Steady-state Plasma Insulin Concentrations Research Articles

Metabolic Clearance Rate of Insulin Is Not Saturable within the Physiological Range

The plasma concentration of insulin is determined by pancreatic beta cell secretion and the metabolic clearance of the hormone. It has been suggested that the concentration of insulin determines its metabolic clearance rate. Also, some reports suggest that clearance is saturable and insulin kinetics are non-linear even within physiologic ranges. We assessed the metabolic clearance rate of insulin at different physiologic concentrations to access if clearance changes with concentration. Using the dog model (n=12), insulin was infused peripherally at 3 incremental rates (dose-response) during the euglycemic clamp. Each infusion rate spanned 90mins, and the last 30mins was considered the steady state. The metabolic clearance rate of insulin was calculated as the ratio of the infusion rate to the steady state plasma concentration. The 3 infusion rates, 1.5, 3.0 and 4.5pmol/kg/min yielded steady state plasma insulin concentrations of 92 ± 8, 165 ± 12 and 256 ± 18pM respectively. The metabolic clearance rate of insulin was consistent and independent of dose (17.8 ±1.7, 19.1 ±1.2 and 18.6 ±1.4 ml/kg/min; p = ns) across the different plasma insulin infusion rates. Also, we found a strong linear correlation (r = 0.99) between the infusion rates and steady state insulin concentrations. Insulin kinetics are linear and the metabolic clearance of insulin is not saturable within physiologic ranges in the conscious dog. Though it’s possible that the site of degradation (i.e., liver vs. periphery) may change with dose.These data demonstrate that changing concentrations of plasma insulin within physiologic concentrations does not change the rate of insulin removal from the plasma. Disclosure I. Asare Bediako: None. R.L. Paszkiewicz: None. O.O. Woolcott: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.

Short-term Effects of Laparoscopic Adjustable Gastric Banding Versus Roux-en-Y Gastric Bypass

Bariatric surgery has been shown to have important long-term metabolic effects resulting in enhanced insulin sensitivity and improved glucose tolerance in patients with type 2 diabetes. The contribution of reduced caloric intake to these beneficial effects of surgery remains unclear. The aim of this study was to compare the short-term effects (1 week) of bariatric surgical procedures with a very low caloric intake (VLCI) on insulin sensitivity (IS) and insulin secretion (ISR) in nondiabetic obese subjects. Twenty obese patients without diabetes (BMI 44.2 ± 0.7 kg/m2) were admitted to the clinic for 1 week. At baseline and 1 week after VLCI (600 kcal/day), subjects received a hyperinsulinemic-euglycemic clamp with tracer infusion to quantify endogenous glucose production (EGP), lipolysis (rate of appearance of glycerol [RaGlycerol]), peripheral insulin sensitivity (insulin-stimulated glucose disposal [M value] divided by the steady-state plasma insulin concentration [M/I]), hepatic insulin sensitivity (Hep-IS [= 1/(EGP ⋅ insulin)]), and adipose insulin sensitivity (Adipo-IS [= 1/(RaGlycerol ⋅ insulin)]). An intravenous glucose bolus was administered at the end of the insulin clamp to measure ISR and β-cell function (disposition index [DI]). Approximately 3 months later, patients were admitted for laparoscopic adjustable gastric banding (LAGB) (n = 10) or Roux-en-Y gastric bypass (RYGB) (n = 10), and were restudied 1 week after surgery under the same caloric regimen (600 kcal/day). After 1 week of VLCI, patients lost 2.1 kg without significant changes in Hep-IS, Adipo-IS, M/I, or DI. RYGB and LAGB led to greater weight loss (5.5 and 5.2 kg, respectively) and to significant improvement in Hep-IS, EGP, and lipolysis. Only RYGB improved Adipo-IS and M/I. No change in ISR or DI was observed in either surgical group. Bariatric surgery improves IS within 1 week. These metabolic effects were independent of caloric intake and more pronounced after RYGB compared with LAGB.

