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At least 19 recordsLinked to original sources
PubMed1991

Insulin secretion, insulin sensitivity and glucose-mediated glucose disposal in Cushing's disease: a minimal model analysis.

OBJECTIVE: We wished to assess the contributions of insulin secretion, insulin sensitivity and glucose-mediated glucose disposal to glucose tolerance in subjects exposed to chronic glucocorticoid excess. DESIGN: Patients with Cushing's disease were subjected to a frequently sampled intravenous glucose tolerance test before and at least 3 months after curative surgery and compared to a control group. PATIENTS: Seven patients with clinical and biochemically proven pituitary dependent Cushing's disease and 10 healthy control subjects were studied. MEASUREMENTS: Paired glucose and insulin plasma profiles were analysed by the Minimal Model method of Bergman, which provided simultaneous estimates of the glucose decay rate, insulin secretion, insulin sensitivity and glucose-mediated and non-insulin-mediated glucose disposal. Data were evaluated by non-parametric statistical analysis and reported as median and interquartile ranges. RESULTS: Basal glucose, insulin, C-peptide and glucagon levels were significantly raised preoperatively and fell towards normal post-operatively. Glucose tolerance assessed as glucose decay rate was reduced significantly preoperatively (pre: 1.3 (0.8-2.0) vs post: 1.6 (1.5-2.6) per min x 10(2), P less than 0.05). First phase insulin release was similar in the Cushing's disease and control subjects. In contrast, second phase insulin release was significantly greater preoperatively and remained high post-operatively compared to control subjects (pre: 18.8 (16.7-23.6) vs post: 16.7 (8.5-18.8) vs control 11.1 (4.5-15.4) mU/g/min2 x 10(-2), P less than 0.002). Median insulin sensitivity was reduced by 60% preoperatively in the Cushing's disease subjects compared to the post-operative Cushing's disease and control subjects (pre: 2.1 (1.3-4.2) vs post: 5.0 (3.2-7.3) vs control 5.1 (2.2-7.2) per min/mU/l x 10(4)). Median glucose-mediated glucose disposal was reduced by 40% in the pre and post-operative Cushing's disease subjects compared to the control group (pre: 1.1 (0.6-2.1) vs post: 1.1 (0.6-2.1) vs control 1.9 (1.4-2.6) per min x 10(2)), but this was not statistically significant. However, non-insulin-mediated glucose disposal was significantly reduced in the preoperative Cushing's disease subjects (pre: 0.55 (0.08-1.59) vs control 1.43 (0.94-2.27) per min x 10(2), P less than 0.05). In the Cushing's disease subjects, glucose tolerance correlated with both insulin sensitivity (rs = 0.84, P less than 0.01) and non-insulin-mediated glucose disposal (rs = 0.56, P less than 0.05). The fractional clearance rate of insulin was unaltered by Cushing's disease. CONCLUSIONS: Cushing's disease subjects are characterized by impaired glucose tolerance due to both reduced insulin sensitivity and non-insulin-mediated glucose disposal, in the presence of enhanced insulin secretion.

Adult↗
PubMed1992

Fat-induced changes in mouse pancreatic islet insulin secretion, insulin biosynthesis and glucose metabolism.

Insulin secretion, insulin biosynthesis and islet glucose oxidation were studied in pancreatic islets isolated from fat-fed diabetic mice of both sexes. Insulin secretion from isolated islets was studied after consecutive stimulation with alpha-ketoisocaproic acid + glutamine, glucose, forskolin, and 12-O-tetradecanoylphorbol 13-acetate. Glucose-induced insulin secretion was impaired in islets from fat-fed mice. This was associated with a reduction of approximately 50% in islet glucose oxidation. Islet insulin secretion stimulated by the non-carbohydrate secretagogues tended to be higher in the fat-fed mice, but a statistically significant effect was not observed. Pancreatic insulin content was reduced by 50%, whereas the islet insulin and DNA content was unchanged after fat feeding. Proinsulin mRNA was reduced by 35% in islets from fat-fed mice, and was associated with a reduction of approximately 50% in glucose-stimulated (pro)insulin biosynthesis. It is concluded that the insulin secretory response of islets isolated from fat-fed mice is similar to the secretory pattern known from human type 2, non-insulin-dependent diabetics, and that a defect in islet glucose recognition, resulting in decreased glucose oxidation, may be responsible for the observed insulin secretory and biosynthetic defects seen after glucose stimulation.

