Adipose tissue insulin resistance in children and adolescents: linking glucose and free fatty acid metabolism to hepatic injury markers.

Resveratrol Supplementation Does Not Improve Metabolic Function in Nonobese Women with Normal Glucose Tolerance

Adipocyte Insulin Resistance Index in Youth along the Span of Glycemia from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D)

Adipose tissue insulin resistance is one of the pathophysiological components of type 2 diabetes. Herein we investigated: 1) adipose insulin resistance index (Adipose-IR) (calculated as fasting insulin × free fatty acids [FFAs]) in youth across the spectrum of adiposity from normal weight to obese and the spectrum from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes, 2) the relationship of Adipose-IR with physical and metabolic characteristics, and 3) the predictive power of Adipose-IR for determining dysglycemia in youth. A total of 205 youth had fasting glucose, insulin, FFA, Adipose-IR, body composition, visceral adipose tissue (VAT), leptin, and adiponectin evaluated. Adipose-IR was 2.2-fold higher in obese NGT, 4.3-fold higher in IGT, and 4.6-fold higher in type 2 diabetes compared with that in normal-weight peers (all P < 0.05). Females with dysglycemia (IGT and type 2 diabetes) had higher Adipose-IR than their male counterparts (P < 0.001). Adipose-IR correlated positively with total body and visceral adiposity, fasting glucose, HOMA-IR, and leptin and negatively with adiponectin. Receiver operating characteristic curve analysis yielded an optimal cutoff for Adipose-IR of 9.3 μU/mL × mmol/L for determining dysglycemia with 80% predictive power. Adipose-IR is a simple surrogate estimate that reflects pathophysiological alterations in adipose tissue insulin sensitivity in youth, with progressive deterioration from normal weight to obese and from NGT to IGT to type 2 diabetes. Adipose-IR can be applied in large-scale epidemiological/observational studies of the natural history of youth-onset type 2 diabetes and its progression or reversal with intervention strategies.

Islet dysfunction in obese women with impaired glucose tolerance

Lifestyle intervention is effective in the prevention of type 2 diabetes in individuals with impaired glucose tolerance (IGT). It is currently unknown whether it has beneficial effects on metabolism to a similar extent, in individuals with normal glucose tolerance (NGT) compared to individuals with IGT. Data from 181 subjects (133 with NGT and at risk for type 2 diabetes and 48 with IGT) who participated in the Tuebingen Lifestyle Intervention Program with increase in physical activity and decrease in caloric intake were included into this study. Body fat distribution was quantified by whole-body magnetic resonance (MR) tomography and liver fat and intramyocellular fat by (1)H-MR spectroscopy. Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT). After 9 +/- 2 months of follow-up, the diagnosis of IGT was reversed in 24 out of 48 individuals. Only 14 out of 133 participants with NGT developed IGT. Body weight decreased in both groups by 3% (both P < 0.0001). Two-hour glucose concentrations during an OGTT decreased in individuals with IGT (-14%, P < 0.0001) but not with NGT (+2%, P = 0.66). Insulin sensitivity increased both in individuals with IGT (+9%, P = 0.04) and NGT (+17%, P < 0.0001). Visceral fat (-8%, P = 0.006), liver fat (-28%, P < 0.0001) and intramyocellular fat (-15%, P = 0.006) decreased in participants with IGT. In participants with NGT these changes were significant for visceral fat (-16%, P < 0.0001) and liver fat (-35%, P < 0.0001). Moderate weight loss under a lifestyle intervention with reduction in total, visceral and ectopic fat and increase in insulin sensitivity improves glucose tolerance in individuals with IGT but not with NGT. In individuals with NGT, the beneficial effects of a lifestyle intervention on fat distribution and insulin sensitivity possibly prevent future deterioration in glucose tolerance.

Recent evidence suggests possible linkage between diabetes mellitus and mitochondrial gene mutation. We surveyed mitochondrial tRNALEU(UUR) (3243) mutation in 7 mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) families and identified 24 mutated subjects (7 MELAS probands and 17 non-MELAS relatives) as well as 11 non-mutant family members. An OGTT in the 24 mutant relatives revealed 14 diabetic subjects, 3 with impaired glucose tolerance and 7 with normal glucose tolerance and all non-mutant family members as having normal glucose tolerance. Insulinogenic index was significantly reduced in the mutant diabetic subjects and those with impaired and normal glucose tolerance in comparison with the normal control subjects and the non-mutant members. Urinary 24-h C-peptide immunoreactivity excretion was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance, compared with the control subjects and the non-mutant family members. Plasma C-peptide immunoreactivity 6 min after glucagon injection was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance compared with the control subjects and the non-mutant family members. Si, an index of insulin sensitivity of the four mutant subjects was within normal range. Islet cell antibodies were negative in sera of eight mutated diabetic subjects, 2 and 6 with impaired and normal glucose tolerance, respectively. Diabetic retinopathy and nephropathy were demonstrated in 7 (50%) and 12 (85.7%) of 14 mutant diabetic subjects, respectively. Neurosensory deafness was demonstrated in 12 (85.7%) of 14 mutated diabetic subjects, (66.7%) of 3 mutated impaired glucose tolerant subjects, but not detected in 6 mutated normal glucose tolerant subjects and 11 non-mutant family members. These findings suggest that the tRNALEU(UUR) mutation is associated with pancreatic beta-cell secretory defect of insulin.