Hyperinsulinemia in individuals with obesity: Role of insulin clearance.

ObjectiveSeveral studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. We aimed to clarify the complex interrelationship that exists between obesity, IR and ICR.MethodsHealthy volunteers (n = 277) had measurement of IR and ICR using the insulin suppression test (IST). IR was quantified by determining the steady-state plasma glucose (SSPG) during the IST. ICR was estimated by dividing the insulin infusion rate by the steady-state plasma insulin concentration. We performed our analysis by stratifying the experimental population into 4 dichotomous categories, varying in obesity and IR. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m2, and IR was defined as SSPG ≥ 150 mg/dl.ResultsIndividuals with obesity had higher fasting insulin compared with individuals without obesity, regardless of IR. ICR was similar between individuals with and without obesity but was higher in IR individuals compared with insulin sensitive individuals. In multivariate analysis, both fasting insulin and SSPG were significantly associated with ICR. No significant relationships were observed between BMI and ICR.ConclusionsReduced ICR in obesity is secondary to IR, not excess adiposity.

Pancreatic secretion, hepatic extraction, and plasma clearance of insulin from steady-state insulin and C-peptide measurements in critically ill patients

Hyperglycaemia is prevalent in critical illness and clinical practice is to reduce blood glucose by intravenous insulin infusion. We estimated pancreatic secretion, hepatic first-pass extraction ratio and plasma insulin clearance per minute from measured serum C-peptide and insulin in 9 critically ill adults in a pseudo steady-state situation, i.e. when nutrition and insulin infusion remained at a constant rate up to the test (min 20, median 240, max 510 min). To estimate pancreatic secretion, a population C-peptide kinetics model was used to convert C-peptide concentration to C-peptide secretion rate. Pancreatic secretion varied 18-fold from 5.2 to 93.5 mU·min -1 , and the lowest secretion rates were in patients older than 70 years or patients with type 2 diabetes. Pancreatic secretion correlated positively, but not significantly with blood glucose. Blood glucose was not correlated with plasma insulin. A two-dimensional regression analysis of hepatic first-pass extraction and plasma insulin clearance showed that the smallest relative error between estimated plasma insulin and measured plasma insulin was obtained for an extraction ratio of 72% and plasma clearance of 0.34 min -1 . Using these values, a negative correlation was found between post-hepatic insulin production and the rate of insulin infusion. These results indicate that 1) hepatic insulin extraction is increased in critical illness. This is also confirmed by the observation that steady-state plasma insulin concentrations in this study were relatively lower when compared to steady-state measurements in normal subjects; 2) blood glucose drives pancreatic secretion moderately; 3) there is substantial variation in pancreatic secretion between patients that cannot be explained from the blood glucose variation, but could be related to patient age and diabetic state; 4) there was also substantial variation in insulin sensitivity between patients, since similar levels of insulin sensitivity would have predicted a negative correlation between blood glucose and plasma insulin; 5) insulin infusions are used to compensate for inadequate pancreatic insulin secretion.

Traversing the Barrier: A Journey of Insulin from Vascular Lumen into Skeletal Muscle