Animals↗
PubMed1999

Dose-related effects of GLP-1 on insulin secretion, insulin sensitivity, and glucose effectiveness in mice.

We examined the dose-related net effects of glucagon-like peptide 1 (GLP-1) on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance in anesthetized mice. GLP-1 dose dependently potentiated insulin secretion after glucose administration, with the half-maximal effect at 1 nmol/kg. GLP-1 also dose dependently reduced the area under the glucose curve (AUC(glucose)) and increased the glucose elimination rate (K(G)) but did not affect the glucose effectiveness (S(G)). Furthermore, the insulin sensitivity index (S(I)) was reduced after administration of GLP-1. Because insulin secretion was stimulated to a larger degree than S(I) was reduced, the peptide increased the global disposition index (GDI = AUC(insulin) x S(I)). Matching plasma insulin levels after GLP-1 by exogenous insulin reproduced the influences of GLP-1 on AUC(glucose), K(G), S(I), and GDI. Finally, the GLP-1 receptor antagonist exendin-3-(9-39) inhibited the actions of GLP-1. We conclude that GLP-1 increases glucose tolerance in the mouse mainly by potently stimulating insulin secretion.

Animals↗
PubMed2006

Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction.

To determine the effects of age and sex on the regulation of postprandial glucose metabolism, glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction were concurrently measured in 145 healthy elderly (aged 70 +/- 1 years) and in 58 young (aged 28 +/- 1 years) men and women before and after ingestion of a mixed meal containing [1-(13)C]glucose. At the time of meal ingestion, [6-(3)H]glucose and [6,6-(2)H(2)]glucose were infused intravenously to enable concurrent measurement of the rates of postprandial endogenous glucose production (EGP), meal appearance, and glucose disappearance. Fasting and postprandial glucose concentrations were higher (P < 0.001) in both elderly women and elderly men compared with young individuals of the same sex. The higher postprandial glucose concentrations in the elderly than young women were caused by higher rates of meal appearance (P < 0.01) and slightly lower (P < 0.05) rates of glucose disappearance immediately after eating. In contrast, higher glucose concentrations in the elderly than young men were solely due to decreased (P < 0.001) glucose disappearance. Although postprandial glucose concentrations did not differ in elderly women and elderly men, rates of meal appearance and glucose disappearance rates both were higher (P < 0.001) in the women. Fasting EGP was higher (P < 0.05) in elderly than young subjects of both sexes and in women than men regardless of age. On the other hand, postprandial suppression of EGP was rapid all groups. Insulin action and secretion were lower (P < 0.001) in the elderly than young men but did not differ in the elderly and young women. This resulted in lower (P < 0.001) meal disposition indexes in elderly than young men but no difference in elderly and young women. Total meal disposition indexes were lower (P < 0.05) in elderly men than elderly women, indicating impaired insulin secretion, whereas disposition indexes were higher (P < 0.05) in young men than young women. Hepatic insulin clearance was greater (P < 0.001) in the elderly than young subjects of both sexes but did not differ between men and women regardless of age. In contrast, the ability of glucose to facilitate its own uptake (glucose effectiveness) was higher (P < 0.001) in women than men but did not differ in elderly and young subjects. Thus, age and sex impact on insulin secretion, insulin action, hepatic insulin extraction, and glucose effectiveness, resulting in substantial differences in the regulation of postprandial glucose metabolism in men and women and in elderly and young subjects.

Adult↗
PubMedDate not supplied

Effect of tequila on homocysteine, insulin secretion, insulin sensitivity, and metabolic profile in healthy men.

