Steady-state Plasma Glucose Research Articles

1321 PREDICTORS OF DIRECTLY MEASURED INSULIN RESISTANCE IN AT-RISK LATINOS WITH AND WITHOUT HEPATITIS C (HCV) INFECTION

Background and Aims: HCV is associated with insulin resistance and disproportionately affects Latinos, who in turn have higher rates of diabetes. Factors predictive of insulin resistance in HCVinfected Latinos are not well understood. We aim to compare insulin sensitivity using direct measurements, and assess host and viral factors associated with insulin resistance in Latinos. Methods: 123 non-cirrhotic, non-diabetic Latinos (52 with HCV) were enrolled. All subjects underwent clinical and metabolic evaluation including oral glucose tolerance test and insulin sensitivity by steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Patients in the lowest tertile of SSPG were defined as insulin sensitive (IS) and in the highest tertile as insulin resistant (IR). Results: Overall patient characteristics were: mean age 43±10 years, 64% male, and BMI 27±5 Kg/m. Among HCV-positive patients, 67% were genotype 1, mean log10 HCV viral load was 5.83 IU/mL, and mean ALT 89±73 IU/mL. The mean SSPG in IS (N=40) was of 65±14mg/dL and in IR (N=41) was 239±35mg/dL. On univariable analysis, IS and IR patients were similar with respect to age, family history of diabetes, and tobacco use. However, IR was positively associated with HCV status (OR 1.83, 95%CI 0.7–4.2), female gender (OR 2.38, 95%CI 0.9–5.8), waist circumference (OR 1.21, 95%CI 1.1–1.3), serum LDL (OR 1.02, 95%CI 1.00–1.03), and triglycerides (OR 1.02, 95%CI 1.01–1.04); and negatively associated with HDL (OR 0.93, 95%CI 0.89–0.97), and current alcohol use (OR 0.43, 95%CI 0.97–1.04). On multivariable analysis, controlling for age and family history of diabetes, female gender (OR 13.74, 95%CI 1.99–94.9, p = 0.008), HCV infection (OR 9.13, 95%CI 1.2– 70.1, p = 0.03), waist circumference (OR 1.14, 95%CI 1.04–1.24, p = 0.006), and triglycerides (OR 1.02, 95%CI 1.00–1.04, p = 0.04) were significantly associated with IR. Conclusions: Along with host factors, HCV infection was associated with nine-fold higher odds of directly measured insulin resistance in Latinos. Although male gender is associated with higher diabetic rates, female gender was a strong predictor of insulin resistance among Latinos. The role of other gender-specific factors influencing insulin resistance in this population requires further investigation. Grant support: National Institute of Health, R01-DK074673 (M.K.) and American Diabetes Foundation 1–08-CR-30 (M.K.).

Evaluation of fasting plasma insulin concentration as an estimate of insulin action in nondiabetic individuals: comparison with the homeostasis model assessment of insulin resistance (HOMA-IR)

Insulin-mediated glucose disposal varies severalfold in apparently healthy individuals, and approximately one-third of the most insulin resistant of these individuals is at increased risk to develop various adverse clinical syndromes. Since direct measurements of insulin sensitivity are not practical in a clinical setting, several surrogate estimates of insulin action have been proposed, including fasting plasma insulin (FPI) concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) calculated by a formula employing fasting plasma glucose (FPG) and FPI concentrations. The objective of this study was to compare FPI as an estimate of insulin-mediated glucose disposal with values generated by HOMA-IR in 758 apparently healthy nondiabetic individuals. Measurements were made of FPG, FPI, triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) concentrations, and insulin-mediated glucose uptake was quantified by determining steady-state plasma glucose (SSPG) concentration during the insulin suppression test. FPI and HOMA-IR were highly correlated (r = 0.98, P < 0.001). The SSPG concentration also correlated to a similar degree (P < 0.001) with FPI (r = 0.60) and HOMA-IR (r = 0.64). Furthermore, the relationship between FPI and TG (r = 0.35) and HDL-C (r = -0.40) was comparable to that between HOMA-IR and TG (r = 0.39) and HDL-C (r = -0.41). In conclusion, FPI and HOMA-IR are highly correlated in nondiabetic individuals, with each estimate accounting for ~40% of the variability (variance) in a direct measure of insulin-mediated glucose disposal. Calculation of HOMA-IR does not provide a better surrogate estimate of insulin action, or of its associated dyslipidemia, than measurement of FPI.

