Indices Of Insulin Action Research Articles

The Effect of Aerobic versus Resistance Training on Insulin Action in Overweight and Obese Adults STRRIDE AT/RT: A Randomized Controlled Trial

The risk for cardiovascular disease increases with the development of insulin resistance. Physical activity, particularly endurance-oriented aerobic training (AT) has proven effective in preventing and ameliorating insulin resistance. The benefits of resistance training (RT) are far reaching but less is known concerning any impact on insulin action when compared with aerobic training. PURPOSE: To compare the effect of RT and AT on fasting indices of insulin action (insulin, glucose and HOMA-IR) independently and in combination. METHODS: Overweight or obese subjects (n=126) were randomized into three supervised six month training groups as follows: 1) Resistance Training (RT, n=43) {three days/wk, three sets/day, 8-12 repetitions/set}, 2) Aerobic Training (AT, n=42), {calorically equivalent to ∼12 miles/wk at 65-80% peak VO2}, 3) Aerobic Training plus Resistance Training (AT/RT, n=39). Fasting values for insulin and glucose were obtained ∼24 hours following the final training bout. RESULTS: There was a significant (P < 0.05) 15% improvement in HOMA-IR in the AT group. The improvement was diminished below the level of significance in the AT/RT group and absent all together in the RT group. As expected this pattern was reflected in fasting insulin and fasting glucose was not altered in any of the groups. CONCLUSIONS: It appears that the RT used in the current study had no effect on insulin action and that RT in combination with AT diminished the positive change evident with aerobic exercise training alone in fasting indices of insulin action.

Clinical assessment of insulin action during late pregnancy in women at risk for gestational diabetes: Association of maternal glycemia with perinatal outcome

ObjectiveWe prospectively evaluated differences in fasting- and oral glucose tolerance test (OGTT)-derived indices of insulin action in Caucasian (Cau) and African-American (AA) pregnant women and compared them with obstetric outcomes. Study designIRB-approved prospective study in 171 pregnant women undergoing a 3-h OGTT. Mathematical modeling was used to evaluate insulin response, insulin activity and glucose tolerance in fasting and postglucose ingestion state. Insulin sensitivity indices derived from fasting (HOMA-IR) and glucose-stimulated values (SIOGTT) were compared. An insulin sensitivity-secretion index (IS-SI) was calculated from the product of the SIOGTT and early-phase insulin secretion. ResultsForty-nine patients had gestational diabetes (GDM), 28 had gestational impaired glucose tolerance (GIGT) and 94 had normal glucose tolerance after an abnormal glucose challenge test (NGT-abnGCT). Insulin sensitivity was lowest in women with GDM. In all groups, pregnant AA women were significantly more insulin resistant than Cau women, based on both HOMA-IR and SIOGTT, but had enhanced insulin secretion compared to their Cau counterparts. The mean IS-SI progressively improved for all women from GDM to GIGT to NGT-abnGCT. Women with NGT-abnGCT had a higher prevalence of large-for-gestational age (LGA) newborns and significantly higher cesarean section rate. DiscussionInsulin measures along with glucose determinations during OGTT testing in pregnant women at risk for diabetes provide valuable information that varies according to race. We observed that pregnant women with a lesser degree of glucose tolerance abnormality during pregnancy who receive no intervention have a higher risk for LGA infants and significantly increased C-section rate (ClinicalTrials.gov number, NCT006874791).

Attenuated Postprandial Insulin Concentrations With Endurance Training Are Not Mediated By Reductions In Incretin Hormones