AIM: The purpose of this study is to identify the effect of a low dose of tequila on homocysteine, insulin secretion, insulin sensitivity, and metabolic profile in healthy young men. METHODS: An open clinical trial was carried out in eight healthy nonobese, young male volunteers. The study was divided in two phases. The first one evaluated metabolic changes, including insulin secretion and sensitivity due to acute administration of 30 ml of straight tequila. The second phase of the study evaluated metabolic effects due to the daily administration of 30 ml of tequila during 30 days. RESULTS: There were no significant metabolic changes after the single oral administration of 30 ml of straight tequila. After the administration of tequila during 30 days, a significant increase in homocysteine levels and a tendency to increase the glucose concentration and to decrease the insulin sensitivity were found. CONCLUSION: Detrimental metabolic changes were observed with the daily administration of 30 ml of tequila during 30 days.

Adult↗
PubMed1995

Effects of glucagon-like peptide-1 (GLP-1) in RINm5F insulinoma cells. Stimulation of insulin secretion, insulin content, and insulin receptor binding.

Glucagon-like peptide-1 (GLP-1) is the major incretin hormone from the distal small intestine which stimulates basal and glucose-induced insulin secretion. Using the rat insulinoma cell line RINm5F (Gazdar et al. 1980) we investigated the effects of GLP-1 on insulin secretion, insulin content, and insulin receptor binding. During a 1 hour incubation, GLP-1 [1 nM] stimulated insulin secretion 2-fold (p < 0.01 vs controls). Incubating RINm5F for 24 h with GLP-1 [1 nM], a 1.6-fold higher cellular insulin content was observed (p < 0.01 vs controls). Moreover, GLP-1 induced a 2-fold higher capacity and a 15-fold higher affinity of 125I-insulin binding on the cell surface (p < 0.01 vs controls). Glucagon, known as a potent stimulator of insulin secretion, yielded a similar effect only in 1,000-fold higher concentrations, whereas the intracellular insulin content as well as insulin receptor binding was not increased. Taken together, in RINm5F insulinoma cells GLP-1 potently stimulates insulin secretion and insulin content, and improves insulin receptor binding.

Animals↗
PubMed2003

Insulin secretion, insulin sensitivity, and hepatic insulin extraction in first-degree relatives of type 2 diabetic patients.

To identify early metabolic abnormalities in type 2 diabetes mellitus, we measured insulin secretion, sensitivity to insulin, and hepatic insulin extraction in 48 healthy normal glucose-tolerant Brazilians, first-degree relatives of type 2 diabetic patients (FH+). Each individual was matched for sex, age, weight, and body fat distribution with a person without history of type 2 diabetes (FH-). Both groups were submitted to a hyperglycemic clamp procedure (180 mg/dl). Insulin release was evaluated in its two phases. The first was calculated as the sum of plasma insulin at 2.5, 5.0, 7.5, and 10.0 min after the beginning of glucose infusion, and the second as the mean plasma insulin level in the third hour of the clamp procedure. Insulin sensitivity index (ISI) was the mean glucose infusion rate in the third hour of the clamp experiment divided by the mean plasma insulin concentration during the same period of time. Hepatic insulin extraction was determined under fasting conditions and in the third hour of the clamp procedure as the ratio between C-peptide and plasma insulin levels. FH+ individuals did not differ from FH- individuals in terms of the following parameters [median (range)]: a) first-phase insulin secretion, 174 (116-221) vs 207 (108-277) microU/ml, b) second-phase insulin secretion, 64 (41-86) vs 53 (37-83) microU/ml, and c) ISI, 14.8 (9.0-20.8) vs 16.8 (9.0-27.0) mg kg-1 min-1/ microU ml-1. Hepatic insulin extraction in FH+ subjects was similar to that of FH- ones at basal conditions (median, 0.27 vs 0.27 ng/microU) and during glucose infusion (0.15 vs 0.15 ng/ micro U). Normal glucose-tolerant Brazilian FH+ individuals well-matched with FH- ones did not show defects of insulin secretion, insulin sensitivity, or hepatic insulin extraction as tested by hyperglycemic clamp procedures.