Is measurement of non-HDL cholesterol an effective way to identify the metabolic syndrome?

Background and aimsThe metabolic syndrome (MetS) has been shown to predict coronary heart disease (CHD). Non-high-density lipoprotein cholesterol (non-HDL-C) is also known to predict CHD, and recent evidence indicated non-HDL-C was able to predict MetS in adolescents. The study aim was to determine whether non-HDL-C serves as a useful metabolic marker for MetS in adults. Methods and resultsFasting non-HDL-C measurements were obtained in 366 non-diabetic adults not on lipid-lowering therapy. In addition to traditional non-HDL-C cut-points based on Adult Treatment Panel III guidelines, receiver-operating characteristic curve analysis was used to identify an optimal cut-point for predicting MetS. A secondary goal was to assess the relationship between non-HDL-C and insulin resistance, defined as the upper tertile of steady-state plasma glucose concentrations measured during the insulin suppression test. Prevalence of MetS was 40% among participants. Those with MetS had higher mean non-HDL-C (4.17 ± 1.0 vs 3.70 ± 0.85 mmol/L, p < 0.001), and the upper vs lower tertile of non-HDL-C concentrations was associated with 1.8-fold increased odds of MetS (p < 0.05). Traditional non-HDL-C cut-points ≥4.14 and ≥4.92 mmol/L demonstrated respective sensitivities 46% and 24% (specificities 72% and 89%) for identifying MetS. The optimal non-HDL-C cut-point ≥4.45 mmol/L had sensitivity 39% (specificity 82%). Comparable results were observed when non-HDL-C was used to identify insulin resistance. ConclusionWhile MetS was associated with increased non-HDL-C, an effective non-HDL-C threshold to predict MetS in adults was not identified. Dyslipidemic nuances may explain why non-HDL-C may be less useful as a metabolic marker for MetS and/or insulin resistance than for CHD.

Gynostemma pentaphyllum Tea Improves Insulin Sensitivity in Type 2 Diabetic Patients.

Aims. To evaluate the effect of the traditional Vietnamese herb Gynostemma pentaphyllum tea on insulin sensitivity in drug-naïve type 2 diabetic patients. Methods. Patients received GP or placebo tea 6 g daily for four weeks and vice versa with a 2-week wash-out period. At the end of each period, a somatostatin-insulin-glucose infusion test (SIGIT) was performed to evaluate the insulin sensitivity. Fasting plasma glucose (FPG), HbA1C, and oral glucose tolerance tests and insulin levels were measured before, during, and after the treatment. Results. FPG and steady-state plasma glucose (SIGIT mean) were lower after GP treatment compared to placebo treatment (P < 0.001). The levels of FPG in the control group were slightly reduced to 0.2 ± 1.5 versus 1.9 ± 1.0 mmol/L in GP group (P < 0.001), and the effect on FPG was reversed after exchanging treatments. The glycometabolic improvements were achieved without any major change of circulating insulin levels. There were no changes in lipids, body measurements, blood pressure, and no reported hypoglycemias or acute adverse effects regarding kidney and liver parameters. Conclusion. The results of this study suggested that the GP tea exerted antidiabetic effect by improving insulin sensitivity.

Analysis of Integrated Insulin-mTOR Signalling Network -Diabetes Perspective

The regulatory action of insulin on the blood glucose homeostasis is mediated by the Insulin signalling pathway. To quantify this regulation, we have integrated the models of Insulin secretion, insulin signalling, mTOR signalling and blood glucose uptake by various tissues. We have analyzed the effect of perturbations in the integrated insulin-mTOR signalling pathway on blood glucose levels. These effects were studied in the tissues in which glucose uptake is dependent on insulin (i.e. muscle, adipose and heart). Seventy five rate parameters in the integrated network were perturbed and the corresponding steady state plasma glucose levels were recorded. The fold changes in these parameters leading to pre-diabetic and diabetic states were characterized. Perturbations in 22 parameters elicited diabetic effect and 31 parameters showed pre-diabetic effects for certain fold change in basal parameter values. In the insulin signalling pathway, the concentrations and phosphorylation states of PTP and PIP3 were most effective in leading to diabetic state with only 3 and -3 fold change in their parameters, respectively. While increasing concentrations of PTEN by five folds also led to diabetic state, decreasing the phosphorylation of IRS, AKT and GSK3 unto 10 folds resulted in diabetic state. In the mTOR pathway, increasing the influence of amino acid on Rheb-GTP localization to the inhibitory complex by 4 folds elicited diabetic state. On the other hand decreasing conversion of RhebGTP to RhebGDP and formation of mTOR-raptor-PRAS40 complex also resulted in diabetic state. This demonstrates the influence of excess amino acid intake on diabetic state. Overall, it was noted that only 2 to 3 fold change in sensitive parameters resulted in pre-diabetic state.

