parathyroidectomy (2.1 v 1.1 pmol/l; p < 0.05). The results indicate that subacute acid base changes do not affect proinsulin cleavage. Although acute calcium loading has no demonstrable effect, chronic hypercalcaemia may influence the mechanism of insulin secretion.

Insulin resistance, insulin, proinsulin, and ambulatory blood pressure in type II diabetes.

Both insulin resistance and insulin concentrations correlate with blood pressure in nondiabetic subjects, but there is no consensus on these relations in subjects with non-insulin-dependent diabetes, perhaps because of the use of nonspecific insulin assays and clinic blood pressure measurement. Therefore, we have investigated the relation between ambulatory blood pressure, insulin sensitivity (measured by an insulin sensitivity test), and levels of insulin and its principal precursors, measured by specific assays, in 24 subjects with non-insulin-dependent diabetes. Insulin sensitivity (glucose metabolic clearance rate) correlated strongly with mean 24-hour ambulatory systolic blood pressure (r = -.650, P < .001). In contrast, there was no relation between this blood pressure index and fasting levels of insulin (r = .096, P = NS) or all insulin-like molecules (r = .077, P = NS). Dichotomized on 24-hour ambulatory systolic blood pressure levels, the hypertensive group was more insulin resistant than the normotensive group (metabolic clearance rate, 3.6 [0.7] versus 6.5 [3.0] mL.kg-1.min-1, P = .006), whereas there was no difference in insulin or proinsulin concentrations among the groups. In multiple regression analysis, insulin sensitivity was the major determinant of blood pressure. We conclude that in subjects with non-insulin-dependent diabetes mellitus, blood pressure is related to insulin sensitivity but not to fasting levels of insulin, suggesting that hyperinsulinemia is probably not the mediator of this relation.

Alterations in Immunoreactive Proinsulin and Insulin Clearance Induced by Weight Loss in NIDDM

Subjects with overt non-insulin-dependent diabetes mellitus (NIDDM) were studied in comparison to obese nondiabetic control subjects and patients with subclinical diabetes. Pancreatic insulin secretion rates were measured by deconvolution of peripheral C-peptide over a 24-h period while subjects consumed an isocaloric mixed diet. Subjects were then placed on caloric restriction for at least 6 weeks, during which time body weight fell by at least 10%. Refeeding with solid mixed meals was then resumed for at least 2 weeks until isocaloric intake was attained, and then the meal profiles were repeated. Before weight loss, insulin, C-peptide, and insulin secretion rates were significantly higher in subjects with subclinical diabetes than in the other two groups. Proinsulin concentrations were significantly greater in the two diabetic groups than in control subjects, but, when expressed as a percentage of the total insulin immunoreactivity, the differences were significant only in the group with overt diabetes. Weight loss because of hypocaloric feeding resulted in a significant increase in the rate of clearance of endogenously secreted insulin but did not affect the clearance of C-peptide. In obese subjects and those with subclinical diabetes, weight loss was associated with a reduction in insulin secretion rates, presumably as a result of improvements in insulin sensitivity. In patients with overt diabetes and hyperglycemia, weight loss improved beta-cell responsiveness to glucose and was associated with an increase in insulin clearance and a reduction in proinsulin immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoradiometric assay of human intact proinsulin applied to patients with type 2 diabetes, impaired glucose tolerance, and hyperandrogenism

We describe an immunoradiometric assay for human intact proinsulin in serum. In this method, one monoclonal antibody, coated onto polyacrylamide beads, cross-reacts with proinsulins and insulin. A sandwich is formed with intact proinsulin, split (65-66) proinsulin, and des (64-65) proinsulin binding with an 125I-labeled monoclonal antibody specific for an epitope at the intact B-C junction of proinsulin. Because split (65-66) and des (64-65) proinsulin concentrations are very low in serum, this assay essentially measures intact proinsulin. When we used 1-mL serum samples, the mean detection limit was 0.4 pmol/L. Mean proinsulin concentrations (pmol/L) were 3.4 (range 1-9.1) in healthy fasting subjects, 28.5 (9.7-101) in patients with type 2 diabetes (treated with metformin and sulfonylureas), 5.0 (1.6-9.3) in women with hyperandrogenism and normal insulinemia, 10.3 (2.6-36) in women with hyperandrogenism and hyperinsulinemia, and 8.5 (4.8-21.3) in patients with impaired glucose tolerance.

Understanding Oral Glucose Tolerance: Comparison of Glucose or Insulin Measurements During the Oral Glucose Tolerance Test with Specific Measurements of Insulin Resistance and Insulin Secretion

The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r = 0.61, p < 0.001) but not insulin resistance (r = -0.05, p > 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = -0.53, p < 0.001) and insulin secretion (r = 0.07, p > 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA) also correlated well with insulin resistance (r = -0.57, p < 0.001) but not insulin secretion (r = 0.01, p > 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.

INSULIN RESISTANCE IN 7 YEAR OLD CHILDREN WHO WERE THIN AT BIRTH

It has been shown recently that men and women who were thin at birth have a high prevalence of impaired glucose tolerance and insulin resistance. These associations may reflect impaired development of skeletal muscle during gestation. To determine whether the relations can be detected in children, we have studied a population sample of 249 British children aged 7 years. Blood was taken for glucose and insulin in the fasting state and 30 minutes after an oral glucose challenge. Plasma insulin, proinsulin, and 32-33 split proinsulin concentrations were determined by two site immunoreactive assays. Mean birthweight was 3359 (sd 510) grams. Glucose at 30 minutes was significantly inversely related to thinness at birth, as measured by the ponderal index (weight/height3). For a given insulin response to the glucose challenge, children who had been thin at birth had high glucose levels at 30 minutes. A high level of 32-33 split proinsulin, a measure of islet cell dysfunction, was related to shortness at birth. Those findings are further evidence that reduced growth in utero is followed by permanent dysfunction of the endocrine pancreas and resistance of peripheral tissues to insulin.

Effects of octreotide on circulating islet B cell products in endogenous hyperinsulinism

The role of somatostatin analogues in the medical management of insulinomas is unclear. We describe an elderly patient with clinical and biochemical features of endogenous hyperinsulinism attributable to a benign islet B cell disorder whose incapacitating neuroglycopaenic symptoms responded dramatically to octreotide 50 micrograms subcutaneously at 2200 h each night. Octreotide suppressed inappropriate plasma concentrations of insulin thereby preventing fasting hypoglycaemia. Fasting concentrations of proinsulin, and 32-33 split proinsulin, as determined by two-site monoclonal antibody-based immunoradiometric assays, were also suppressed by octreotide.