Copyright: © 2013 Wang H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Plasma insulin must traverse the vascular endothelium to reach its major sites of action on myocytes and adipocytes. In study simultaneously measuring plasma and lymphatic insulin concentrations in normal, conscious dogs during euglycemic insulin clamps it was found that the steady-state plasma insulin concentration was consistently higher than lymph with a rough ratio of 3:2 during the basal period. In addition, while plasma insulin concentration rose quickly to reach the steady-state during the insulin clamp, the lymph insulin concentration rose very slowly indicating a barrier function of the vascular endothelium. Most importantly, this study showed that the dynamics of glucose disposal correlated very strikingly with the insulin concentration in lymph but not plasma, suggesting that trans-capillary insulin transport is a rate limiting step for peripheral insulin action [1]. Consistent with this, direct injection of insulin into canine skeletal muscle in vivo was recently noted to significantly hasten the onset of muscle glucose utilization compared with intravenously delivered insulin [2]. Multiple other studies also support such an important role of vascular endothelium during insulin clamp by measurement of the insulin concentration within skeletal muscle interstitium in humans and animals using either lymphatic sampling or microdialysis methods [3-7]. Results obtained using either method indicate that even after several hours of steady state hyperinsulinemia, muscle interstitial insulin concentration is only 40-50% of that in plasma and the time course for insulin-mediated glucose disposal during the euglycemic clamp correlates strongly with interstitial but not plasma insulin concentrations. Based on these findings, it has been estimated that slow trans-endothelial insulin transport may account for 30-40% of insulin resistance seen with human obesity or type-2 diabetes [3,8,9].

Complete correction of anemia by erythropoiesis-stimulating agents is associated with insulin resistance in hemodialysis patients

Insulin resistance and anemia secondary to erythropoietin deficiency characterize patients with end-stage kidney disease. In a cross-sectional analysis, we examined the relationship between erythropoietin-mediated correction of anemia and insulin sensitivity in nondiabetic hemodialysis patients. Insulin sensitivity (euglycemic-hyperinsulinemic clamp) and endogenous glucose production (primed-continuous infusion of [6,6-(2)H(2)]glucose) were determined in two groups of patients with normal hemoglobin (n:8; mean hemoglobin: 14.0±0.3g/dl) or with mild anemia (n:10; mean hemoglobin: 12.1±0.9g/dl). The patients with normal hemoglobin were receiving higher (P<0.05) erythropoietin doses than those with mild anemia (171±73 and 91±39Ukg(-1)wk(-1), respectively). The two groups were matched for all other potential determinants of insulin resistance. Endogenous glucose production was similar in the two groups of patients in the postabsorptive state and was completely suppressed by insulin infusion. During the hyperinsulinemic clamp, the rate of glucose infusion to maintain euglycemia was significantly lower (P<0.01) in the patients with normal hemoglobin levels [166±31mg(m(2))(-1)min(-1)] than in those with mild anemia [251±49mg(m(2))(-1)min(-1)] and in a group of matched controls [275±68mg(m(2))(-1)min(-1)]. In pooled patients, individual values of hemoglobin concentrations inversely correlated with the rates of insulin-mediated glucose infusion, both as absolute values (r=-0.58; P<0.05) and as values normalized by steady-state plasma insulin concentration (r=-0.74; P<0.001). In conclusion, this exploratory study indicates that complete correction of anemia by erythropoietin treatment in patients with end-stage kidney disease on hemodialysis is associated with impaired insulin sensitivity.

Visceral fat dominant distribution in male type 2 diabetic patients is closely related to hepatic insulin resistance, irrespective of body type

BackgroundAll previous studies that investigated the association between abdominal fat distribution and insulin resistance evaluated subcutaneous and visceral fat area and/or volume, but these values were not related to the body type of each subject. In the present study we have examined the association between abdominal fat distribution and peripheral (muscle)/hepatic sensitivity to insulin using the visceral to abdominal subcutaneous fat area ratio (VF/SF ratio) in male patients with type 2 diabetes mellitus. This ratio defines the predominancy of visceral or subcutaneous abdominal adiposity, independent of the body type of each individual.MethodsThirty-six type 2 diabetic male patients underwent a euglycemic insulin clamp (insulin infusion rate = 40 mU/m2·min) with 3-3H-glucose to measure insulin-mediated total body (primarily reflects muscle) glucose disposal (TGD) and suppression of endogenous (primarily reflects liver) glucose production (EGP) in response to a physiologic increase in plasma insulin concentration. Abdominal subcutaneous (SF) and intraabdominal visceral fat (VF) areas were quantitated with magnetic resonance imaging (MRI) at the level of L4–5.ResultsTGD and TGD divided by steady state plasma insulin concentration during the insulin clamp (TGD/SSPI) correlated inversely with body mass index (BMI), total fat mass (FM) measured by 3H2O, SF and VF areas, while VF/SF ratio displayed no significant relationship with TGD or TGD/SSPI. In contrast, EGP and the product of EGP and SSPI during the insulin clamp (an index hepatic insulin resistance) correlated positively with VF/SF ratio, but not with BMI, FM, VF or SF.ConclusionWe conclude that, independent of the individual's body type, visceral fat dominant accumulation as opposed to subcutaneous fat accumulation is associated with hepatic insulin resistance, whereas peripheral (muscle) insulin resistance is more closely related to general obesity (i.e. higher BMI and total FM, and increased abdominal SF and VF) in male patients with type 2 diabetes.