Measurement of insulin-mediated glucose uptake: Direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp

BackgroundTwo direct measurements of peripheral insulin sensitivity are the M value derived from the euglycemic, hyperinsulinemic clamp (EC) and the steady-state plasma glucose (SSPG) concentration derived from the insulin suppression test (IST). Prior work suggests that these measures are highly correlated, but the agreement between them is unknown. To determine the agreement between SSPG and M and to develop transformation equations to convert SSPG to M and vice versa, we directly compared these two measurements in the same individuals. MethodsA total of 15 nondiabetic subjects (9 women and 6 men) underwent both an EC and a modified version of the IST within a median interval of 5days. We performed standard correlation metrics of the two measures and developed transformation regression equations for the two measures. ResultsThe mean±SD age of the subjects was 57±7years and body mass index, 27.7±3.9kg/m2. The median (interquartile range) SSPG concentration was 6.7 (5.1, 9.8) mmol/L and M value, 49.6 (28.9, 64.2) μmol/min/kg-LBM. There was a highly significant correlation between SSPG and M (r=−0.87, P <0.001). The relationship was best fit by regression models with exponential/logarithmic functions (R2=0.85). Bland–Altman plots demonstrated an excellent agreement between these measures of insulin action. ConclusionThe SSPG and M are highly related measures of insulin sensitivity and the results provide the means to directly compare the two measurements.

Insulin Sensitivity and Variability in Hepatitis C Virus Infection Using Direct Measurement

Studies investigating insulin resistance (IR) in chronic hepatitis C virus (HCV) infection have used surrogate measures of IR that have limited reliability. We aimed to describe the distribution and risk factors associated with IR and its change over time in HCV using direct measurement. One hundred two non-cirrhotic, non-diabetic, HCV-infected subjects underwent clinical, histologic, and metabolic evaluation, and 27 completed repeat evaluation at 6 months. Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Three subjects with diabetes were excluded and 95 completed all testing. SSPG ranged from 39 to 328 mg/dL (mean 135 mg/dL) and was stable over time (mean SSPG change -0.3 mg/dL). SSPG was associated with Latino ethnicity (Coef 67, 95 % CI 37-96), BMI (Coef 19 per 5 kg/m(2), 95 % CI 5-32), ferritin (Coef 1.4 per 10 ng/ml, 95 % CI 0.2-2.5), male gender (Coef -48, 95 % CI -80 to -16), and HDL (Coef -16, 95 % CI -28 to -5 mg/dL). Current tobacco use (Coef 55, 95 % CI 19-90), steatosis (Coef -44, 95 % CI -86 to -3), and increases in BMI (Coef 30 per 5 kg/m(2), 95 % CI 6-53) and triglyceride (Coef 3.5 per 10 mg/dL, 95 % CI 0.3-6.7) predicted change in SSPG. There was a wide spectrum of insulin resistance in our HCV population. Host factors, rather than viral factors, appeared to more greatly influence insulin action and its change in HCV.

Relations between obesity, insulin resistance, and 25-hydroxyvitamin D

Although low circulating 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance and obesity, the relations between these 3 variables have not been completely resolved. The objective was to compare circulating 25(OH)D concentrations in apparently healthy individuals who were matched for degree of obesity or insulin sensitivity. This was a case-control study in which 78 apparently healthy individuals were classified as being normal weight (NW) or obese (OB) on the basis of their BMI and as being insulin sensitive (IS) or insulin resistant (IR) on the basis of their steady state plasma glucose (SSPG) concentration during the insulin suppression test. Groups did not differ in terms of age, sex distribution, race, or mean (± SD) plasma 25(OH)D concentration. Values for 25(OH)D were 32 ± 10, 30 ± 10, and 28 ± 8 ng/mL in NW-IS, OB-IS, and OB-IR groups, respectively. These concentrations were essentially identical when comparing IR with IS subjects matched for BMI or when comparing OB with NW subjects matched for SSPG. Concentrations of 25(OH)D ≤ 30 ng/mL were somewhat more common in OB subjects than in NW subjects (54% compared with 35%), but SSPG concentrations were not different within either the IR or IS groups when subgroups with 25(OH)D concentrations ≤ 30 or > 30 ng/mL were compared. In 78 individuals, 47% of whom were vitamin D deficient or insufficient (≤ 30 ng/mL), 25(OH)D concentrations did not vary with differences in insulin sensitivity (SSPG concentration) when matched for BMI (OB-IR compared with OB-IS). Similarly, when matched for SSPG concentrations, plasma 25(OH)D concentrations were not different in NW or OB individuals (NW-IS compared with OB-IS).