Adult↗
PubMed1984

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects.

The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.

Adolescent↗
PubMed1994

Insulin secretion, insulin action and non-insulin-dependent glucose uptake in pancreas transplant recipients.

To assess individual factors responsible of overall glucose tolerance after successful pancreas transplantation, an i.v. glucose tolerance test, with frequent blood sampling and tolbutamide administration to elicit a second insulin response was used to estimate insulin sensitivity (SI) and glucose effectiveness (SG) with Bergman's minimal model. Insulin secretion was calculated from the combined insulin-C-peptide kinetics method. These parameters were quantified in identically immunosupressed transplants: ISPx, four segmental pancreas recipients with impaired glucose tolerance; TSPx, five segmental pancrease recipients with normal glucose tolerance; WPx, five whole pancreas recipients with normal glucose tolerance; and in two controls groups, Kx, eight nondiabetic kidney recipients, and Ns, eight normal subjects. All participants had normal fasting plasma glucose and normal glycosylated hemoglobin A1C levels. The glucose tolerance KG value was significantly reduced only in ISPx compared with Ns (P < 0.05). SI was reduced by 60% in ISPx, WPx, and Kx compared with normal subjects (P < 0.05), whereas SI was reduced by 30% in TSPx compared with normal controls (P = NS). The reduction in SG was the same in all pancreas transplanted groups, as compared to Kx and Ns (by 33% and 40%, respectively, P < 0.05). The first-phase insulin secretion (0-5 min) was markedly reduced in ISPx and TSPx compared with Ns (by 76% and 50%), to Kx (by 84% and 66%) and to WPx (by 73% and 45%), respectively (P < 0.05), but similar to Ns in WPx. The overall incremental insulin secretion was reduced in ISPx compared with Ns, WPx, and Kx (by 38%, 62%, and 73%, respectively, P < 0.05) and reduced in TSPx compared to WPx and Kx (by 47% and 67%, respectively, P < 0.05) Ns secreted 43% of the total amount of insulin during the first phase the corresponding value was only 13% in ISPx vs. 24% in TSPx, 24% in Kx, and 25% in WPx, respectively (P < 0.05). In conclusion, after pancreas transplantation, the overall glucose tolerance is determined by the net effect of reductions in insulin sensitivity and glucose effectiveness and in the adaptability of the beta-cells to ensure sufficient insulin secretion. beta-cell function was impaired in both the whole pancreas and segmental transplant recipients, and the failure to increase insulin secretion sufficiently leads to glucose intolerance.

Adult↗
PubMed1995

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non- and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM.

Age of Onset↗
PubMed1990

Insulin secretion, insulin sensitivity and glucose-mediated glucose disposal in thyrotoxicosis: a minimal model analysis.

In order to evaluate simultaneously in thyrotoxic subjects the relative contributions of insulin secretion, insulin-sensitivity (SI) and glucose-mediated (SG) glucose disposal to overall glucose tolerance, seven non-obese patients with thyrotoxicosis were studied by the minimal model analysis of the frequently sampled intravenous glucose tolerance test, before and greater than 1 month after being rendered euthyroid, and compared with eight healthy control subjects. Basal glucose, C-peptide and glucagon levels were similar in all groups but, in the toxic and euthyroid states, basal insulin levels were significantly elevated compared to the control group (11.2 +/- 2.0 and 7.9 +/- 1.1 vs 5.1 +/- 0.6 microU/ml, mean +/- SE, P less than 0.02). FFA levels were raised in the thyrotoxic subjects prior to treatment (0.95 +/- 0.11 vs 0.68 +/- 0.08 and 0.54 +/- 0.08 mmol/l, P less than 0.02). Glucose tolerance (Kg) was reduced in the thyrotoxic subjects compared to the euthyroid state (1.16 +/- 0.12 vs 1.44 +/- 0.13 per min, P less than 0.025) and control group (1.44 +/- 1.0 per min, 0.05 less than P less than 0.1). First phase (phi 1) and second phase (phi 2) insulin release were both significantly elevated in the thyrotoxic and euthyroid states compared to the control group (phi 1 7.10 +/- 1.88 and 5.29 +/- 1.03 vs 1.72 +/- 0.17 microU/mg/min X 10(-2), P less than 0.01; phi 2 18.64 +/- 3.14 and 16.74 +/- 4.48 vs 9.23 +/- 0.74 microU/mg/min X 10(-2) respectively, P less than 0.02). SG was similar in all groups but SI was significantly reduced in the thyrotoxic subjects compared to the control group (2.24 +/- 0.62 vs 5.92 +/- 1.50/min/microU/ml X 10(4), P less than 0.02) and rose post-treatment in the euthyroid subjects (4.23 +/- 1.75/min/microU/ml X 10(4)). In the thyrotoxic subjects before and after treatment, log SI correlated negatively with basal FFA levels (r = -0.57, P less than 0.05) and with phi 2 (r = -0.58, P less than 0.05). The fractional clearance rate of insulin was unaltered by the thyrotoxic state. It is concluded that in thyrotoxicosis the impairment of Kg is due to reduced insulin sensitivity in the presence of enhanced insulin secretion, but glucose-mediated glucose disposal is unaltered by the toxic state.