Strong association between insulin resistance in liver and skeletal muscle in non‐diabetic subjects

To examine the association between insulin resistance in skeletal muscle and liver in non-diabetic subjects. A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic-hyperinsulinaemic clamp performed with (3)[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin-stimulated rate of total glucose disposal during the insulin clamp divided by steady-state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP x FPI). Hepatic insulin resistance was strongly correlated (r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty-eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty-three per cent of subjects were discordant for muscle and hepatic insulin resistance (P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2-h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. In non-diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2-h plasma glucose concentrations and strongly correlates with hepatic insulin resistance.

Muscle and Liver Insulin Resistance Indexes Derived From the Oral Glucose Tolerance Test

Bastard et al. (1,2) have examined the correlation between the oral glucose tolerance test (OGTT)-derived muscle insulin resistance index and the total glucose disposal divided by the steady-state plasma insulin concentration (TGD/SSPI) during the euglycemic insulin clamp in obese postmenopausal women and reported a lower correlation coefficient (2) compared with that reported earlier in a more heterogeneous population (3). Further, the correlation between the OGTT-derived muscle insulin resistance index (3) and TGD/SSPI was not significantly …

Sibutramine improves insulin sensitivity without alteration of serum adiponectin in obese subjects with Type 2 diabetes

To evaluate the effect of sibutramine on weight loss, insulin sensitivity and serum adiponectin levels in obese patients with Type 2 diabetes. This study is a randomized, double-blind, placebo-controlled parallel comparison study of sibutramine 15 mg/day and placebo. Forty-eight eligible obese patients with Type 2 diabetes (age between 30 and 75 years with body mass index > or = 27 kg/m(2)) were randomly assigned to receive either placebo (n = 24) or sibutramine (15 mg/day) (n = 24) for 6 months. Fifteen subjects in each group underwent meal tests and modified insulin suppression tests before and after 6 months' treatment. After 6 months of sibutramine treatment statistically significant changes from baseline were observed for body weight (85.4 +/- 2.5 vs. 82.9 +/- 2.4 kg, P < 0.005) and body mass index (32.0 +/- 0.7 vs. 31.4 +/- 0.6 kg/m(2), P < 0.05) without a significant alteration of waist-hip ratio (W/H), blood pressure, heart rate, glycaemic parameters or lipid profiles. The steady-state plasma glucose (SSPG) level during the modified insulin suppression test was significantly reduced in the sibutramine group (17.33 +/- 2.92 vs. 14.29 +/- 4.19 mmol/l, P < 0.05) despite similar steady-state plasma insulin (SSPI) concentrations. In addition, serum adiponectin and C-reactive protein (CRP) levels remained unchanged, although modest weight reduction was achieved after sibutramine treatment. There were also no significant correlations between changes in serum adiponectin and reduction of SSPG or body weight. Daily ambient plasma insulin and glucose concentrations in response to a test meal were not significantly different in subjects receiving sibutramine treatment. We conclude that treatment with sibutramine 15 mg once daily effectively reduces weight and enhances insulin sensitivity without alteration of serum adiponectin levels in obese patients with Type 2 diabetes.