Impact of Insulin Resistance on HCV Treatment Response and Impact of HCV Treatment on Insulin Sensitivity Using Direct Measurements of Insulin Action

OBJECTIVEInsulin resistance, as measured by surrogate markers, is associated with lower response to hepatitis C virus (HCV) therapy and may improve with HCV eradication. We prospectively evaluated the impact of directly measured insulin resistance and abnormal glucose metabolism on achieving sustained virologic response (SVR) with HCV therapy and assessed whether SVR results in improved insulin sensitivity and fasting glucose.RESEARCH DESIGN AND METHODSA total of 50 noncirrhotic, nondiabetic, HCV-infected patients (27 untreated, 23 treated with pegylated interferon/ribavirin, nonrandomized) underwent clinical and histologic evaluation and 75-g oral glucose tolerance test. Insulin sensitivity was assessed directly with insulin suppression test by measuring steady-state plasma glucose (SSPG) concentration during a 240-min infusion of octreotide, glucose, and insulin. Of the subjects, 43 had at least one follow-up evaluation.RESULTSPatient characteristics were median age 48, 57% male, and 52% white. SVR was achieved in 61% (14 of 23) of treated subjects. SVR was independently associated with HCV genotypes 2 and 3 (odds ratio 8.8 [95% CI 1.2–61.7]) but was not strongly associated with insulin sensitivity. When controlling for elapsed time between measurements, being on interferon, and BMI, SSPG decreased by 36 mg/dL (−88 to 16) in those with SVR and decreased by 28 mg/dL (−93 to 38) in those without SVR, compared with the untreated group. BMI (coefficient 9.1 per 5 units; 95% CI 5.3–12.9) and interferon use (coefficient 56; 95% CI 6.8–105) were associated with SSPG.CONCLUSIONSInsulin resistance does not appear to be strongly associated with SVR. HCV therapy may improve insulin resistance regardless of virologic response; however, BMI and interferon use were clearly associated with insulin resistance.

Risk for obstructive sleep apnea in obese, nondiabetic adults varies with insulin resistance status

Obstructive sleep apnea (OSA) is an increasingly common sleep disorder, especially among obese adults. Early identification of adults at risk for OSA would be of substantial benefit; however, the magnitude of the obesity epidemic requires that screening be performed judiciously. The study's aim was to utilize questionnaires that assess OSA risk and symptoms to test the hypothesis that the most insulin-resistant subset of obese individuals is at highest risk for OSA. Nondiabetic, overweight to obese volunteers underwent direct quantification of insulin sensitivity by measuring steady-state plasma glucose concentrations during the insulin suppression test. Insulin-sensitive and insulin-resistant individuals were administered the Berlin and STOP questionnaires to determine OSA risk status, and Epworth Sleepiness Scale (ESS) to evaluate daytime sleepiness. Fasting insulin and lipid/lipoprotein measurements were performed. Insulin-mediated glucose disposal differed threefold (p < 0.001) between equally obese, insulin-resistant (n = 22) and insulin-sensitive (n = 14) individuals, associated with higher fasting insulin and triglyceride and lower high-density lipoprotein cholesterol (HDL-C) concentrations in insulin-resistant individuals. Fourteen (64 %) insulin-resistant as compared with 2 (14 %) insulin-sensitive individuals were found to be at high risk for OSA by both questionnaires (p < 0.01). Whereas half of insulin-resistant individuals met the ESS criteria for excessive daytime sleepiness, only one insulin-sensitive individual did (p = 0.011). High risk for OSA and excessive daytime sleepiness is prevalent among the insulin-resistant subgroup of obese individuals. Surrogate estimates of insulin resistance based on fasting insulin, triglycerides, and/or HDL-C can be used to help identify those obese adults who would benefit most from OSA screening and referral for polysomnography.