Adult↗
PubMed1994

Effect of naltrexone treatment on insulin secretion, insulin action and postprandial thermogenesis in obesity.

For many years a series of studies has been carried out to evaluate the role of endogenous opioid peptides on glucose metabolism. In this work we studied the influence of endogenous opioid peptides on insulin response to OGTT and glucose-induced thermogenesis before and after a prolonged oral treatment with Naltrexone (50 mg/daily for 6 days), an opioid receptor antagonist, in a group of 9 obese subjects. Moreover in obese patients we evaluated the effect of this anti-opioid drug on insulin secretion and insulin sensitivity during an IVGTT using the minimal model approach. We compared the pre-treatment results with data coming from a group of 5 normal-weight subjects. We measured blood glucose, plasma insulin and C-peptide concentrations and evaluated the following parameters: first (phi 1) and second (phi 2) phase of beta-cell sensitivity, insulin sensitivity and glucose effectiveness. Obese subjects displayed an increased insulin response to oral and i.v. glucose load, due to an increased first phase of insulin secretion (phi 1), a reduced insulin sensitivity (Si) and glucose effectiveness (Sg) in respect to normal-weight subjects. They showed no difference in glucose and insulin area during oral load and in their profiles during i.v. glucose load after naltrexone treatment. Similarly no significant variation in insulin sensitivity and glucose effectiveness was observed. The glucose-induced thermogenesis, measured by indirect calorimetry, was not modified by naltrexone. Therefore our study demonstrates that endogenous opioids do not play any role in the impairment of peripheral insulin sensitivity and energy expenditure in human obesity.

Adult↗
PubMed1980

Relationship between insulin secretion, insulin content and dry weight of single rat pancreatic islets.

Single islets were incubated at glucose 5 mM for 60 min and subsequently at glucose 15 nM for 30 min. The insulin content of the incubated islets was proportional to the dry weight of the islets. The insulin secretion (Y) demonstrated a curvilinear relationship with the dry weight (X) of the islets, which could be described by the function Y = aX2/3 (a being a constant). On basis of this function it can be calculated that the insulin secretion of a particular islet is proportional to its outer surface. The consequence of this is that small sized islets secrete relatively much more insulin than large islets. Islets isolated with either purified or crude collagenase gave the same results except that a higher basal insulin secretion was observed with crude collagenase.

Animals↗
PubMed1999

Discovery of a Met300Val variant in Shc and studies of its relationship to birth weight and length, impaired insulin secretion, insulin resistance, and type 2 diabetes mellitus.