In nondiabetic, human immunodeficiency virus–infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic, human immunodeficiency virus (HIV)-infected patients with and without lipodystrophy. We studied 18 HIV-infected patients with lipodystrophy (LIPO) on antiretroviral therapy and 25 HIV-infected patients without lipodystrophy (controls) of whom 18 were on antiretroviral therapy and 7 were not. Posthepatic insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU·m −2·min −1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting insulin (130%, P < .001), impaired insulin sensitivity index (M value , −29%, P < .001), and reduced MCRi (−17%, P < .01). Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin ( r = −0.56, P < .02 and r = −0.68, P < .002) and positively with M value ( r = 0.63, P < .01 and r = 0.65, P < .004). In controls, MCRi correlated inversely with fasting insulin ( r = −0.47, P < .02) and positively with M value ( r = 0.57, P < .004); however, the correlations between HEXi and these parameters were insignificant ( P > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy.

Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy.

We previously reported that prenatal and suckling exposure to a maternal diet rich in animal fat leads to cardiovascular dysfunction in young adult rat offspring with subsequent development of dyslipidemia and hyperglycemia. We have further investigated glucose homeostasis in adult female offspring by euglycemic-hyperinsulinemic clamp and by dynamic assessment of glucose-stimulated insulin secretion in isolated, perifused pancreatic islet cells. Additionally, given the link between reduced mitochondrial DNA (mtDNA) content and the development of type 2 diabetes mellitus, we have measured mtDNA in organs from young adult animals. Sprague-Dawley rats were fed a diet rich in animal fat or normal chow throughout pregnancy and weaning. Infusion of insulin (5 mU.kg(-1).min(-1)) resulted in a higher steady-state plasma insulin concentration in 1-year-old offspring of fat-fed dams (OHF, n = 4) vs. offspring of control dams (OC, n = 4, P < 0.01). Glucose-stimulated insulin secretion in isolated islets from 9-mo-old OHF was significantly reduced compared with OC (n = 4, P < 0.05). Transmission electron micrography showed altered insulin secretory granule morphology in OHF pancreatic beta-cells. Kidney mtDNA was reduced in 3-mo-old OHF [16S-to-18S gene ratio: OC (n = 10) 1.05 +/- 0.19 vs. OHF (n = 10) 0.66 +/- 0.06, P < 0.05]. At 6 mo, gene chip microarray of OHF aorta showed reduced expression of the mitochondrial genome. Prenatal and suckling exposure to a diet rich in animal fat leads to whole body insulin resistance and pancreatic beta-cell dysfunction in adulthood, which is preceded by reduced tissue mtDNA content and altered mitochondrial gene expression.

Methods for quantifying insulin resistance in human immunodeficiency virus-positive patients

Various indirect indices have been used in human immunodeficiency virus (HIV)-infected individuals to assess insulin resistance, but the validity of these measures has not been rigorously assessed by comparison with physiologic methods of quantifying insulin-mediated glucose uptake (IMGU). We directly measured IMGU in 50 nondiabetic HIV-positive subjects by determining the steady-state plasma glucose (SSPG) concentration in response to a 3-hour continuous infusion of insulin, glucose, and somatostatin. Because steady-state plasma insulin concentrations were similar (∼60 μU/mL) in all subjects, the SSPG concentrations provided direct assessments of insulin action. Relationships between SSPG levels and various surrogate measures of IMGU derived from the 75-g oral glucose tolerance test (OGTT) were determined. The indirect measure of IMGU most closely related to SSPG concentrations was the total integrated insulin response to a 75-g glucose load ( r = 0.78, P < .01), accounting for approximately two thirds of the variability in SSPG ( r 2 = 0.61). Other indirect measures of IMGU, including the homeostasis assessment for insulin resistance (HOMA-IR), were also significantly related to SSPG values, but had lower magnitudes of correlation ( r = 0.43 to 0.61), thereby possessing limited ability to predict SSPG variability ( r 2 = 0.18 to 0.37). In conclusion, indirect measures of IMGU need to be applied with caution when evaluating insulin action in HIV-infected patients.

