Earlier prospective studies have identified insulin action and secretion as predictors of T2DM in populations with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) (2-h OGTT < 7.8 and 7.8-11 mmol/L, respectively). Fasting plasma glucose (FPG), an additional and recently modified (normal <5.6 mmol/L) diagnostic criterion is associated with insulin secretion. We wanted to establish whether insulin secretion persists as an independent predictor of T2DM in individuals with no clinical evidence of impaired glucose regulation based on FPG and 2-h plasma glucose concentrations.
Insulin action (M, euglycemic-hyperinsulinemic clamp), insulin secretion (acute insulin response (AIR), IVGTT), and adiposity (%Fat, DXA or densitometry) were compared at baseline in 358 Pima Indians (232M/126F, 18-44 years old) with normal glucose regulation of whom 61 (35M/26F) developed diabetes (DIAB) during a median follow-up time of 7.6 years.
In proportional-hazard analysis, % Fat (HR = 1.52, p = 0.03), M (HR = 0.51, p = 0.04) and AIR (HR = 0.64, p = 0.003) predicted the development of diabetes after adjustment for age and sex. In regression analysis adjusting for age, sex, %Fat and M at baseline, the non-diabetic group (NON-DM) had a higher AIR (p = 0.0002) than the DIAB group; the positive association of AIR with adiposity observed in the NON-DM group was absent in the DIAB group. Cumulative incidence rates (12y) for diabetes were highest (48%) in subjects with both M and AIR below the population median and lowest (11%) in subjects with both M and AIR above the population median.
AIR can predict diabetes prior to the current clinical indicators of impaired glucose regulation. Published in 2006 by John Wiley & Sons, Ltd.
type 2 diabetes; insulin action; insulin secretion; obesity
OBJECTIVE—The purpose of this study was to elucidate the mechanisms of diabetes reversibility after malabsorptive bariatric surgery.
RESEARCH DESIGN AND METHODS—Peripheral insulin sensitivity and β-cell function after either intravenous (IVGTT) or oral glucose tolerance (OGTT) tests and minimal model analysis were assessed in nine obese, type 2 diabetic subjects before and 1 month after biliopancreatic diversion and compared with those in six normal-weight control subjects. Insulin-dependent whole-body glucose disposal was measured by the euglycemic clamp, and glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were also measured.
RESULTS—The first phase of insulin secretion after the IVGTT was fully normalized after the operation. The disposition index from OGTT data was increased about 10-fold and became similar to the values found in control subjects, and the disposition index from IVGTT data increased about 3.5-fold, similarly to what happened after the euglycemic clamp. The area under the curve (AUC) for GIP decreased about four times (from 3,000 ± 816 to 577 ± 155 pmol · l−1 · min, P < 0.05). On the contrary, the AUC for GLP1 almost tripled (from 150.4 ± 24.4 to 424.4 ± 64.3 pmol · l−1 · min, P < 0.001). No significant correlation was found between GIP or GLP1 percent changes and modification of the sensitivity indexes independently of the route of glucose administration.
CONCLUSIONS—Restoration of the first-phase insulin secretion and normalization of insulin sensitivity in type 2 diabetic subjects after malabsorptive bariatric surgery seem to be related to the reduction of the effect of some intestinal factor(s) resulting from intestinal bypass.
KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered β-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different stimuli.
RESEARCH DESIGN AND METHODS
We genotyped 1,578 nondiabetic subjects at increased risk of type 2 diabetes for rs151290, rs2237892, rs2237895, and rs2237897. All participants underwent an oral glucose tolerance test (OGTT); glucagon-like peptide (GLP)-1 and gastric inhibitory peptide secretion was measured in 170 participants. In 519 participants, a hyperinsulinemic-euglycemic clamp was performed, in 314 participants an intravenous glucose tolerance test (IVGTT), and in 102 subjects a hyperglycemic clamp combined with GLP-1 and arginine stimuli.
rs151290 was nominally associated with 30-min C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P ≤ 0.01). rs2237892, rs2237895, and rs2237897 were nominally associated with OGTT-derived insulin secretion indexes (all P < 0.05). No SNPs were associated with β-cell function during intravenous glucose or GLP-1 administration. However, rs151290 was associated with glucose-stimulated gastric inhibitory polypeptide and GLP-1 increase after adjustment in the dominant model (P = 0.0042 and P = 0.0198, respectively). No associations were detected between the other SNPs and basal or stimulated incretin levels (all P ≥ 0.05).
Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems to be explained not by altered incretin signaling but most likely by changes in incretin secretion.
The aim of the study was to find a simple intravenous glucose tolerance test (IVGTT) that can be used to estimate insulin sensitivity.
In 20 healthy volunteers aged between 18 and 51 years (mean, 28) comparisons were made between kinetic parameters derived from a 12-sample, 75-min IVGTT and the Mbw (glucose uptake) obtained during a hyperinsulinemic euglycemic glucose clamp. Plasma glucose was used to calculate the volume of distribution (Vd) and the clearance (CL) of the injected glucose bolus. The plasma insulin response was quantified by the area under the curve (AUCins). Uptake of glucose during the clamp was corrected for body weight (Mbw).
There was a 7-fold variation in Mbw. Algorithms based on the slope of the glucose-elimination curve (CL/Vd) in combination with AUCins obtained during the IVGTT showed statistically significant correlations with Mbw, the linearity being r2 = 0.63-0.83. The best algorithms were associated with a 25-75th prediction error ranging from -10% to +10%. Sampling could be shortened to 30-40 min without loss of linearity or precision.
Simple measures of glucose and insulin kinetics during an IVGTT can predict between 2/3 and 4/5 of the insulin sensitivity.
OBJECTIVE— This study assessed insulin and glucagon secretion in relation to insulin sensitivity in Caucasian women who develop impaired glucose tolerance (IGT) versus those who maintain normal glucose tolerance (NGT) over a 12-year period.
RESEARCH DESIGN AND METHODS— At baseline and after 3, 8, and 12 years, glucose tolerance (75-g oral glucose tolerance test), insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin and glucagon secretion (2- to 5-min responses to 5 g arginine i.v. at fasting, 14 and >25 mmol/l glucose) were determined in 53 healthy Caucasian women (aged 58 years at baseline) who all had NGT at baseline.
RESULTS— During the 12-year period, 26 subjects developed IGT, whereas the remaining 27 subjects maintained NGT throughout the 12-year period. Subjects developing IGT had lower insulin sensitivity than those maintaining NGT in the tests preceding diagnosis of IGT (P ≤ 0.05). When judged in relation to insulin sensitivity, β-cell glucose sensitivity and maximal insulin secretion were lower in those who later developed IGT than in those maintaining NGT at all tests (P ≤ 0.05). Furthermore, subjects who developed IGT had defective suppression of glucagon secretion by glucose in the test preceding diagnosis of IGT when they still had NGT (P ≤ 0.05).
CONCLUSIONS— β- and α-cell dysfunction are evident several years before diagnosis of IGT, and islet dysfunction is manifested as impaired glucose sensitivity of the β- and α-cells and reduced maximal insulin secretion.
Individuals with normal glucose tolerance (NGT), whose 1-h postload plasma glucose is ≥155 mg/dL (NGT 1h-high), have an increased risk of type 2 diabetes. The purpose of this study was to characterize their metabolic phenotype.
RESEARCH DESIGN AND METHODS
A total of 305 nondiabetic offspring of type 2 diabetic patients was consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp.
Compared with individuals with a 1-h postload plasma glucose <155 mg/dL (NGT 1h-low), NGT 1h-high individuals exhibited lower insulin sensitivity after adjustment for age, sex, and BMI. Insulin secretion estimated from the OGTT did not differ between the two groups of individuals. By contrast, compared with NGT 1h-low individuals, the acute insulin response during an IVGTT and the disposition index were significantly reduced in NGT 1h-high individuals after adjustment for age, sex, and BMI. Incretin effect, estimated as the ratio between total insulin responses during OGTT and IVGTT, was higher in NGT 1h-high individuals compared with NGT 1h-low individuals.
NGT 1h-high individuals may represent an intermediate state of glucose intolerance between NGT and type 2 diabetes characterized by insulin resistance and reduced β-cell function, the two main pathophysiological defects responsible for the development of type 2 diabetes. Postload hyperglycemia is the result of an intrinsic β-cell defect rather than impaired incretin effect.