The incretin hormones, glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), are released from the intestine after food ingestion and stimulate the pancreas to secrete insulin. Together, these hormones account for approximately half of the postprandial rise in plasma insulin concentrations. Although endurance exercise training improves insulin action on glucose disposal in skeletal muscle and results in a concomitant decrease in postprandial insulin secretion from the pancreas, it is not known if a reduction in incretin hormones contributes to the lower insulin response. PURPOSE: To determine if long-term endurance training is associated with lower plasma GLP1 and GIP responses to oral glucose ingestion. METHODS: Fifteen master endurance athletes (56 ± 2y) and 14 healthy non-exercising control subjects (57 ± 2y) underwent 2h, 75 g oral glucose tolerance tests (OGTTs) during which blood samples were acquired every 30 minutes to assess glucose, insulin, GLP1, and GIP concentrations by using commercially available assays. An index of insulin action (ISI) was calculated based on glucose and insulin concentration from the OGTT. VO2max was assessed using indirect calorimetry and body fat was quantified using DXA. RESULTS: Athletes had higher VO2max (54 ± 2 vs 34 ± 2 mL/kg/min; P < 0.0001) and lower body fat (14 ± 1 vs 23 ± 1%; P <0.0001) than controls. While the area under the curve (AUC) for glucose from the OGTT did not differ between groups (P = 0.12), athletes had 41% lower insulin AUC (P = 0.02) and two-fold greater ISI (0.001). Athletes and controls did not differ in terms of GLP1 AUC (346 ± 65 vs. 414 ± 80 pM·min, p= 0.52) or GIP AUC (19.4 ± 1.3 vs. 18.0 ± 1.4 ng/mL·min, P = 0.49). CONCLUSIONS: These findings suggest the lower postprandial insulin responses that occur in athletes are not modulated by reductions in postprandial concentrations of the intestinally derived incretin hormones, GLP1 and GIP. Supported by NIH General Clinical Research Center RR00036, NIH Clinical Nutrition Research Unit DK56341, Saint Louis University Beaumont Award, and the Longer Life Foundation.

Observation of insulin resistance and beta-cell dysfunction In the hypertension patients with impaired glucose tolerance

Objective To study change of insulin resistance and beta-cell function of the patients in hyper-tension with normal glucose tolerance(NGT) to phthogonesis of type 2 diabetes mellitus(T2DM). Methods 84 pa-tients with hypertension were divided into NGT group,and groups of impaired glucose tolerance(IGT) with groups of T2DM. The blood pressure, height, weight, waist circumference, hip circumference, high-density lipoproteins (HDL-C)and total cholesterol(TC) ,fasting plasma glucose(FPG) and fasting plasma insulin(FINS) were measured to deter-mine the body mass index(BMI) ,waist/hip ratio(WHR) ,insulin secretion function[ including Homa β-cell function index(HBCI) and fasting β-cell function index(FBCI)] and insulin resistance level [ including Homa model insulin resistance index(IR) and insulin action index(IAI)] ,statistic comparison were measured between the groups of dif-ferent glucose tolerances. Results The BMI, WHR, diastolic blood pressure ( DBP), TC in IGT group and T2DM group were bigger or higher than those in NGT group ( P<0.05, P<0.01 ), the IAI, HOMA-IS and FBCI in T2DM group were lower than those in NGT group with these in NGT group were lower than those in NGT group( P<0.05 ,P<0.01 ). The HOMA-IR in IGT group and T2DM group were higher than those in NGT group with these in T2DM group were higher than those in NGT group. Conclusion T2DM group and IGT group had more insulin resistance level,sensitivity of insulin and islet β-cell function decrease than those in IGT group,the IGT group and T2DM group are analogous at the body weight is heavier, with waist/hips ratio, triglyceride level and DBP are higher than those in the NGT group in clinic. Key words: Insulin resistance; Islets of langerhuns; Hypertension; Impaired glucose tolerance

Indices of insulin action calculated from fasting glucose and insulin reflect hepatic, not peripheral, insulin sensitivity in African-American and Caucasian adolescents.