Adaptation of ovine fetal pancreatic insulin secretion to chronic hypoglycaemia and euglycaemic correction

Fetal pancreatic adaptations to relative hypoglycaemia, a characteristic of intra-uterine growth restriction, may limit pancreatic β-cell capacity to produce and/or secrete insulin. The objective of this study was to measure β-cell responsiveness in hypoglycaemic (H) fetal sheep and ascertain whether a 5 day euglycaemic recovery period would restore insulin secretion capacity. Glucose-stimulated insulin secretion (GSIS) was measured in euglycaemic (E) control fetuses, fetuses made hypoglycaemic for 14 days, and in a subset of 14-day hypoglycaemic fetuses returned to euglycaemia for 5 days (R fetuses). Hypoglycaemia significantly decreased plasma insulin concentrations in H (0.13 ± 0.01 ng ml−1) and R fetuses (0.11 ± 0.01 ng ml−1); insulin concentrations returned to euglycaemic control values (0.30 ± 0.01 ng ml−1) in R fetuses (0.29 ± 0.04 ng ml−1) during their euglycaemic recovery period. Mean steady-state plasma insulin concentration during the GSIS study was reduced in H fetuses (0.40 ± 0.07 vs. 0.92 ± 0.10 ng ml−1 in E), but increased (P < 0.05) in R fetuses (0.73 ± 0.10 ng ml−1) to concentrations not different from those in the E group. Nonlinear modelling of GSIS showed that response time was greater (P < 0.01) in both H (15.6 ± 2.8 min) and R (15.4 ± 1.5 min) than in E fetuses (6.3 ± 1.1 min). In addition, insulin secretion responsiveness to arginine was reduced by hypoglycaemia (0.98 ± 0.11 ng ml−1 in H vs. 1.82 ± 0.17 ng ml−1 in E, P < 0.05) and did not recover (1.21 ± 0.15 ng ml−1 in R, P < 0.05vs. E). Thus, a 5 day euglycaemic recovery period from chronic hypoglycaemia reestablished GSIS to normal levels, but there was a persistent reduction of β-cell responsiveness to glucose and arginine. We conclude that programming of pancreatic insulin secretion responsiveness can occur in response to fetal glucose deprivation, indicating a possible mechanism for establishing, in fetal life, a predisposition to type 2 diabetes.

Adaptation of ovine fetal pancreatic insulin secretion to chronic hypoglycaemia and euglycaemic correction

Fetal pancreatic adaptations to relative hypoglycaemia, a characteristic of intra-uterine growth restriction, may limit pancreatic beta-cell capacity to produce and/or secrete insulin. The objective of this study was to measure beta-cell responsiveness in hypoglycaemic (H) fetal sheep and ascertain whether a 5 day euglycaemic recovery period would restore insulin secretion capacity. Glucose-stimulated insulin secretion (GSIS) was measured in euglycaemic (E) control fetuses, fetuses made hypoglycaemic for 14 days, and in a subset of 14-day hypoglycaemic fetuses returned to euglycaemia for 5 days (R fetuses). Hypoglycaemia significantly decreased plasma insulin concentrations in H (0.13 +/- 0.01 ng ml(-1)) and R fetuses (0.11 +/- 0.01 ng ml(-1)); insulin concentrations returned to euglycaemic control values (0.30 +/- 0.01 ng ml(-1)) in R fetuses (0.29 +/- 0.04 ng ml(-1)) during their euglycaemic recovery period. Mean steady-state plasma insulin concentration during the GSIS study was reduced in H fetuses (0.40 +/- 0.07 vs. 0.92 +/- 0.10 ng ml(-1) in E), but increased (P < 0.05) in R fetuses (0.73 +/- 0.10 ng ml(-1)) to concentrations not different from those in the E group. Nonlinear modelling of GSIS showed that response time was greater (P < 0.01) in both H (15.6 +/- 2.8 min) and R (15.4 +/- 1.5 min) than in E fetuses (6.3 +/- 1.1 min). In addition, insulin secretion responsiveness to arginine was reduced by hypoglycaemia (0.98 +/- 0.11 ng ml(-1) in H vs. 1.82 +/- 0.17 ng ml(-1) in E, P < 0.05) and did not recover (1.21 +/- 0.15 ng ml(-1) in R, P < 0.05 vs. E). Thus, a 5 day euglycaemic recovery period from chronic hypoglycaemia reestablished GSIS to normal levels, but there was a persistent reduction of beta-cell responsiveness to glucose and arginine. We conclude that programming of pancreatic insulin secretion responsiveness can occur in response to fetal glucose deprivation, indicating a possible mechanism for establishing, in fetal life, a predisposition to type 2 diabetes.