Recent data suggested that sex hormone–binding globulin (SHBG) levels decrease when fat accumulates in the liver and that circulating SHBG may be causally involved in the pathogenesis of type 2 diabetes in humans. In the present study, we investigated mechanisms by which high SHBG may prevent development to diabetes.
RESEARCH DESIGN AND METHODS
Before and during a 9-month lifestyle intervention, total body and visceral fat were precisely measured by magnetic resonance (MR) tomography and liver fat was measured by 1H-MR spectroscopy in 225 subjects. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test (ISOGTT) and measured by a euglycemic hyperinsulinemic clamp (ISclamp, n = 172). Insulin secretion was measured during the OGTT and an ivGTT (n = 172).
SHBG levels correlated positively with insulin sensitivity (ISOGTT, P = 0.037; ISclamp, P = 0.057), independently of age, sex, and total body fat. In a multivariate model, these relationships were also significant after additional adjustment for levels of the adipokine adiponectin and the hepatokine fetuin-A (ISOGTT, P = 0.0096; ISclamp, P = 0.029). Adjustment of circulating SHBG for liver fat abolished the relationships of SHBG with insulin sensitivity. In contrast, circulating SHBG correlated negatively with fasting glycemia, before (r = −0.17, P = 0.009) and after (r = −0.14, P = 0.04) adjustment for liver fat. No correlation of circulating SHBG with adjusted insulin secretion was observed (OGTT, P = 0.16; ivGTT, P = 0.35). The SNP rs1799941 in SHBG was associated with circulating SHBG (P ≤ 0.025) but not with metabolic characteristics (all P > 0.18).
Possible mechanisms by which high circulating SHBG prevents the development of type 2 diabetes involve regulation of fasting glycemia but not alteration of insulin secretory function.
To identify physiological and clinical variables associated with development of type 2 diabetes up to 12 years after pregnancies complicated by gestational diabetes.
RESEARCH DESIGN AND METHODS
Seventy-two islet cell antibody–negative nondiabetic Hispanic women had oral (oGTT) and intravenous (ivGTT) glucose tolerance tests, glucose clamps, and body composition assessed between 15 and 30 months after pregnancies complicated by gestational diabetes mellitus (GDM). They returned for oGTTs at 15-month intervals until they dropped out, developed diabetes, or reached 12 years postpartum. Cox regression analysis was used to identify baseline predictors and changes during follow-up that were associated with development of type 2 diabetes.
At baseline, relatively low insulin sensitivity, insulin response, and β-cell compensation for insulin resistance were independently associated with development of diabetes. During follow-up, weight and fat gain and rates of decline in β-cell compensation were significantly associated with diabetes, while additional pregnancy and use of progestin-only contraception were marginally associated with diabetes risk.
In Hispanic women, GDM represents detection of a chronic disease process characterized by falling β-cell compensation for chronic insulin resistance. Women who are farthest along at diagnosis and/or deteriorating most rapidly are most likely to develop type 2 diabetes within 12 years after the index pregnancy. Weight gain, additional pregnancy, and progestin-only contraception are potential modifiable factors that increase diabetes risk.
Individuals with Turner syndrome (TS) are at increased risk for impaired glucose tolerance (IGT) and diabetes mellitus. It is unknown if pharmacological growth hormone (GH) treatment commonly used to treat short stature in TS alters this risk.
To compare adiposity and glucose tolerance in GH-treated vs. untreated girls with TS
In a cross sectional study, GH-treated girls with TS (n=76, age 13.6±3.7 yrs) were compared with girls with TS that never received GH (n=26, age 13.8±3.5 yrs). Protocol studies took place in the NIH CRC from 2001–2006 and included oral glucose tolerance tests, body composition analysis by DEXA and abdominal fat quantification by MRI. GH was not given during testing.
Total body fat (35±8% vs. 28±8%, P<0.0001), subcutaneous abdominal fat (183 vs. 100 cc3, P= 0.001) and intra-abdominal fat (50 vs. 33 cc3, P<0.0001) were significantly greater in untreated girls. Fasting glucose and insulin were similar but the response to oral glucose was significantly impaired in the untreated group (28% vs. 7% with IGT, P=0.006). A specific excess of visceral fat and insulin resistance was apparent only in post-pubertal girls that had never received GH. GH-treated girls demonstrated lower adiposity compared to untreated girls for an average of 2 years after discontinuation of GH.