Insulin stimulates muscle glucose uptake and inhibits hepatic glucose production. Measures of insulin sensitivity or insulin resistance must take both of these actions into account. Homeostatic model assessment of insulin resistance (HOMA(IR)) and quantitative insulin sensitivity check index (QUICKI) are two simple measures of insulin resistance and insulin sensitivity that are derived from fasting glucose and insulin levels as such it is likely that they reflect primary hepatic insulin action and not muscular effects. To prove this hypothesis, the relationships of HOMA(IR) and QUICKI to peripheral insulin sensitivity (S(I)(*)) and hepatic insulin resistance (HIR) were assessed in 34 adolescents (age 13.5 +/- 2.9 yr, body mass index 23.0 +/- 5.7, mean +/- SD; 16 Caucasian and 14 African-American). S(I)(*) and HIR were determined using the stable-labeled, frequently sampled intravenous glucose tolerance test (250 mg total glucose/kg, 13% [6,6]-D(2)-glucose). The former was calculated using the one-compartment minimal model and stable glucose concentration (S(I)(*)), and the latter was determined over the last hour of the study by multiplying hepatic glucose production (Steele's equation) by mean plasma insulin concentration. As expected, HOMA(IR) and QUICKI were significantly related to HIR (log HOMA(IR) and log HIR, r = 0.73, p < 0.001; QUICKI and log HIR, r = -0.69, p < 0.001) but not S(I)(*). When both S(I)(*) and HIR were included in the equations, only the relationships to log HIR were significant (log HOMA(IR), p < 0.001; QUICKI, p < 0.001). The relationships were similar in African-American and Caucasian subjects. These results demonstrate that in adolescents, HOMA(IR) and QUICKI assess hepatic but not peripheral insulin action.

Patterns of association between PPARγ genetic variation and indices of adiposity and insulin action in African-Americans and whites: the CARDIA Study

We performed a combination of single-variant- and haplotype-based analyses to investigate the association of peroxisome-proliferator-activated receptor gamma (PPARgamma) gene sequence variation with indices of adiposity, including body mass index (BMI) and waist girth, as well as insulin action, including fasting blood glucose and insulin levels. Nine polymorphisms, selected based on race-specific pairwise linkage disequilibrium relations and/or potential functional relevance, were assayed in 3,875 African-American and white young adults from the Coronary Artery Risk Development in Young Adults Study. These polymorphisms were C25819G (C-681G), C65746G (Pro12Ala), G67222A, A69208G, G81556T, T95872C, T115432G, C127599T, and C148157T (C1431T). They defined seven and six common haplotypes in African-Americans and whites, respectively. Patterns of associations of PPARgamma genetic variation with the metabolic traits differed between the two racial groups, with some exceptions. Haplotype CCGGCTCC was associated with a significant reduction in glucose levels in both racial groups (P<0.001 in each group), and the G69208 allele was associated with lower glucose levels in lean African-Americans and in whites (both P=0.02). Two haplotypes, relatively unique to whites, were associated with measures of adiposity and glucose levels. Two haplotypes, relatively unique to African-Americans, were associated with glucose levels. There were no significant effects of PPARgamma haplotypes on measures of body size in this racial group, but a novel polymorphism, G67222A, significantly modulated the relation between BMI and glucose levels (P interaction, 0.003). This study provides evidence that variants, other than Pro12Ala, influence variation in body size and indices of insulin action. It underscores the role of genetic and environmental contexts in shaping the patterns of associations of PPARgamma sequence variants with metabolic traits in human populations.

Metabolic Effect of Sirolimus Versus Mycophenolate Mofetil on Pancreatic Graft Function in the Early Posttransplant Period

Metabolic effects of immunosuppressive agents are of great importance in pancreas or islet transplantation. The aim of our study was to compare effects of tacrolimus-based immunosuppression in conjunction with sirolimus (RAPA) versus mycophenolate mofetil (MMF) on glucose metabolism in type 1 diabetic recipients following a simultaneous pancreas and kidney transplantation (SPK). We examined 30 insulin-independent patients after SPK with venous systemic drainage of the pancreatic graft. All recipients had good kidney graft function. Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA lc), standard intravenous glucose tolerance test (IVGTT), and trough RAPA levels were assessed in pancreas recipients before elective steroid withdrawal. Insulin sensitivity was evaluated using the homeostasis model assessment (HOMA-IR). The groups did not differ in age, BMI, posttransplant period, steroid daily dose, HbA lc, and fasting glycemia. We did not find any significant difference in the IVGTT response. Area under the curve of insulin levels during IVGTT and HOMA-IR were significantly lower in the RAPA group. Trough levels of RAPA had no significant impact on any of the examined parameters. Glucose tolerance measured with the use of IVGTT was similar in patients treated with RAPA and MMF. However, recipients on sirolimus treatment had significantly lower insulinemia during the test and consequently more favorable indices of insulin action as assessed by HOMA-IR.