Abstract P149: A Large-scale Multi Ethnic Study of a Direct Measure of Insulin Sensitivity Demonstrates That South Asians are the Most Insulin Resistant Ethnic Group in the US

Introduction: Insulin resistance (IR) is a known risk factor for heart disease. Few studies have compared race/ethnic differences in IR using ‘gold standard’ direct measures of insulin sensitivity. Methods: A total of 892 non-diabetic subjects (548 White, 106 South Asian, 103 East Asian, 86 Hispanic and 49 Black) underwent a 4-hour insulin suppression test (IST) as a part of various IR related studies at Stanford over the last ∼20 years. We used generalized estimating equations assuming an exchangeable correlation structure to determine the association between race/ethnicity and steady state plasma glucose (SSPG) derived from an IST, accounting for correlation of outcomes among subjects from the same study. We similarly determined whether differences in plasma triglyceride (TG) and high-density lipoprotein (HDL) levels among race/ethnic groups could be explained by differences in SSPG. All analyses were adjusted for age, sex, and BMI. Results: Significant differences among the race/ethnic groups in SSPG were observed (p &lt;0.001). South Asians were the most insulin resistant group with a mean increase in SSPG of 38 mg/dL, compared to whites after controlling for age, sex, and BMI, a difference equivalent to ∼1/2 of the standard deviation of SSPG. East Asians were the next most resistant group (mean +33 mg/dl SSPG compared to whites) followed by Hispanics (+20 mg/dl), Whites, and Blacks (−7 mg/dl). South Asians were the only group with significantly higher TG (mean +1.16 fold, p=0.04) and lower HDL (−3.0 mg/dl, p=0.02) levels compared to whites but these differences were no longer evident after controlling for SSPG. In contrast, Blacks had significantly lower TG (mean 0.8 fold, p = 0.006) compared to whites, but this difference was not at all mitigated after adjusting for SSPG. Blacks also had no significant differences in HDL compared to whites. Conclusions: Direct measures of insulin sensitivity suggest that South Asians are the most insulin resistant race/ethnic group in the US even after adjusting for the principal determinants of IR. IR may be largely responsible for differences in TG and HDL observed between South Asian and other race/ethnic groups. The etiologies behind differences in insulin sensitivity across race/ethnic groups remain to be determined.

A LARGE-SCALE MULTI ETHNIC STUDY OF A DIRECT MEASURE OF INSULIN SENSITIVITY DEMONSTRATES THAT SOUTH ASIANS ARE THE MOST INSULIN RESISTANT ETHNIC GROUP IN THE US

Methods: A total of 892 non-diabetic subjects (548 White,106 South Asian, 103 East Asian, 86 Hispanic and 49 Black) underwent a 4-hour insulin suppression test (IST) as a part of IR related studies at Stanford over the last ~20 years. We used generalized estimating equations assuming an exchangeable correlation structure to determine the association between race/ethnicity and steady state plasma glucose (SSPG) derived from an IST, accounting for correlation of outcomes among subjects from the same study. We similarly determined whether differences in plasma triglyceride (TG) and high-density lipoprotein (HDL) levels among race/ethnic groups could be explained by differences in SSPG. All analyses were adjusted for age, sex, and BMI.

Assessment of factors associated with pre‐diabetes in HCV infection including direct and dynamic measurements of insulin action

Although hepatitis C (HCV) is associated with diabetes, few studies have examined pre-diabetes in this population. We aimed to evaluate factors associated with pre-diabetes in HCV-infected patients, including direct measurement of insulin action. Ninety-seven non-cirrhotic, non-diabetic and HCV-infected patients underwent clinical evaluation and oral glucose tolerance testing (OGTT). Insulin sensitivity was measured directly by steady-state plasma glucose (SSPG) concentration during insulin suppression test. Early phase and total insulin secretion were determined using OGTT. Rates of pre-diabetes were as follows: 21% impaired fasting glucose (IFG), 7% impaired glucose tolerance (IGT) and 9% combined IFG/IGT. Twelve percent of Caucasians, 50% of African Americans and 70% of Latinos had pre-diabetes (P = 0.002). Patient characteristics among the glucose metabolism categories were similar except those with combined IFG/IGT had a higher body mass index (BMI) vs normal glucose tolerance (NGT) (30 vs 26 kg/m(2), P = 0.007) and lower LDL vs NGT and IGT (74, 104 and 112 mg/dL, respectively, P ≤ 0.01). On multivariable analysis, non-Caucasian race (OR 23.1, P = 0.003), BMI (OR 3.4, P = 0.02) and greater liver inflammation (OR 7.9, P = 0.03) predicted IFG, whereas non-Caucasian race (OR 14.8, P = 0.01) and SSPG (OR 1.1 per 10 units, P = 0.01) predicted IGT. Early and total insulin secretion adjusted for the degree of insulin resistance was decreased in pre-diabetes compared with NGT (P = 0.01 and P = 0.02, respectively). Pre-diabetes is highly prevalent among HCV-infected patients, and in some instances, coincides with host responses to the virus. In most cases, however, factors that are associated with pre-diabetes in HCV-infected patients are similar to those observed in the non-HCV population.