Abdominal adiposity is significantly lower and glucose tolerance significantly better in GH-treated vs. untreated girls with TS, suggesting that beneficial effects upon body composition and regional fat deposition outweigh transient insulin antagonism associated with GH administration.
X chromosome; adiposity; diabetes; short stature; insulin
We examined the relationships between insulin sensitivity (IS), skeletal muscle (SM) mass and SM quality in youth. Forty obese adolescent boys (body mass index ≥95th percentile, 12–18 years) participated in this study. IS and glucose tolerance was measured by a 3 h hyperinsulinemic–euglycemic clamp and a 2 h oral glucose tolerance test (OGTT), total SM mass and intermusular adipose tissue (IMAT) by whole-body magnetic resonance imaging, and muscular strength by one-repetition maximum leg and bench press. IMAT was associated (P<0.05) with IS (r= −0.53) and OGTT-insulin area under the curve (AUC; r=0.31). Similarly, muscular strength was associated (P<0.05) with both IS (r=0.39) and OGTT-insulin AUC (r= −0.32). By contrast, total SM mass was not associated with IS or any OGTT parameters (P>0.1). After accounting for race and tanner stage, IMAT and muscular strength remained significantly associated with IS, together explaining a total of 41% of the variance in IS. Our findings suggest that SM quality, but not SM mass, is associated with IS in obese adolescent boys.
SM mass; intermuscular adipose tissue; muscular strength; IS; childhood obesity
To assess the glucose disposition index (DI) using an oral glucose tolerance test (OGTT; oDI) compared with the DI measured from the combination of the euglycemic-hyperinsulinemic and hyperglycemic clamps (cDI) in obese pediatric subjects spanning the range of glucose tolerance.
Overweight/obese adolescents (n=185) with varying glucose tolerance (87 normal [NGT], 54 impaired [IGT], 31 with type 2 diabetes [T2DM] and 13 with type 1 diabetes [OT1DM]) completed an OGTT and both a hyperinsulinemic-euglycemic and a hyperglycemic clamp study. Indices of insulin sensitivity and β-cell function were calculated, and four different oDI estimates were calculated as the products of insulin and C-peptide-based sensitivity and secretion indices.
Mirroring the differences across groups by cDI, the oDI estimates were greatest in NGT and lowest in T2DM and OT1DM. The insulin-based oDI estimates correlated with cDI overall (r≥0.74, P<0.001) and within each glucose tolerance group (r≥0.40, P<0.001). Also, oDI and cDI predicted 2-h OGTT glucose similarly.
Oral disposition index is a simple surrogate estimate of β-cell function relative to insulin sensitivity that can be applied to obese adolescents with varying glucose tolerance in large-scale studies where the applicability of clamp studies is limited due to feasibility, cost and labor intensiveness.
disposition index; beta cell function; obesity; pediatric; insulin sensitivity
We sought to determine whether obese adolescents with high-“normal” 2-h post-oral glucose tolerance test glucose levels display defects in insulin secretion and sensitivity associated with future development of impaired glucose tolerance (IGT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and insulin secretion by applying mathematical modeling during the hyperglycemic clamp in 60 normal glucose tolerance (NGT) obese adolescents, divided into three groups based on the 2-h glucose values (<100, 100–119, 120–139 mg/dL), and in 21 IGT obese adolescents. Glucose tolerance was reevaluated after 2 years. Insulin sensitivity decreased significantly across 2-h glucose NGT categories, while the highest NGT category and IGT group were similar. First-phase insulin secretion decreased across NGT categories, while no difference was found between the highest NGT group and IGT subjects. Second-phase secretion was similar across all NGT and IGT groups. The disposition index (CDI) decreased across NGT categories, while no difference was observed between the highest NGT and IGT subjects. Age and CDI were the best predictors of 2-h glucose after two years. Across rising categories of normal 2-h glucose levels, NGT obese adolescents exhibit significant impairment of β-cell function relative to insulin sensitivity associated with the development of IGT.