To investigate the risk factors in patients with newly-diagnosed type 2 diabetics with coronary heart disease

目的 通过对52例首诊2型糖尿病(DM)并冠心病(CHD)患者进行分析,以探讨首诊2型DM并CHD患者的危险因素.方法 52例首诊2型DM并CHD为Ⅰ组.40例首诊2型DM无并CHD为Ⅱ组.两组进行年龄、平均动脉血压(MAP)、体重指数(BMI)统计,并检测胆固醇(TC)、甘油三脂(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、糖化血红蛋白(HbA1C)、空腹血糖(FPG)、C-肽(C-P)、胰岛素(Ins)、餐后2 h血糖(2hPG),并计算胰岛素敏感指数(IAI).各指标两组进行统计学比较.结果 BMI、MAP、TG、HDL、LDL、2hPG、HbA1C、IAI两组比较差异有显著意义,年龄、FPG、TC比较差异无显著意义.结论高血压、肥胖、高甘油三脂、高密度脂蛋白降低、低密度脂蛋白增高、2hPG、HbA1C、高胰岛素血症、胰岛素抵抗是首诊2型DM并CHD的危害因素。

Serum markers of GH and insulin action in 12-year-old children born small for gestational age

Our aim was to determine whether markers of growth hormone and insulin action differ between children born small for gestational age (SGA) and those born of an appropriate size for gestational age (AGA). Fifty-five SGA children and their 55 age- and sex-matched AGA control subjects were studied in a case-control setting at 12 years of age. We examined serum concentrations of insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-1 and IGFBP-3, sex hormone binding globulin (SHBG), leptin, fasting insulin, and blood glucose. Insulin sensitivity was evaluated by the homeostasis model assessment for insulin resistance (HOMA-IR). The body mass index (BMI), sex, and puberty-adjusted mean serum IGF-I concentration was higher in the SGA than in the AGA children (303.4 vs 282.3 microg/l, P = 0.006). The mean serum concentrations of IGF-II, IGFBP-I, IGFBP-3, SHBG, fasting insulin, blood glucose and HOMA-IR did not differ between the SGA and the AGA group. The BMI, sex, and puberty-adjusted mean serum leptin concentration was lower in the SGA than in the AGA children (7.9 vs 10.1 microg/l, P = 0.037). In multiple logistic regression analysis, high HOMA-IR predicted high serum IGF-I levels in the SGA children (odds ratio 8.3; 95% confidence interval 1.7-41; P = 0.010), whereas in the AGA group HOMA-IR did not associate with the serum IGF-I level. The BMI, sex, and puberty-adjusted mean serum IGF-I concentration was significantly higher and the leptin concentration was lower in the SGA than in the AGA children. No differences were found in the indices of insulin action or sensitivity between the SGA and AGA children at 12 years of age. However, HOMA-IR strongly associated with serum IGF-I levels in the SGA children.