Plasma glucose and insulin responses to mixed meals: Impaired fasting glucose re-visited

In individuals with varying glucose tolerance, glucose and insulin comparisons are usually made based on response to oral glucose challenge. However, an oral glucose tolerance test may not reflect daylong glucose and insulin excursions in response to meals. To better understand individuals with impaired fasting glucose (IFG), we compared insulin action as well as plasma glucose and insulin responses to mixed meals in individuals with normal fasting glucose (NFG; n = 141) and IFG (n = 148) concentrations. Insulin action was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Plasma glucose and insulin concentrations were measured before and hourly after two mixed meals. SSPG concentrations were significantly higher in the IFG group (11.8 ± 3.6 vs. 9.1 ± 3.8 mmol/l). Mean hourly daylong glucose (6.4 ± 0.07 vs. 5.5 ± 0.04 mmol/l) and insulin (390 ± 20 vs. 279 ± 15 pmol/l) concentrations were also higher in those with IFG (p < 0.001). Daylong incremental meal-stimulated glucose response, however, was comparable (p = 0.77) in the two groups, whereas the incremental insulin response was 44% higher in the IFG group. Although individuals are currently defined as having IFG based on fasting plasma glucose concentration, our data show that these individuals with IFG also are insulin resistant and have higher daylong insulin concentrations.

Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice

Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In wild-type mice, hyperinsulinemic-euglycemic clamp conditions stimulated the retention of both plasma triglyceride-derived FA and plasma albumin-bound FA in the various white adipose tissues (WAT) but not in other tissues, including brown adipose tissue (BAT). Intracerebroventricular (ICV) administration of insulin induced a similar pattern of tissue-specific FA partitioning. This effect of ICV insulin administration was not associated with activation of the insulin signaling pathway in adipose tissue. ICV administration of tolbutamide, a K(ATP) channel blocker, considerably reduced (during hyperinsulinemic-euglycemic clamp conditions) and even completely blocked (during ICV administration of insulin) WAT-specific retention of FA from plasma. This central effect of insulin was absent in CD36-deficient mice, indicating that CD36 is the predominant FA transporter in insulin-stimulated FA retention by WAT. In diet-induced insulin-resistant mice, these stimulating effects of insulin (circulating or ICV administered) on FA retention in WAT were lost. In conclusion, in insulin-sensitive mice, circulating insulin stimulates tissue-specific partitioning of plasma-derived FA in WAT in part through activation of K(ATP) channels in the CNS. Apparently, circulating insulin stimulates fatty acid uptake in WAT but not in BAT, directly and indirectly through the CNS.

Simultaneous measurement of glucose transport and utilization in the human brain

Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, K(M)(t) and V(max)(t), in humans have so far been obtained by measuring steady-state brain glucose levels by proton ((1)H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMR(glc)) obtained from other tracer studies, such as (13)C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state (1)H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ∼17 mmol/l for ∼2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMR(glc), this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain.

Comparison of two methods using plasma triglyceride concentration as a surrogate estimate of insulin action in nondiabetic subjects: triglycerides × glucose versus triglyceride/high-density lipoprotein cholesterol

The objective was to compare relationships between insulin-mediated glucose uptake and surrogate estimates of insulin action, particularly those using fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations. Insulin-mediated glucose uptake was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test in 455 nondiabetic subjects. Fasting TG, HDL-C, glucose, and insulin concentrations were measured; and calculations were made of the following: (1) plasma concentration ratio of TG/HDL-C, (2) TG × fasting glucose (TyG index), (3) homeostasis model assessment of insulin resistance, and (4) insulin area under the curve (insulin-AUC) during a glucose tolerance test. Insulin-AUC correlated most closely with SSPG (r ∼ 0.75, P < .001), with lesser but comparable correlations between SSPG and TG/HDL-C ratio, TyG index, homeostasis model assessment of insulin resistance, and fasting TG and insulin (r ∼ 0.60, P < .001). Calculations of TG/HDL-C ratio and TyG index correlated with SSPG concentration to a similar degree, and the relationships were comparable to estimates using fasting insulin. The strongest relationship was between SSPG and insulin-AUC.