The Shc adaptor proteins corresponding to the 46-, 52-, and 66-kDa isoforms are key transducers of growth promotion and gene expression, which are being phosphorylated by all known receptor tyrosine kinases after stimulation by growth factors such as insulin and insulin-like growth factor I. Several studies have demonstrated a relationship between intrauterine growth retardation and impaired glucose tolerance or type 2 diabetes later in life. It is unclear whether this finding is partially explained by genetic factors. In this context, abnormalities in Shc proteins are considered to be a plausible candidate. Therefore, the aim of this study was to analyze whether genetic variability of the Shc isoforms causes a decrease in cell growth and cell differentiation that could be manifested by a decrease in birth weight and length, impaired acute insulin secretion after i.v. glucose, insulin resistance, and eventually a higher prevalence of type 2 diabetes. By single strand conformation polymorphism-heteroduplex analysis of 70 patients with diabetes mellitus and subsequent nucleotide sequencing of identified single strand conformation polymorphism variant, we discovered a Met300Val substitution of the 52-kDa isoform. The amino acid variant was predicted to be present in all 3 isoforms of Shc. In a genotype-phenotype study of 360 young healthy subjects, the allelic frequency of the codon 300 polymorphism was 4.2%. In this cohort, no significant differences could be shown between carriers and noncarriers in birth weight and length, the acute insulin response to i.v. glucose, or the insulin sensitivity index, as estimated from an i.v. glucose tolerance test. In an association study of 313 type 2 diabetic patients and 226 matched glucose-tolerant subjects, there was no significant difference in allelic frequency of the Shc variant (5.1% in diabetic patients vs. 3.1% in control subjects; P = 0.11). In conclusion, by itself the Met300Val polymorphism of Shc has no major impact on birth weight and length, insulin sensitivity index, acute glucose-induced insulin secretion, or prevalence of random type 2 diabetes mellitus.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Insulin secretion, insulin sensitivity and hepatic insulin extraction in primary hyperparathyroidism before and after surgery.

OBJECTIVE: Primary hyperparathyroidism (pHPT) is associated with hypertension, hyperinsulinaemia, and insulin resistance. The present study investigated the causes of these metabolic disturbances by quantifying insulin sensitivity and glucose effectiveness, and by assessing the time course of beta-cell insulin secretion and hepatic insulin extraction, during a dynamic condition such as after an intravenous glucose load. In addition, we evaluated the possible link between metabolic disorders and high blood pressure. SUBJECTS: We studied 16 patients with pHPT, before and 12 weeks after parathyroidectomy; eight of these patients were re-evaluated one year after surgery. The control group consisted of 18 healthy volunteers. DESIGN AND MEASUREMENTS: All subjects underwent an oral and a frequently sampled intravenous glucose tolerance test. The data from the intravenous glucose tolerance test were analysed by means of the minimal model technique which yields relevant parameters to comprehend the metabolic status of the single individual. RESULTS: The glucose intolerance condition was characterized by a severely impaired insulin sensitivity in pHPT (3.2 +/- 0.5 vs 9.5 +/- 1.5 x 10(4)/min/(microU/ml) of control subjects; P < 0.001), as well as by a reduced glucose effectiveness, (0.02 +/- 0.002 vs 0.03 +/- 0.003/min of control subjects; P < 0.04). Total insulin secretion during the 4 hours of the test was almost twofold elevated in comparison to the control subjects (32795 +/- 4769 vs 16864 +/- 1850 pM, P < 0.004) and its basal component significantly correlated with the high blood pressure. Hepatic extraction of insulin was significantly increased in pHPT (85 +/- 2 vs 76 +/- 2%, P < 0.03), possibly as a compensatory mechanism of hypersecretion, which however did not prevent peripheral hyperinsulinaemia in pHPT. Patients with pHPT were divided into two subgroups with normal and impaired glucose tolerance. The patients with impaired glucose tolerance had a significant reduction of first phase insulin response, although their basal and stimulated insulin levels were higher. Tissue insulin sensitivity and glucose effectiveness did not significantly differ between the two subgroups. After surgery, all the biochemical parameters (former hypercalcaemia, hypophosphataemia, elevated parathormone levels) were normalized, insulin sensitivity significantly improved (6 +/- 1 x 10(4)/min/(microU/ml), P < 0.001), whereas glucose effectiveness remained completely unchanged. Basal and stimulated insulin responses were insignificantly lowered after surgery, and hepatic extraction did not change either. CONCLUSIONS: Patients with pHPT exhibited decreased insulin sensitivity and insulin hypersecretion. The latter is only partially ameliorated by increased hepatic insulin extraction. After surgery, although the biochemical abnormalities were fully reversible, the metabolic changes improved only partially.