The effect of nitric oxide synthase inhibitor on improved insulin action by pioglitazone in high-fructose-fed rats

The present study was performed to investigate whether nitric oxide synthase (NOS) inhibition influences the increased whole-body insulin action by pioglitazone in high-fructose-fed rats. Male Wistar rats aged 6 weeks were randomly divided into 3 groups and each group was fed one of the following diets for 3 weeks: standard chow diet (control group), high-fructose diet (fructose-fed group), and high-fructose diet plus pioglitazone (pioglitazone-treated group). The control and pioglitazone-treated groups were further divided into 2 subgroups respectively, and some rats of each subgroup were infused the NOS inhibitor, N G-monomethyl- l-arginine (L-NMMA), during the euglycemic clamp studies. In vivo insulin action was determined by the 2-step (3 and 30 mU/kg body weight [BW]/min low- and high-dose, respectively) hyperinsulinemic euglycemic clamp procedure in the awake condition. Glucose infusion rate (GIR) was considered as the index of insulin action. Endothelium-type NOS (eNOS) and inducible NOS (iNOS) in skeletal muscle were also measured. At the low-dose clamp, high-fructose feeding produced a marked decrease in GIR compared with the control group. Pioglitazone-treated animals showed a significant increase in GIR, reaching a similar level as the control group. However, the improved GIR was decreased to the level of the fructose-fed group by L-NMMA infusion. The GIR of the control group was not affected by L-NMMA infusion. The same tendency as the low-dose clamp was found at the high-dose clamp. In skeletal muscle, eNOS and iNOS protein content were not affected by high-fructose feeding and/or pioglitazone treatment. These results suggest that NOS inhibition can decrease the improved insulin resistance by pioglitazone in high-fructose-fed rats. Therefore, although NOS protein content is not changed by high-fructose feeding and/or pioglitazone treatment, it could be concluded that nitric oxide (NO) plays an important role in the improvement of insulin action by pioglitazone.

Indices of Insulin Action, Disposal, and Secretion Derived From Fasting Samples and Clamps in Normal Glucose-Tolerant Black and White Children

To validate fasting indices of insulin sensitivity and secretion in a diverse pediatric population against gold standard estimates from euglycemic and hyperglycemic clamps. A total of 31 children (mean BMI 25.1 +/- 4.9 kg/m(2), mean age 8.7 +/- 1.4 years, 15 girls and 16 boys, 12 black and 19 white) underwent euglycemic and hyperglycemic clamps 2-6 weeks apart to derive insulin sensitivity indices (SI (Eug clamp) and SI (Hyper clamp)). Fasting samples were used to derive the homeostasis model assessment of insulin resistance index (HOMA-IR), HOMA of percent beta-cell function (HOMA-B%), quantitative insulin sensitivity check index (QUICKI), insulinogenic index, antilipolytic insulin sensitivity index (ISI-FFA), and C-peptide-to-insulin ratio. The QUICKI correlated best with SI (Eug clamp) (r = 0.69, P < 0.05) and had greater correlations to SI (Eug clamp) than did either SI (Hyper clamp) (r = 0.45, P < 0.05) or the HOMA-IR (r = -0.51, P < 0.05). Both fasting insulin and the insulinogenic index correlated well with first- and steady-phase insulin secretion (r's from 0.79 to 0.86, P < 0.05). HOMA-B% was not as highly correlated (r = 0.69-0.72, P < 0.05). Fasting C-peptide-to-insulin ratio was not significantly correlated with clamp-derived metabolic clearance rate of insulin. ISI-FFA was not correlated with the degree of free fatty acid suppression obtained from the clamps. The QUICKI, fasting insulin, and the insulinogenic index all closely correlate with corresponding clamp-derived indices of insulin sensitivity and secretion in this diverse pediatric cohort. These results, if replicated in similarly diverse populations, suggest that estimates based on fasting samples can be used to rank order insulin secretion and sensitivity in pediatric cohorts.

Prevalence and features of pancreatic islet cell autoimmunity in women with gestational diabetes from different ethnic groups.