Estimates of Insulin Secretory Function in Apparently Healthy Volunteers Vary as a Function of How the Relevant Variables Are Quantified

Several surrogate estimates have been used to define relationships between insulin action and pancreatic β-cell function in healthy individuals. Because it is unclear how conclusions about insulin secretory function depend on specific estimates used, we evaluated the effect of different approaches to measurement of insulin action and secretion on observations of pancreatic β-cell function in individuals whose fasting plasma glucose (FPG) was <7.0 mmol/L (126 mg/dL). We determined 2 indices of insulin secretion [homeostasis model assessment of β-cell function (HOMA-β) and daylong insulin response to mixed meals], insulin action [homeostasis model assessment of insulin resistance (HOMA-IR) and steady-state plasma glucose (SSPG) concentration during the insulin suppression test], and degree of glycemia [fasting plasma glucose (FPG) and daylong glucose response to mixed meals] in 285 individuals with FPG <7.0 mmol/L. We compared the relationship between the 2 measures of insulin secretion as a function of the measures of insulin action and degree of glycemia. Assessment of insulin secretion varied dramatically as a function of which of the 2 methods was used and which measure of insulin resistance or glycemia served as the independent variable. For example, the correlation between insulin secretion (HOMA-β) and insulin resistance varied from an r value of 0.74 (when HOMA-IR was used) to 0.22 (when SSPG concentration was used). Conclusions about β-cell function in nondiabetic individuals depend on the measurements used to assess insulin action and insulin secretion. Viewing estimates of insulin secretion in relationship to measures of insulin resistance and/or degree of glycemia does not mean that an unequivocal measure of pancreatic β-cell function has been obtained.

Endogenous Chronic Hyperinsulinemia Does Not Increase the Production Rate of VLDL Apolipoprotein B: Proof from a Kinetic Study in Patients with Insulinoma

It is currently suggested that chronic hyperinsulinemia is a causal factor for the increased production rate of very-low-density lipoproteins (VLDL) associated with metabolic syndrome. However, the involvement of hyperinsulinemia independently of the other abnormalities also observed in metabolic syndrome has never been proven in humans. We used patients with insulinoma showing hyperinsulinemia but no insulin resistance as a model and conducted an apolipoprotein B (apoB) kinetic study in seven patients with insulinoma, seven insulin-resistant (IR) obese patients, and 12 controls. Insulinemia was higher in patients with insulinoma or IR than in controls both in the fasting state [2.4-fold (P = 0.039) and 3.1-fold (P = 0.003), respectively] and in the fed state [3.5-fold (P = 0.006) and 2.6-fold (P = 0.05), respectively]. Patients with insulinoma were not IR (steady state plasma glucose = 80 ± 46 mg/dl, a value lower than in IR subjects (231 ± 75, P = 0.0013). In the fed state, triglyceridemia and VLDL apoB pool size were higher in IR subjects compared with controls and patients with insulinoma [208 ± 56 vs. 89 ± 30 mg/dl (P < 0.0001) and 96 ± 42 mg/dl (P < 0.0001), respectively, for triglyceridemia and 3.56 ± 0.60 vs. 1.85 ± 0.88 mg/kg (P = 0.004) and 2.32 ± 1.79 (P = 0.052) mg/kg for VLDL apoB pool size]. The production rate of VLDL apoB in subjects with insulinoma was not significantly different from that in controls (14.56 ± 7.43 vs. 16.40 ± 7.70 mg/kg · d) but was higher in IR subjects compared with these two groups [25.66 ± 12.84 mg/kg · d (P = 0.046 and 0.035, respectively)]. Chronic endogenous hyperinsulinemia is not directly responsible for any increase in the production rate of VLDL apoB in humans.

Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice

Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (n = 8) received one of the following: CORT 108297 (80 mg/kg QD), CORT 108297 (40 mg/kg BID), mifepristone (30 mg/kg BID), rosiglitazone (10 mg/kg QD), or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.