Obese women with polycystic ovary syndrome (PCOS) manifest impaired insulin-stimulated release of a d-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) insulin mediator during oral glucose tolerance testing (OGTT), which appears to be restored by the administration of metformin. This suggests that either obesity or PCOS is associated with a defect in the coupling of the stimulation of the insulin receptor by insulin to the release of the DCI-IPG mediator. The objective of this study was to compare the release of bioactive DCI-IPG between normal nonobese women and obese PCOS women during stimulation with two different concentrations of insulin when glucose levels are clamped.
We performed a cross-sectional case–control study at the clinical research center of an academic medical center. A two-step euglycemic–hyperinsulinemic clamp was carried out in 8 nonobese normal and 8 obese PCOS women, during which DCI-IPG bioactivity was monitored.
At baseline, PCOS women were significantly more obese, hyperinsulinemic, and insulin resistant than the controls. During the clamp studies, DCI-IPG bioactivity increased significantly over the first 45 min of the low-insulin step of the clamp in normal nonobese women (P = 0.046) and then decreased to baseline levels; DCI-IPG increased again after initiation of the high-insulin step (P = 0.029). Despite higher insulin levels during the clamp in PCOS women, DCI-IPG bioactivity remained flat throughout both insulin steps and was thus significantly lower than in controls during the initial periods of both steps.
The coupling between insulin action and the release of the DCI-IPG mediator is selectively impaired in obese PCOS women, which may contribute to the insulin resistance in these women.
Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m2), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = −0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = −0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.
Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.
RESEARCH DESIGN AND METHODS
Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m2 per min) combined with 3-[3H] glucose infusion.
Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]).
Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.
Impaired glucose tolerance (IGT) and high body mass index (BMI) are recognized risk factors for type 2 diabetes mellitus (T2DM). However, data suggest that also underweight predisposes people to develop T2DM. Here, we experimentally tested if already moderate underweight is associated with impaired glucose tolerance as compared to normal weight controls. Obese subjects were included as additional reference group.
We included three groups of low weight, normal weight, and obese subjects comprising 15 healthy male participants each. All participants underwent a standardized hyperinsulinemic-euglycemic glucose clamp intervention to determine glucose tolerance. In addition, insulin sensitivity index (ISI) was calculated by established equation.
ISI values were higher in low and normal weight than in obese subjects (P < 0.010) without any difference between low and normal weight groups (P = 0.303). Comparable to obese participants (P = 0.178), glucose tolerance was found decreased in low weight as compared with normal weight subjects (P = 0.007). Pearson's correlation analysis revealed a positive relationship between glucose tolerance and BMI in low (P = 0.043) and normal weight subjects (P = 0.021), an effect that was found inverse in obese participants (P = 0.028).
Our study demonstrates that not only obese but also healthy people with moderate underweight display glucose intolerance. It is therefore suggested that all deviations from normal BMI may be accompanied by an increased risk of developing T2DM in later life indicating that the maintenance of body weight within the normal range has first priority in the prevention of this disease.
OBJECTIVE—Impaired glucose tolerance (IGT) represents a pre-diabetic state. Controversy continues in regards to its pathophysiology. The aim of this study was to investigate the differences in insulin sensitivity (IS) and secretion in obese adolescents with IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes.
RESEARCH DESIGN AND METHODS—A total of 12 obese adolescents with NGT, 19 with IGT, and 17 with type 2 diabetes underwent evaluation of insulin sensitivity (3-h hyperinsulinemic [80mu/m2/min]–euglycemic clamp), first-phase insulin and second-phase insulin secretion (2-h hyperglycemic clamp), body composition, and abdominal adiposity. Glucose disposition index (GDI) was calculated as the product of first-phase insulin × insulin sensitivity.
RESULTS—Insulin-stimulated glucose disposal was significantly lower in subjects with type 2 diabetes compared with subjects with NGT and IGT, with no difference between the latter two. However, compared with youth with NGT, youth with IGT have significantly lower first-phase insulin and C-peptide levels and GDI (P = 0.012), whereas youth with type 2 diabetes have an additional defect in second-phase insulin. Fasting and 2-h glucose correlated with GDI (r = −0.68, P < 0.001 and r = −0.73, P < 0.001, respectively) and first-phase insulin but not with insulin sensitivity.