To assess the prevalence and characteristics of islet cell autoimmunity amongst women with gestational diabetes selected from South Asian and Afro-Caribbean as well as European populations. Cross-sectional retrospective survey of subject cohort. Three hundred and twenty-one women with a recent history of gestational diabetes (173 European, 86 South Asian and 62 Afro-Caribbean), a median (range) of 22 (1-150) months postpartum. Antibodies to Glutamic acid decarboxylase were found in 13 (4%) of these women. There was no difference in the prevalence of anti-glutamic acid decarboxylase positivity between the three ethnic groups (European 4.6%, South Asian 3.5%, Afro-Caribbean 3.2%). Anti-glutamic acid decarboxylase positive women were leaner than anti-glutamic acid decarboxylase negative women (body mass index, median (upper-lower quartile) 23.9 (22.5-26.7) vs 26.6 (23.4-30.5)kg/m2, P = 0.03, P = 0.049 allowing for ethnicity). There was no difference between glutamic acid decarboxylase-positive and glutamic acid decarboxylase-negative women for age, family history of diabetes, waist/hip ratio, prevalence of insulin treatment during pregnancy, postpartum glucose status, lipid profile and indices of insulin action and beta-cell function. Markers of islet cell autoimmunity are found as frequently in gestational diabetes women of South Asian and Afro-Caribbean origin, as they are in European subjects. Identification of future risk of type 1 diabetes is relevant to the planning of clinical management and intervention strategies in women with gestational diabetes of all major ethnic groups.

Prevalence and features of pancreatic islet cell autoimmunity in women with gestational diabetes from different ethnic groups

Objective To assess the prevalence and characteristics of islet cell autoimmunity amongst women with gestational diabetes selected from South Asian and Afro-Caribbean as well as European populations. Design Cross-sectional retrospective survey of subject cohort. Population Three hundred and twenty-one women with a recent history of gestational diabetes (173 European, 86 South Asian and 62 Afro-Caribbean), a median (range) of 22 (1-150) months postpartum. Results Antibodies to Glutamic acid decarboxylase were found in 13 (4%) of these women. There was no difference in the prevalence of anti-glutamic acid decarboxylase positivity between the three ethnic groups (European 4.6%, South Asian 3.5%, Afro-Caribbean 3.2%). Anti-glutamic acid decarboxylase positive women were leaner than anti-glutamic acid decarboxylase negative women (body mass index, median (upper-lower quartile) 23.9 (22.5–26.7) vs 26.6 (23.4-30.5)kg/m 2, P=0.03, P=0.049 allowing for ethnicity). There was no difference between glutamic acid decarboxylase-positive and glutamic acid decarboxylase-negative women for age, family history of diabetes, waist/hip ratio, prevalence of insulin treatment during pregnancy, postpartum glucose status, lipid profile and indices of insulin action and beta-cell function. Conclusions Markers of islet cell autoimmunity are found as frequently in gestational diabetes women of South Asian and Afro-Caribbean origin, as they are in European subjects. Identification of future risk of type 1 diabetes is relevant to the planning of clinical management and intervention strategies in women with gestational diabetes of all major ethnic groups.

The relative contribution of insulin secretory capacity, insulin action, and incretins to metabolic control after islet transplantation in dogs.

Adequate metabolic control is central to the concept of islet transplantation, but has received limited attention. We studied metabolic control in 8 dogs at 6-9 months after intrasplenic autografting of approximately 25% of the normal mass islets--as compared to 30 controls. A similar posttransplant reduction to approximately 25% of the insulin secretory capacity as assessed by intravenous arginine stimulation during 35 mM glucose clamps, mirrored the reduction of the islet mass. Postprandially, in contrast, the insulin response had increased to 140% in the islet recipients--with a concomitant rise of glycemia to approximately 8.5 mM. Posttransplant, the insulin secretory capacity correlated both with the index of insulin action (which averaged 55% of the normal value) as assessed by euglycemic hyperinsulinemic clamps, and--inverse--with the postprandial glucose excursions. Because insulin action did not correlate with postprandial glucose, the insulin secretory capacity appears to be the primary determinant of the impaired glucose tolerance. Marked postprandial hyperglucagonemia, and a virtually absent pancreatic polypeptide response in the grafted animals, may also have contributed to the impaired glucose tolerance. Posttransplant, infusion of a physiological dose of the gut hormone glucagon-like peptide-1 during 8.5 mM glucose clamps--mimicking the postprandial glycemia--potentiated glucose-stimulated insulin 175%. Thus, after transplantation of a suboptimal islet mass, postprandial glucose excursions are restrained by hyperglycemic potentiation of the entero-insular axis, which may account for the difference in the insulin response to the intravenous and oral challenges. Because, the insulin secretory capacity reflects the islet mass and appears to be the major determinant of glucoregulation, transplantation of a larger islet mass may allow near-normal glycemic control.