Correlation between the glucose clamp technique and the homeostasis model assessment in hypertension

The homeostasis model assessment (HOMA) has been extensively used as a reliable surrogate marker for measuring insulin resistance in patients with diabetes mellitus and in normal subjects. Comparative data in another insulin resistance state, hypertension, is lacking. The goal of the present study was to obtain that information by testing the correlation of HOMA with the euglycemic hyperinsulinemic clamp in 36 hypertensive and 27 normotensive subjects. Clamp-derived insulin sensitivity was calculated as the glucose disposal rate over steady-state plasma insulin concentration. Homeostasis model assessment was computed using the formula (fasting glucose × fasting insulin)/22.5. There was significant correlation between the clamp and HOMA for both the hypertensive (r = −0.64, P < .0001) and normotensive subjects (r = −0.58, P = .002). The HOMA can be used reliably as a less expensive and less cumbersome alternative for measuring insulin resistance in hypertension.

Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols

It is not known whether total circulating lipid hydroperoxides are increased in insulin-resistant individuals and whether this correlates with depletion of liposoluble antioxidant vitamins that are consumed during lipid peroxidation. The goal of this study was to define the relation between resistance to insulin-mediated glucose disposal and plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins in healthy volunteers. Insulin-mediated glucose disposal was determined in 36 healthy, nondiabetic volunteers by measuring their steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations in response to a 180-min constant infusion of octreotide, insulin, and glucose. In addition, fasting plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins were determined by using the FOX 2 assay and liquid chromatography. Statistically significant direct relations were observed between SSPG and mean arterial blood pressure (r = 0.44, P: = 0.008) and plasma lipid hydroperoxide concentrations (r = 0.42, P: = 0.01), whereas significant inverse correlations were found between SSPG and alpha-carotene (r = -0.58, P: = 0.0002), beta-carotene (r = -0.49, P: = 0.004), lutein (r = -0.35, P: = 0.04), alpha-tocopherol (r = -0. 36, P: = 0.04), and delta-tocopherol (r = -0.45, P: = 0.007). Variations in insulin-mediated glucose disposal in healthy individuals are significantly related to plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins. These findings suggest that total plasma lipid peroxidation is increased in insulin-resistant individuals at an early, preclinical stage, ie, well before the development of glucose intolerance and type 2 diabetes.