CONCLUSIONS—Compared with youth with NGT, obese adolescents with IGT have evidence of a β-cell defect manifested in impaired first-phase insulin secretion, with a more profound defect in type 2 diabetes involving both first- and second-phase insulin. GDI shows a significantly declining pattern: it is highest in NGT, intermediate in IGT, and lowest in type 2 diabetes. Such data suggest that measures to prevent progression or conversion from pre-diabetes to type 2 diabetes should target improvement in β-cell function.
Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a marker of Insulin Resistance (IR). Euglycemic-hyperinsulinemic clamp is the gold standard for measuring whole body IR (hepatic + peripheral IR). However, it is an invasive and expensive procedure. Homeostasis Model Assessment Index for Insulin Sensitivity (HOMA-IS), Quantitative Insulin Sensitivity Check Index (QUICKI) for hepatic IR and Insulin Sensitivity Index (ISI0,120), and Whole Body Insulin Sensitivity Index (WBISI) for whole body IR are the indices calculated after Oral Glucose Tolerance Test (OGTT). We used these indices as noninvasive methods of IR (inverse of insulin sensitivity) estimation and compared hepatic/peripheral components of whole body IR in NAFLD. Methods. 113 morbidly obese, nondiabetic subjects who underwent gastric bypass surgery and intraoperative liver biopsy were included in the study. OGTT was performed preoperatively and the indices were calculated. Subjects were divided into closely matched groups as normal, fatty liver (FL) and Non-Alcoholic Steatohepatitis (NASH) based on histology. Results. Whole body IR was significantly higher in both FL and NASH groups (NAFLD) as compared to Normal, while hepatic IR was higher only in NASH from Normal. Conclusions. FL is a manifestation of peripheral IR but not hepatic IR.
Therapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition.
Indinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy.
Fasting glucose (4.9 ± 0.1 versus 5.2 ± 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 ± 12.2 versus 83.9 ± 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 ± 1.7 versus 15.9 ± 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 ± 0.3 versus 2.8 ± 0.5; P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 ± 0.4 versus 6.5 ± 0.6 mmol/l; P < 0.05) and insulin levels (223.1 ± 48.8 versus 390.3 ± 108.8 pmol/l; P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 ± 1.4 versus 8.6 ± 1.2 mg/kg · min per µU/ml insulin; 95% confidence interval 0.6–3.0; P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 ± 1.4 versus 15.2 ± 1.4 kg; P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography.
In the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.
HIV protease inhibitors; indinavir; insulin resistance; body composition; cholesterol; triglycerides; diabetes; lipodystrophy; HIV; AIDS
Retinoid X receptor (RXR) γ is a nuclear receptor-type transcription
factor expressed mostly in skeletal muscle, and regulated by nutritional
conditions. Previously, we established transgenic mice overexpressing
RXRγ in skeletal muscle (RXRγ mice), which showed lower blood
glucose than the control mice. Here we investigated their glucose
RXRγ mice were subjected to glucose and insulin tolerance tests, and
glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and
glucose uptake were analyzed. Microarray and bioinformatics analyses were
done. The glucose tolerance test revealed higher glucose disposal in
RXRγ mice than in control mice, but insulin tolerance test revealed no
difference in the insulin-induced hypoglycemic response. In the
hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was
higher in RXRγ mice than in control mice, indicating an
insulin-independent increase in glucose uptake. There was no difference in
the rate of glucose infusion needed to maintain euglycemia (glucose infusion
rate) between the RXRγ and control mice, which is consistent with the
result of the insulin tolerance test. Skeletal muscle from RXRγ mice
showed increased Glut1 expression, with increased glucose uptake, in an
insulin-independent manner. Moreover, we performed in vivo
luciferase reporter analysis using Glut1 promoter
(Glut1-Luc). Combination of RXRγ and PPARδ
resulted in an increase in Glut1-Luc activity in skeletal
muscle in vivo. Microarray data showed that RXRγ
overexpression increased a diverse set of genes, including glucose
metabolism genes, whose promoter contained putative PPAR-binding motifs.