Impaired insulin-induced glucose uptake by extrahepatic tissue is hallmark of NIDDM patients who have or will develop hypertension and microalbuminuria.

Insulin resistance may be a mechanism linking non-insulin-dependent diabetes mellitus (NIDDM) to hypertension and cardiovascular mortality. Microalbuminuria also is an independent risk factor of cardiovascular mortality and of hypertension. Little information is available in the literature on the relationship between microalbuminuria and insulin action. This study investigated the relationships between blood pressure (BP) levels, microalbuminuria, and insulin resistance in NIDDM patients. Seventy-five NIDDM patients attending the outpatient clinic of the Department of Internal Medicine of the University Hospital in Padua, Italy participated in the cross-sectional part of our study. These subjects were divided into four groups on the basis of BP levels and albumin excretion rate (AER): 28 normotensive normoalbuminuric (NIDDM1), 19 hypertensive normoalbuminuric (NIDDM2), 15 normotensive microalbuminuric (NIDDM3), and 13 hypertensive microalbuminuric patients (NIDDM4). We defined microalbuminuria as an AER > 20 micrograms/min. Patients with BP levels > 145/90 mmHg were considered hypertensive. A group of 20 normal subjects served as control subjects. The results from the cross-sectional study indicate that the mean of insulin-induced whole-body glucose utilization, primarily an index of extrahepatic insulin action, was lower at all insulin infusion steps in the group of hypertensive and/or microalbuminuric patients than in the group of normotensive normoalbuminuric patients and control subjects. Hepatic glucose output, an index of insulin action in the liver, was on average less efficiently inhibited in all of the patients than in the control subjects, regardless of the BP levels or the AER.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance versus insulin secretion in the hypertension of obesity.

We measured the degree of association between obesity, blood pressure, insulin resistance, and insulin secretion in 72 male and female obese hypertensive, obese nonhypertensive, and normal weight control subjects. Baseline weight, body mass index, percent body fat, waist/hip ratio, and systolic and diastolic blood pressures were obtained. Insulin sensitivity was assessed according to Bergman's minimal model. Twelve-hour urinary c-peptide was measured after a standard liquid meal. Insulin action was inversely associated with blood pressure status, obesity status, and age. Meal-stimulated c-peptide excretion significantly correlated with systolic blood pressure and percent fat but not with body mass index or age. Multivariate regression analysis indicated that, of the measures of body composition, percent fat and waist/hip ratio had the strongest correlation with insulin action either alone or in combination with c-peptide excretion. Obese hypertensive patients had an index of insulin action (10(-4).min-1/[microunits/ml]) of 1.34 +/- 0.19, which was significantly (p less than 0.003) lower than in the obese nonhypertensive patients (index, 2.26 +/- 0.10) or the nonobese subjects (index, 5.41 +/- 0.26, p less than 0.001). Meal-stimulated c-peptide excretion (nmol/kg lean body mass) was increased only in the obese hypertensive group (0.32 +/- 0.01) and was significantly higher (p less than 0.001) than in the obese nonhypertensive (0.16 +/- 0.01) or the nonobese subjects (0.14 +/- 0.01). These results support the hypothesis that abnormalities in blood pressure regulation, insulin-stimulated glucose uptake, and insulin secretion coexist.