Insulin-mediated glucose disposal is decreased in normal subjects with relatively low plasma magnesium concentrations

The relationship between the plasma magnesium (Mg) concentration and steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations at the end of a 180-minute infusion of octreotide, insulin, and glucose was determined in 98 healthy nondiabetic subjects. For the purposes of data analysis, the population was divided into tertiles on the basis of the plasma Mg concentration: I, plasma Mg 0.83 mmol/L; II, plasma Mg 0.84 to 0.91 mmol/L; and III, plasma Mg 0.92 mmol/L. The three groups were identical in terms of age, gender distribution, and degree of obesity. However, both fasting plasma insulin (P < .05) and SSPG (P < .05) concentrations were significantly higher in the tertile (I) with the lowest plasma Mg concentration. Furthermore, there was a significant inverse correlation between plasma Mg and SSPG concentrations (r = -.27, P < .01) in the entire population. These results indicate that variations in the plasma Mg concentration have a relatively modest but significant effect on insulin-mediated glucose disposal in healthy subjects, with lower plasma Mg concentrations associated with increased insulin resistance.

Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers.

The goal of this study was to define the relationship between a quantitative measure of the ability of physiological hyperinsulinemia to stimulate glucose disposal and several surrogate measures of insulin resistance. Insulin-mediated glucose disposal was quantified in 490 healthy nondiabetic volunteers by determining the steady-state plasma glucose (SSPG) concentration in response to a continuous infusion of somatostatin, insulin, and glucose. Because the steady-state plasma insulin concentration was similar in all subjects during the infusion (approximately 60 microU/ml), the SSPG concentration provided a direct estimate of insulin-mediated glucose disposal. Relationships between this specific measure of insulin resistance and several surrogate estimates of insulin resistance based on plasma glucose and insulin concentrations were then defined. The surrogate measure of insulin resistance most closely related to the direct determination of insulin action was the total integrated insulin response to a 75-g oral glucose challenge with correlation coefficients (r) varying from 0.67 to 0.79. Fasting plasma insulin concentration was significantly correlated (r = 0.61, P<0.001) to the specific estimate of insulin action. Two other surrogate estimates of insulin action, the ratio of fasting glucose-to-fasting insulin concentration and the homeostasis model assessment for insulin resistance, were no more closely related to SSPG than the fasting plasma insulin concentration. The total integrated insulin response to oral glucose is the best surrogate measure of insulin resistance, accounting for approximately two-thirds of the variability in insulin-mediated glucose disposal. Fasting insulin concentration accounted for approximately one-third of the variability in insulin-mediated glucose disposal, and the use of fasting plasma glucose and insulin concentrations to calculate more sophisticated estimates of insulin resistance appears to offer little advantage over the fasting plasma insulin concentration. Given the large number of nondiabetic individuals in this study, the results should have general application in population-based studies, providing evidence for both the utility and limitation of the use of these surrogate measures.

Insulin regulation of plasma free fatty acid concentrations is abnormal in healthy subjects with muscle insulin resistance

This study evaluated the ability of insulin to regulate free fatty acid (FFA) concentrations in healthy nondiabetic subjects selected to be either insulin-resistant or -sensitive on the basis of insulin-mediated glucose disposal by muscle. Comparisons of steady-state plasma glucose (SSPG), insulin (SSPI), and FFA concentrations were made at the end of 3 infusion periods: (1) under basal insulin conditions (approximately 10 microU/mL), (2) in response to isoproterenol-induced stimulation of lipolysis at the same basal insulin concentration, and (3) following inhibition of isoproterenol-induced lipolysis by a 2-fold increase in the insulin concentration. The results showed that steady-state FFA concentrations were significantly higher under basal conditions (360 +/- 73 v 158 +/- 36 microEq/L, P = .02), in response to isoproterenol-induced lipolysis (809 +/- 92 v433 +/- 65 microEq/L, P = .005), and following insulin inhibition of isoproterenol-induced lipolysis (309 +/- 65 v 159 +/- 37 microEq/L, P = .06). These differences were found despite the fact that SSPG concentrations were also higher in insulin-resistant individuals during all 3 infusion periods. These results demonstrate that the ability of insulin to regulate plasma FFA concentrations is impaired in healthy subjects with muscle insulin resistance, indicating that insulin-resistant individuals share defects in the ability of insulin to stimulate muscle glucose disposal and to inhibit adipose tissue lipolysis.