Recent evidence suggests possible linkage between diabetes mellitus and mitochondrial gene mutation. We surveyed mitochondrial tRNA(LEU(UUR)) (3243) mutation in 7 mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) families and identified 24 mutated subjects (7 MELAS probands and 17 non-MELAS relatives) as well as 11 non-mutant family members. An OGTT in the 24 mutant relatives revealed 14 diabetic subjects, 3 with impaired glucose tolerance and 7 with normal glucose tolerance and all non-mutant family members as having normal glucose tolerance. Insulinogenic index was significantly reduced in the mutant diabetic subjects and those with impaired and normal glucose tolerance in comparison with the normal control subjects and the non-mutant members. Urinary 24-h C-peptide immunoreactivity excretion was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance, compared with the control subjects and the non-mutant family members. Plasma C-peptide immunoreactivity 6 min after glucagon injection was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance compared with the control subjects and the non-mutant family members. Si, an index of insulin sensitivity of the four mutant subjects was within normal range. Islet cell antibodies were negative in sera of eight mutated diabetic subjects, 2 and 6 with impaired and normal glucose tolerance, respectively. Diabetic retinopathy and nephropathy were demonstrated in 7 (50%) and 12 (85.7%) of 14 mutant diabetic subjects, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose Tolerance and Cardiovascular Risk in Young Adult African Americans

Approximately 25 years ago, our research group1 2 used quantitative methods to show that resistance to insulin-mediated glucose disposal was present in patients with either impaired glucose tolerance or NIDDM. These initial observations have been confirmed on multiple occasions since then, and there is now a large body of evidence that shows that this defect is present in the vast majority of glucose-intolerant individuals.3 4 5 6 7 8 In addition, several reports9 10 11 demonstrated that first-degree relatives of patients with NIDDM are also relatively insulin resistant compared with well-matched volunteers without a family history of NIDDM. Finally, prospective studies12 13 14 15 16 have identified insulin resistance and/or compensatory hyperinsulinemia as the initial defect in the development of NIDDM. Thus, the central role of insulin resistance in the pathogenesis and clinical course of patients with NIDDM has been well established. Of greater relevance to the IRAS study of “Insulin Sensitivity and Atherosclerosis” published in this issue of Circulation 17 is recent awareness that the ability of insulin to mediate glucose disposal can differ by as much as 10-fold in subjects with normal glucose tolerance.18 19 Because the degree of insulin resistance in a substantial portion of these persons approaches that seen in patients with impaired glucose tolerance or NIDDM, it is assumed that they are able to secrete enough insulin to overcome the insulin resistance and maintain normal glucose tolerance. Unfortunately, the philanthropic response on the part of the pancreatic β-cell is not without cost, and in 1988,20 it was emphasized that these individuals were at increased risk to have higher plasma TG and lower HDL cholesterol concentrations and higher blood pressure. More importantly, it was suggested that the cluster of abnormalities associated with insulin resistance, designated as Syndrome X, significantly increased …