Relationships Between Plasma Lipoprotein Concentrations and Insulin Action in an Obese Hyperinsulinemic Population

Relationships have been observed between lipoprotein concentrations and insulin action. These relationships may be important in explaining the association of insulin resistance and abnormalities of lipoprotein metabolism found in obesity, diabetes, and hypertriglyceridemia. We have measured plasma lipoprotein concentrations and indices of insulin action in 85 men and 56 women, all of whom were normolipidemic and had normal glucose tolerance. The subjects were obese Southwestern American Indians (body mass index 34 +/- 1). Insulin action was measured via the hyperinsulinemic clamp with simultaneous indirect calorimetry. Triglyceride concentrations were inversely related to rates of total insulin-mediated glucose disposal (in men and women, respectively, r = -.37, P less than .01; r = -.24, P less than .10), glucose storage (r = -.31, P less than .01; r = -.25, P less than .10), increase in glucose oxidation (r = -.29, P less than .01; r = -.24, P less than .10), and, in men only, suppression of endogenous glucose production (r = -.32, P less than .01). High-density lipoprotein (HDL) cholesterol concentration was positively related to rates of total insulin-mediated glucose disposal (r = .35, P less than .01; r = .33, P less than .05), increase in carbohydrate oxidation (r = .40, P less than .001; r = .39, P less than .001), suppression of endogenous glucose production (r = .24, P less than .05; r = .29, P less than .05), and, in men only, glucose storage (r = .35, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Tolbutamide does not alter insulin requirement in Type 1 (insulin-dependent) diabetes.

We examined whether tolbutamide has any acute or short-term effects on insulin action in Type 1 (insulin-dependent) diabetes. A euglycaemic glucose clamp was performed in seven Type 1 diabetic patients without clinical insulin resistance by infusing glucose at a constant rate of 0.01 mmol X kg-1 X min-1 for 3h together with a simultaneous insulin infusion using an 'artificial pancreas'. The insulin infusion rate required to maintain blood glucose at 6.7 mmol/l at a set low glucose infusion rate provides an index of insulin action in vivo. The euglycaemic clamp was performed on 3 separate days in the same patient: (1) in the basal state; (2) during simultaneous intravenous tolbutamide infusion of 0.5 g/h, and (3) after treatment with 2.5 g tolbutamide/day for 6 days in addition to insulin. The insulin infusion rate needed to maintain the set blood glucose level did not differ significantly between the three experimental conditions (1.2 +/- 0.2 versus 1.3 +/- 0.3 versus 1.2 +/- 0.3 U/h). Plasma glucagon, growth hormone, non-esterified fatty acid and glycerol levels did not differ between control or sulphonylurea treatment studies. The results suggest that tolbutamide does not exert any acute or short-term effects on insulin action in vivo in Type 1 diabetes. Our results do not provide support for the idea that this agent is a clinically useful adjunct to insulin in such patients.

Hepatic insulin effects independent of changes in Ca ++ metabolism

The possibility of Ca ++ acting as second messenger for insulin in rat liver was investigated using the net stimulation of 14C-glucose incorporation into glycogen by isolated hepatocytes as an index of insulin action. An insulin effect could be partially sustained in the virtual absence of Ca ++ and Mg ++ and a maximal insulin effect could be observed in the presence of either Ca ++ or Mg ++, suggesting that extracellular Ca ++ is not required for insulin action. Inhibiting the activity of calmodulin, an intracellular mediator of Ca ++ action, with trifluoperazine had little effect on insulin action. The efflux of 45Ca from prelabeled hepatocytes was not altered by the presence of insulin arguing against insulin-induced changes in Ca ++ fluxes. Collectively, these results do not support the role of Ca ++ as second messenger for insulin action in liver.

Insulin action on the cultured human fibroblast. Glucose uptake, protein synthesis, RNA synthesis.

After cultured human fibroblasts had been maintained in a serum-free medium for twenty-four hours, a biologic effect of physiologic concentrations of insulin was demonstrated. Insulin at physiologic concentrations (0.1 mil./ml.) stimulated glucose uptake and uridine incorporation into RNA by cultured human fibroblasts. Incorporation of leucine into protein was a less sensitive index of insulin action. Fetal fibroblasts were more sensitive than adult fibroblasts to the insulin effect on RNA metabolism. This may be in part the reason for the faster growth rate of fetal fibroblasts.