Systemic glucose metabolism was increased in transgenic mice overexpressing
RXRγ. The enhanced glucose tolerance in RXRγ mice may be mediated at
least in part by increased Glut1 in skeletal muscle. These results show the
importance of skeletal muscle gene regulation in systemic glucose
metabolism. Increasing RXRγ expression may be a novel therapeutic
strategy against type 2 diabetes.
The β2-adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resistance. We examined the hypothesis that ADRB2 Arg16Gly–Gln27Glu haplotype is associated with body composition, glucose tolerance, and insulin sensitivity in obese, postmenopausal women. Obese (>35% body fat), postmenopausal (age 45–75 years) women (n = 123) underwent genotyping, dual-energy X-ray absorptiometry, and computed tomography scans, exercise testing (VO2max), 2-h oral glucose tolerance tests (OGTTs), and hyperinsulinemic–euglycemic clamps (80 mU/m2/min). Analysis of covariance (ANCOVA) tested for differences among haplotypes, with race, % body fat, and VO2max as covariates. We found that ADRB2 haplotype was independently associated with % body fat, abdominal fat distribution, VO2max, insulin sensitivity (M/ΔInsulin), and glucose tolerance (ANOVA, P < 0.05 for all). Women homozygous for Gly16–Gln27 haplotype had the highest % body fat (52.7 ± 1.9%), high abdominal fat, low M/ΔInsulin (0.49 ± 0.08 mg/kg/min/pmol/l/102), and impaired glucose tolerance (IGT) during an OGTT (G120 = 10.2 ± 0.9 mmol/l). Women homozygous for Gly16–Glu27 haplotype also had low M/ΔInsulin (0.51 ± 0.05 mg/kg/min/pmol/l/102) and IGT (G120 = 8.2 ± 0.7 mmol/l). Subjects with Arg16–Gln27/Gly16–Gln27 haplotype combination had the highest VO2max (1.84 ± 0.07 l/min) and M/ΔInsulin (0.7 ± 0.04 mg/kg/min/pmol/l/102), and normal glucose tolerance (G120 = 6.4 ± 0.4 mmol/l), despite being obese. These data show associations of the ADRB2 Arg16Gly–Gln27Glu haplotype with VO2max and body composition, and an independent association with glucose metabolism, which persists after controlling for body composition and fitness. This suggests that ADRB2 haplotypes may mediate insulin action, glucose tolerance, and potentially risk for type 2 diabetes mellitus (T2DM) in obese, postmenopausal women.
Some individuals with normal glucose tolerance (NGT) exhibit a 1-h excursion of plasma glucose during oral glucose tolerance testing as high as that of individuals with impaired glucose tolerance (IGT). The aim of this study was to characterize their metabolic phenotype.
RESEARCH DESIGN AND METHODS
A total of 1,205 healthy volunteers (aged 29–61 years) underwent assessment of 1) oral glucose tolerance and 2) insulin sensitivity (standardized euglycemic-hyperinsulinemic clamp), as part of the Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study.
One-hour plasma glucose correlated better than 2-h plasma glucose with total insulin secretion (r = 0.43), β-cell glucose sensitivity (r = −0.46), and β-cell rate sensitivity (r = −0.18). Receiver operating characteristic analysis identified 8.95 mmol/l as the best cutoff value for prediction of IGT from 1-h plasma glucose (sensitivity 77% and specificity 80%). Participants with NGT with 1-h plasma glucose >8.95 mmol/l had larger waist circumference, higher BMI, lower insulin sensitivity, higher fasting glucose, and higher insulin secretion than their counterparts with 1-h plasma glucose ≤8.95 mmol/l (P < 0.001 for all comparisons). Moreover, they exhibited lower β-cell glucose sensitivity (P < 0.001), β-cell rate sensitivity (P < 0.001), and potentiation factor (P = 0.026). When compared with conventionally defined IGT, they were not different in waist circumference and BMI, hepatic insulin extraction, β-cell glucose sensitivity, β-cell rate sensitivity, and potentiation factor but did have greater insulin sensitivity along with reduced basal (P = 0.001) and total insulin secretion (P = 0.002).