To determine the association between the hypertriglyceridaemic waist phenotype, a combination of enlarged waist circumference and increased triglyceride levels, and β-cell function in subjects with normal glucose tolerance and those with impaired glucose tolerance. We studied 1344 outpatients clinic without diabetes. Overnight fasting blood samples were obtained to measure plasma glucose, insulin and lipids. An oral glucose tolerance test was performed in all subjects. All patients were divided in four groups, two groups with normal glucose tolerance and two with impaired glucose tolerance, with or without the hypertriglyceridaemic waist phenotype. Insulin resistance and β-cell function were calculated by homeostatsis model assessment 2 indices. Twenty per cent of subjects showed the hypertriglyceridaemic waist phenotype and 23.8% had impaired glucose tolerance. We found a progressive significant increase (P < 0.001) of insulin resistance from subjects with normal glucose tolerance without the hypertriglyceridaemic waist phenotype with respect to patients with impaired glucose tolerance with the hypertriglyceridaemic waist phenotype. In subjects with normal glucose tolerance, the hypertriglyceridaemic waist phenotype was associated with a mild, but not significant, increase of homeostatsis model assessment 2-β levels; but, in patients with impaired glucose tolerance, the hypertriglyceridaemic waist phenotype was associated with significantly lower homeostatsis model assessment 2-β levels [127.0 (103.0-162.7) vs. 123.0 (96.0-147.0); P < 0.05]. The hypertriglyceridaemic waist phenotype displayed a higher (odds ratio 95% CI) β-cell dysfunction of 1.8 (1.3-2.6) and insulin resistance of 5.0 (2.7-8.5) compared with 1.3 (0.9-1.9) and 2.4 (1.8-3.2), respectively, of waist circumference alone. In this study, the hypertriglyceridaemic waist phenotype is associated with increased insulin resistance and an overstimulation of β-cell function in subjects with normal glucose tolerance, while patients with impaired glucose tolerance with the hypertriglyceridaemic waist phenotype showed a reduction in β-cell function. These data suggest the importance of the identification of patients with impaired glucose tolerance combined with the hypertriglyceridaemic waist phenotype for an early intervention in relation to the high risk of developing Type 2 diabetes.

Diabetes mellitus in patients with thalassaemia major is caused by secondary haemochromatosis due to transfusional iron overload. The pathogenetic mechanisms leading from siderosis to diabetes are still poorly understood. This study aimed at assessing the influence of insulin resistance and insulin deficiency on that process. Glucose, insulin and C-peptide levels during oral glucose tolerance tests (OGTT) from 36 thalassaemic patients with normal ( n=23), impaired ( n=6), or diabetic glucose tolerance ( n=7) and 32 control subjects were examined. Insulin secretion and insulin sensitivity were assessed by established calculated indices. Fasting, 2h and integrated glucose concentration were significantly increased in thalassaemic patients with normal glucose tolerance compared to controls (5.01/4.59 mmol/l, 6.33/5.17 mmol/l, and 844.2/739.3 mmol/l per min, respectively; all P<0.03). Patients with impaired glucose tolerance presented hyperinsulinaemia and delayed peak insulin during OGTT. The C-peptide/insulin ratio was decreased in patients with abnormal glucose tolerance compared to controls (5.85/7.33 x 10(3)pmol/l per min, P<0.03). It was negatively correlated with age in patients ( r=-0.45, P<0.01), but positively in controls ( r=0.43, P<0.03). Insulin sensitivity was significantly reduced in patients with impaired glucose tolerance or diabetes compared to controls. In addition, a significant decrease in patients with normal glucose tolerance was shown by two insulin sensitivity indices (all P<0.05). In thalassaemia patients, insulin sensitivity was negatively correlated with age. Insulin secretion capacity according to the homeostasis assessment model was significantly reduced in patient groups compared to controls (Kruskal-Wallis-test, P<0.004). Insulin resistance is of central importance for the development of diabetes mellitus in patients with secondary haemochromatosis. An additional early defect in beta-cell secretion cannot be excluded.

Current mathematical models of postprandial glucose metabolism in people with normal and impaired glucose tolerance rely on insulin measurements and are therefore not applicable in clinical practice. This research aims to develop a model that only requires glucose data for parameter estimation while also providing useful information on insulin sensitivity, insulin dynamics and the meal-related glucose appearance (GA). The proposed glucose-only model (GOM) is based on the oral minimal model (OMM) of glucose dynamics and substitutes the insulin dynamics with a novel function dependant on glucose levels and GA. A Bayesian method and glucose data from 22 subjects with normal glucose tolerance are utilised for parameter estimation. To validate the results of the GOM, a comparison to the results of the OMM, obtained by using glucose and insulin data from the same subjects is carried out. The proposed GOM describes the glucose dynamics with comparable precision to the OMM with an RMSE of 5.1 ± 2.3 mg/dL and 5.3 ± 2.4 mg/dL, respectively and contains a parameter that is significantly correlated to the insulin sensitivity estimated by the OMM (r = 0.7) Furthermore, the dynamic properties of the time profiles of GA and insulin dynamics inferred by the GOM show high similarity to the corresponding results of the OMM. The proposed GOM can be used to extract useful physiological information on glucose metabolism in subjects with normal glucose tolerance. The model can be further developed for clinical applications to patients with impaired glucose tolerance under the use of continuous glucose monitoring data.

See article in J. Gastroenterol. Hepatol. 2010; 25: 1687–1691.

Abnormal glucose tolerance in cystic fibrosis: Why should patients be screened?

Objective To evaluate clinical features,insulin sensitivity and β-cell function of pregnant women with different glucose tolerance status,so as to identify the possible risk factors for adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM).Methods We retrospectively analyzed the clinical data of 360 pregnant women with positive results of 50 g glucose challenge test who received antenatal care and admitted for delivery in the period from January 2009 to June 2012 in Peking Union Medical College Hospital.According to the result of 100 g oral glucose tolerance test (OGTT),the 360 women were divided into GDM group (n =83),impaired glucose tolerance (IGT) group (n =75),and normal glucose tolerance (NGT) group (n =202).The blood glucose level in all those women was controlled in normal range for gestational period.We compared the general clinical data,biochemical indexes,insulin resistance index,insulin sensitivity index,function index of islet β-cell,first-and second-phase insulin secretion,insulin secretion-sensitivity index as well as the pregnancy outcomes of the 3 groups,analyzing the possible risk factors for adverse pregnancy outcomes in women with GDM.Results Compared with the NGT group,the pregnant women in GDM group were older [(33.1 ± 3.7) years vs.(31.7 ± 3.4) years,P =0.008],had higher systolic blood pressure [(115.8 ± 9.7) mmHg vs.(111.4 ± 13.5) mmHg (1 mmHg =0.133 kPa),P =0.031] and diastolic blood pressure in first trimester [(75.4 ±9.0) mmHg vs.(71.8 ±8.8) mmHg,P =0.010],higher positive rate of family history of diabetes in first-degree relatives (37.3％ vs.22.3％,P =0.012),positive rate of insulin therapy (10.8％ vs.0％,P =0.001),serum triglyceride level [(2.8 ±0.9) mmol/L vs.(2.3 ±0.9) mmol/L,P =0.001],free fatty acid level [(486.7 ± 137.6) μmol/L vs.(438.1 ± 140.7) μmol/L,P =0.033],and C-reactive protein level [(5.7 ± 4.3) mg/L vs.(3.6 ± 3.0) mg/L,P =0.001].The GDM group had a larger pre-pregnancy body mass index [(22.6 ± 2.9) kg/m2] than that in IGT group [(21.3 ± 2.7) kg/m2] (P =0.049) and NGT group [(21.2 ±2.8) kg/m2] (P =0.003).In the order from NGT to IGT to GDM group,the hemoglobin A1c [(5.2 ± 0.3) ％ vs.(5.3 ± 0.3) ％ vs.(5.4 ± 0.3) ％,P =0.001,P =0.007],the areas under curve of glucose [(20.4±2.0) mmol · h/L vs.(22.9 ± 1.5) mmol · h/L vs.(26.9 ±2.1) mmol · h/L,both P=0.001] and the areas under curve of insulin [(1.7 ±0.9) × 103 pmol · h/L vs.(2.1 ± 1.1) × 103 pmol · h/L vs.(2.7±1.3) ×103 pmol · h/L,P=0.001,P=0.007] increased gradually,while insulin sensitivity index (88.1 ± 52.1 vs.80.0 ± 30.6 vs.50.0 ± 24.1,P =0.001,P =0.014) and insulin secretion-sensitivity index (134 507.0 ± 43 291.0 vs.102 542.0 ± 15 291.0 vs.77 582.0 ± 20 764.0,both P =0.001) decreased gradually.The insulin resistance index in the GDM group (3.3 ± 2.2) was significantly higher than that in IGT (2.2 ± 1.0) and NGT groups (3.0 ± 1.1) (both P =0.001).The function of β-cell,first-and second-phase insulin secretion were not significantly different among the 3 groups.Compared with the NGT group,pregnant women with GDM had shorter gestational age [(38.8 ± 1.1) weeks vs.(39.4 ± 1.1) weeks,P=0.004] and higher incidence of adverse pregnancy outcomes (44.6％ vs.21.8％,P =0.001).Seven risk factors predicting adverse pregnancy outcomes in women with GDM were identified,including pre-pregnancy body mass index (P=0.017),0-,1-,and 2-hour blood glucose in 100 g OGTT (P=0.036,P=0.009,P=0.004),3-hour insulin (P =0.014),and hemoglobin A1 c (P =0.002) and C-reactive protein (P =0.005) in second trimester,among which 1-hour blood glucose displayed the highest coefficient (OR =2.767).Conclusions Pregnant women with GDM have elevated blood pressure,dyslipidemia and increased inflammatory cytokine C-reactive protein.Women with GDM and IGT both show insulin resistance and β-cell dysfunction,and these impairments are more severe in women with GDM.Higher pre-pregnancy body mass index and blood glucose levels during pregnancy are associated with adverse pregnancy outcomes in women with GDM. Key words: Gestational diabetes mellitus ; Insulin sensitivity ; Islet β-cell function ; Adverse pregnancy outcomes