C-Peptide↗
PubMed2004

Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial [ISRCTN08745124].

BACKGROUND: The present study aimed at investigating in healthy volunteers the effects of diazepam and clonazepam on beta-cell function, insulin sensitivity and glucose effectiveness based on the frequently sampled intravenous (0.5 gkg-1) glucose tolerance test with minimal-model analysis. METHODS: The study was designed as a double-blind, placebo-controlled, cross-over clinical trial. Diazepam (10 mg) and clonazepam (1 mg) were infused during 30 min to 15 male subjects with a mean age of 22 years (range: 20-29), after informed consent was given. Benzodiazepines were assayed by capillary gas chromatography with electron capture, insulin by radioimmunoassay and glucose by the enzymatic glucose oxidase method. RESULTS: Both benzodiazepines induced significant psychotropic effects. The acute insulin responses (AIR) were significantly and negatively correlated with the clonazepam plasma concentrations (r = -0.609, P < 0.05, n = 14). However, the mean AIR was not significantly different between the benzodiazepine-treated subjects and the controls. In addition, the parameters of glucose assimilation were significantly decreased as compared with placebo in the subgroup of 7 subjects with plasma clonazepam concentrations higher than 6.0 ng ml-1 (median and lower limit of effective therapeutic concentrations): 1.37 +/- 0.3 versus 2.84 +/- 0.60 x 10(-2)min-1 (P = 0.028) for the coefficient of glucose tolerance (Kg), 2.18 +/- 0.29 versus 3.71 +/- 0.89 x 10(-4)microUml-1min-1 (P = 0.018) for insulin sensitivity (Si) and 1.80 +/- 0.39 versus 3.59 +/- 0.71 x 10(-2)min-1 (P = 0.028) for glucose effectiveness at basal insulin (Sg). These parameters were not significantly modified when diazepam was administered; plasma levels of this drug however, were below the effective therapeutic concentrations (300 ng ml-1) from min 15 after the end of the perfusion. CONCLUSION: The present results suggest that a benzodiazepine, in particular clonazepam, may alter insulin secretion and insulin sensitivity after a single administration in healthy volunteers.

Adult↗
PubMed2000

The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C-peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults.

The aim of the present study was to evaluate the long-term (30 months) metabolic effects of recombinant human GH (rhGH) given in a mean dose of 6.7 microg/kg x day (= 1.6 IU/day), in 11 patients with adult GH deficiency. Glucose metabolism was evaluated by an oral glucose tolerance test and an iv (frequently sampled iv glucose tolerance test) glucose tolerance test, and body composition was estimated by dual-energy x-ray absorptiometry. Treatment with rhGH induced persistent favorable changes in body composition, with a 10% increase in lean body mass (P < 0.001) and a 12% reduction of fat mass (P < 0.002); however, the glucose tolerance deteriorated significantly, and three patients developed impaired glucose tolerance. Fasting insulin level (P < 0.003) and the homeostasis model assessment insulin resistance score increased significantly, indicating a deterioration in insulin sensitivity; whereas the insulin sensitivity index, calculated from the frequently sampled iv glucose tolerance test, only decreased slightly. The clearance of C-peptide and insulin increased 100% and 60%, respectively, and the prehepatic insulin secretion was tripled during rhGH treatment; but related to the impairment in glucose tolerance, beta-cell response was still inappropriate. Our conclusion is that long-term rhGH-replacement therapy in GH deficiency adults induced a significant deterioration in glucose tolerance, profound changes in kinetics of C-peptide, and insulin and prehepatic insulin secretion, despite an increase in lean body mass and a reduction of fat mass. Therefore, rhGH treatment may precipitate diabetes in some patients already susceptible to the disorder.

Adult↗