Higher values of 1-h plasma glucose may identify an intermediate condition between NGT and IGT characterized by greater insulin resistance, reduced β-cell glucose sensitivity, and reduced β-cell rate sensitivity.
Obese African-American (AA) subjects have higher resting and stimulated insulin concentrations than obese Caucasians (C), which could not be explained by the severity of obesity or the degree of insulin sensitivity. We investigated whether differences in glucagon-like peptide-1 (GLP-1), the most potent incretin that regulates insulin secretion, might explain racial differences in insulin response. Accordingly, we measured fasting and stimulated glucose, insulin, and GLP-1 levels during a 3-h oral glucose tolerance test (OGTT) in 26 obese C (age 38 ± 2 y, body mass index 44 ± 1 kg/m2) and 16 obese AA (age 36 ± 2 y, BMI 46 ± 2 kg/m2) subjects. Corrected insulin response (CIR30), a measure of β-cell activity, whole body insulin sensitivity index (WBISI), and area under the curve (AUC) for insulin, GLP-1, and C-peptide/insulin ratio were computed from the OGTT.
Glucose levels, fasting and during the OGTT, were similar between racial groups; 32% of the C and 31% of the AA subjects had impaired glucose tolerance. With a similar WBISI, AAs had significantly higher CIR30 (2.3 ± 0.4 vs 1.01 ± 0.1), insulin response (IAUC: 23 974 ± 4828 vs 14 478 ± 1463), and lower insulin clearance (0.07 ± 0.01 vs 0.11 ± 0.01) than C (all, P<0.01). Obese AAs also had higher fasting GLP-1 (6.7 ± 2.5 vs 4.5 ± 1.1) and GLP-1AUC (1174.7 ± 412 vs 822.4 ± 191) than C (both, P<0.02). Our results indicate that obese AAs had higher concentrations of GLP-1 both at fasting and during the OGTT than obese C. The increased GLP-1 concentration could explain the greater insulin concentration and the increased prevalence of hyperinsulinemia-associated disorders including obesity and type 2 diabetes in AAs.
GLP-1; insulin; racial; β-cell activity
To analyze insulin resistance (IR) and determine the need for a 2-hour oral glucose tolerance test (OGTT) for the identification of IR and impaired glucose tolerance (IGT) in lean nondiabetic women with polycystic ovary syndrome (PCOS).
This was a cross-sectional analysis of treatment-naive women with PCOS who enrolled in a university-based clinical trial. Nondiabetic women with PCOS based on the Eunice Kennedy Shriven National Institute of Child Health and Human Development (NICHD) definition, aged 18–43 years and weighing ≤113 kg, were evaluated. Glucose and insulin levels were assessed at times 0, 30, 60, 90, and 120 minutes after a 75-g glucose load. Lean was defined as body mass index (BMI) <25 kg/m2. Multiple linear regression was performed.
A cohort of 78 women was studied. The prevalence of IR was 0% among lean women vs. 21% among nonlean subjects based on fasting insulin I0 and 40%–68% based on two different homeostatic model assessment (HOMA) cutoff points (p < 0.005). All women with IR had a BMI ≥ 28. Controlling for age and race, BMI explained over 57% of the variation in insulin fasting (Io), glucose fasting/Io (Go/Io), the qualitative insulin sensitivity check index (QUICKI), and HOMA and was a highly significant predictor of these outcomes (p < 0.0001). Only 1 of 31 (3%) of the lean PCOS women had IGT based on a 2-hour OGTT, and no lean subjects had IGT based on their fasting blood glucose.
Diabetes mellitus, IGT, and IR are far less common in young lean women with PCOS compared with obese women with PCOS. These data imply that it is unnecessary to routinely perform either IR testing or 2-hour OGTT in lean women with PCOS; however, greater subject accumulation is needed to determine if OGTT is necessary in lean women with PCOS. BMI is highly predictive of both insulin and glucose levels in women with PCOS.
The E23K variant in the Kir6.2 subunit of the ATP-sensitive K+ channel (KATP channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance.
RESEARCH DESIGN AND METHODS
Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope–labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted.
Insulin secretory responses to oral and intravenous glucose were reduced by ∼40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is ∼40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion.
The E23K variant leads to overactivity of the KATP channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes.