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1.  Performance of HbA1c as an Early Diagnostic Indicator of Type 1 Diabetes in Children and Youth 
Diabetes Care  2012;35(9):1821-1825.
The aim of this study was to evaluate HbA1c as an alternative criterion for impaired glucose tolerance (IGT) or type 1 diabetes (T1D) in high-risk subjects <21 years of age.
Subjects <21 years of age who participated in the prospective DPT-1, TEDDY, TRIGR, and Type 1 Diabetes TrialNet Natural History (TrialNet) studies and had an HbA1c within 90 days of an OGTT with a 2-h plasma glucose (2-hPG) measure were included. An OGTT of 140–199 mg/dL defined IGT, and an OGTT with 2-hPG ≥200 mg/dL or fasting plasma glucose ≥126 mg/dL defined diabetes. HbA1c ≥5.7% defined IGT, and HbA1c ≥ 6.5% defined diabetes. Receiver-operating characteristic curve analysis was used to assess diagnostic accuracy of HbA1c compared with OGTT.
There were 587 subjects from DPT-1, 884 from TrialNet, 91 from TEDDY, and 420 from TRIGR. As an indicator for IGT, HbA1c sensitivity was very low across the studies (8–42%), and specificity was variable (64–95%). With HbA1c ≥6.5% threshold used for T1D diagnosis, the sensitivity was very low and specificity was high (sensitivity and specificity: DPT-1 24 and 98%, TrialNet 28 and 99%, TEDDY 34 and 98%, and TRIGR 33 and 99%, respectively). The positive predictive value of HbA1c ≥6.5% for the development of T1D was variable (50–94%) across the four studies.
HbA1c ≥6.5% is a specific but not sensitive early indicator for T1D in high-risk subjects <21 years of age diagnosed by OGTT or asymptomatic hyperglycemia. Redefining the HbA1c threshold is recommended if used as an alternative criterion in diagnosing T1D.
PMCID: PMC3425003  PMID: 22699293
2.  Type 2 Diabetes Can Be Prevented With Early Pharmacological Intervention 
Diabetes Care  2011;34(Suppl 2):S202-S209.
In the U.S., ∼21 × 106 individuals have type 2 diabetes, and twice as many have impaired glucose tolerance (IGT). Approximately 40–50% of individuals with IGT will progress to type 2 diabetes over their lifetime. Therefore, treatment of high-risk individuals with IGT to prevent type 2 diabetes has important medical, economic, social, and human implications. Weight loss, although effective in reducing the conversion of IGT to type 2 diabetes, is difficult to achieve and maintain. Moreover, 40–50% of IGT subjects progress to type 2 diabetes despite successful weight reduction. In contrast, pharmacological treatment of IGT with oral antidiabetic agents that improve insulin sensitivity and preserve β-cell function—the characteristic pathophysiological abnormalities present in IGT and type 2 diabetes—uniformly have been shown to prevent progression of IGT to type 2 diabetes. The most consistent results have been observed with the thiazolidinediones (Troglitazone in the Prevention of Diabetes [TRIPOD], Pioglitazone in the Prevention of Diabetes [PIPOD], Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication [DREAM], and Actos Now for the Prevention of Diabetes [ACT NOW]), with a 50–70% reduction in IGT conversion to diabetes. Metformin in the U.S. Diabetes Prevention Program (DPP) reduced the development of type 2 diabetes by 31% and has been recommended by the American Diabetes Association (ADA) for treating high-risk individuals with IGT. The glucagon-like peptide-1 analogs, which augment insulin secretion, preserve β-cell function, and promote weight loss, also would be expected to be efficacious in preventing the progression of IGT to type 2 diabetes. Because individuals in the upper tertile of IGT are maximally/near-maximally insulin resistant, have lost 70–80% of their β-cell function, and have an ∼10% incidence of diabetic retinopathy, pharmacological intervention, in combination with diet plus exercise, should be instituted.
PMCID: PMC3632162  PMID: 21525456
3.  Risk factors for impaired glucose tolerance in obese children and adolescents 
World Journal of Diabetes  2010;1(4):129-134.
AIM: To investigate which obese children have an increased risk for impaired glucose tolerance (IGT), a risk factor for later diabetes.
METHODS: We studied 169 European untreated obese children and adolescents with normal glucose tolerance at baseline. Waist circumference, fasting glucose, lipids, blood pressure, pubertal stage, 2 h glucose in oral glucose tolerance test (oGTT), and HbA1c were determined at baseline and 1 year later.
RESULTS: One year after baseline, 19 (11.2%) children demonstrated IGT, 4 (2.4%) children had impaired fasting glucose, no (0%) child suffered from diabetes, and 146 (86%) children still showed normal glucose tolerance. At baseline, the children with IGT and with normal glucose tolerance in a one-year follow-up did not differ significantly in respect of any analyzed parameter, apart from pubertal stage. The children developing IGT entered puberty significantly more frequently (37% vs 3%, P < 0.001). One year after baseline, the children with IGT demonstrated significantly increased waist circumference, blood pressure values, insulin and triglyceride concentrations, and insulin resistance index HOMA. The children remaining in the normal glucose tolerance status 1 year after baseline did not demonstrate any significant changes.
CONCLUSION: During the study period of 1 year, more than 10% of the obese children with normal glucose tolerance converted to IGT. Repeated screening with oGTT seems meaningful in obese children entering puberty or demonstrating increased insulin resistance, waist circumference, blood pressure, or triglyceride concentrations.
PMCID: PMC3083893  PMID: 21537438
Impaired glucose tolerance; Risk factors; Lipids; Blood pressure; Pubertal stage; Waist circumference
4.  Urinary N-acetyl-β-d-Glucosaminidase Levels are Positively Correlated With 2-Hr Plasma Glucose Levels During Oral Glucose Tolerance Testing in Prediabetes 
Urinary N-acetyl-β-D-glucosaminidase (NAG) excretion is increased in patients with impaired glucose tolerance (IGT). This study investigated when during the oral glucose tolerance test (OGTT) the plasma glucose, urine glucose, and insulin levels correlate most strongly with urinary N-acetyl-β-d-glucosaminidase (NAG) levels in prediabetic subjects.
The OGTT was administered to 80 subjects who had not yet received a diagnosis of diabetes mellitus (DM) and in whom HbA1c levels were ≤6.8% and fasting plasma glucose levels were <7.0 mmol/l. Forty-two subjects had normal glucose tolerance (NGT), 31 had impaired glucose tolerance (IGT), and 7 had DM according to World Health Organization criteria. Serum levels of cystatin C, the estimated glomerular filtration rate, the urinary albumin-to-creatinine (Cr) ratio, urinary and serum β2-microglobulin, and urinary NAG were measured as markers of renal function.
NAG levels were significantly higher in subjects with DM and in subjects with IGT than in subjects with NGT. No significant associations were observed between glycemic status and other markers of renal function. Multiple linear regression analysis showed that the NAG level was positively correlated with plasma glucose levels at 120 min of the OGTT and was associated with the glycemic status of prediabetic patients.
These results suggest that postprandial hyperglycemia is an independent factor that causes renal tubular damage in prediabetes patients.
PMCID: PMC3558795  PMID: 23143631
cystatin C; N-acetyl-β-d-glucosaminidase; tubular dysfunction; impaired glucose tolerance; diabetic nephropathy
5.  Insulin secretion and sensitivity during oral glucose tolerance test in Korean lean elderly women. 
Journal of Korean Medical Science  2001;16(5):592-597.
Impaired glucose tolerance (IGT) and type 2 diabetes including undiagnosed isolated postchallenge hyperglycemia (IPH) are common in the elderly. The aim of this study was to investigate the insulin secretion and sensitivity in Korean elderly lean diabetic women. Forty-one lean women aged 65-88 years took 2 hr oral glucose tolerance test (OGTT) and were stratified according to the WHO criteria (normal glucose tolerance [NGT], n=20; IGT, n=6; and type 2 diabetics, n=15 including seven IPH). HbA1c and fructosamine progressively increased from the NGT to the diabetic subjects (p=0.006 and p=0.001, respectively). Compared with subjects with NGT, the insulinogenic index, a marker of early insulin secretion and the AUC(ins), a marker of total insulin secretion, decreased significantly in diabetic group [0.53 (-0.44 -1.45) vs. 0.18 (0.00 -1.11), p=0.03 and 306+/-165 vs. 199+/-78 pmol/L, p=0.02 respectively]. A significant difference was found in the AUC(c-peptide) among each group (221+/-59 vs. 206+/-34 vs. 149+/-51 pmol/L, p=0.001 for each). The homeostasis model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, was not different among the groups. We conclude that compared with NGT subjects, elderly lean women with diabetes have impaired oral glucose-induced insulin secretion but have relatively preserved insulin sensitivity. This suggests that insulin resistance is not necessarily an essential component of Korean elderly lean diabetic women.
PMCID: PMC3057583  PMID: 11641528
6.  Pioglitazone Improves In Vitro Viability and Function of Endothelial Progenitor Cells from Individuals with Impaired Glucose Tolerance 
PLoS ONE  2012;7(11):e48283.
Evidence suggests that the PPARγ-agonist insulin sensitizer pioglitazone, may provide potential beneficial cardiovascular (CV) effects beyond its anti-hyperglycaemic function. A reduced endothelial progenitor cell (EPC) number is associated with impaired glucose tolerance (IGT) or diabetes, conditions characterised by increased CV risk.
To evaluate whether pioglitazone can provide benefit in vitro in EPCs obtained from IGT subjects.
Materials and Methods
Early and late-outgrowth EPCs were obtained from peripheral blood mononuclear cells of 14 IGT subjects. The in vitro effect of pioglitazone (10 µM) with/without PPARγ-antagonist GW9662 (1 µM) was assessed on EPC viability, apoptosis, ability to form tubular-like structures and pro-inflammatory molecule expression.
Pioglitazone increased early and late-outgrowth EPC viability, with negligible effects on apoptosis. The capacity of EPCs to form tubular-like structures was improved by pioglitazone in early (mean increase 28%; p = 0.005) and late-outgrowth (mean increase 30%; p = 0.037) EPCs. Pioglitazone reduced ICAM-1 and VCAM-1 adhesion molecule expression in both early (p = 0.001 and p = 0.012 respectively) and late-outgrowth (p = 0.047 and p = 0.048, respectively) EPCs. Similarly, pioglitazone reduced TNFα gene and protein expression in both early (p = 0.034;p = 0.022) and late-outgrowth (p = 0.026;p = 0.017) EPCs compared to control. These effects were prevented by incubation with the PPARγ-antagonist GW9662.
Pioglitazone exerts beneficial effects in vitro on EPCs isolated from IGT subjects, supporting the potential implication of pioglitazone as a CV protective agents.
PMCID: PMC3489677  PMID: 23139771
7.  Skin Autofluorescence Based Decision Tree in Detection of Impaired Glucose Tolerance and Diabetes 
PLoS ONE  2013;8(6):e65592.
Diabetes (DM) and impaired glucose tolerance (IGT) detection are conventionally based on glycemic criteria. Skin autofluorescence (SAF) is a noninvasive proxy of tissue accumulation of advanced glycation endproducts (AGE) which are considered to be a carrier of glycometabolic memory. We compared SAF and a SAF-based decision tree (SAF-DM) with fasting plasma glucose (FPG) and HbA1c, and additionally with the Finnish Diabetes Risk Score (FINDRISC) questionnaire±FPG for detection of oral glucose tolerance test (OGTT)- or HbA1c-defined IGT and diabetes in intermediate risk persons.
Participants had ≥1 metabolic syndrome criteria. They underwent an OGTT, HbA1c, SAF and FINDRISC, in adition to SAF-DM which includes SAF, age, BMI, and conditional questions on DM family history, antihypertensives, renal or cardiovascular disease events (CVE).
218 persons, age 56 yr, 128M/90F, 97 with previous CVE, participated. With OGTT 28 had DM, 46 IGT, 41 impaired fasting glucose, 103 normal glucose tolerance. SAF alone revealed 23 false positives (FP), 34 false negatives (FN) (sensitivity (S) 68%; specificity (SP) 86%). With SAF-DM, FP were reduced to 18, FN to 16 (5 with DM) (S 82%; SP 89%). HbA1c scored 48 FP, 18 FN (S 80%; SP 75%). Using HbA1c-defined DM-IGT/suspicion ≥6%/42 mmol/mol, SAF-DM scored 33 FP, 24 FN (4 DM) (S76%; SP72%), FPG 29 FP, 41 FN (S71%; SP80%). FINDRISC≥10 points as detection of HbA1c-based diabetes/suspicion scored 79 FP, 23 FN (S 69%; SP 45%).
SAF-DM is superior to FPG and non-inferior to HbA1c to detect diabetes/IGT in intermediate-risk persons. SAF-DM’s value for diabetes/IGT screening is further supported by its established performance in predicting diabetic complications.
PMCID: PMC3672176  PMID: 23750268
8.  Correlation Between Prediabetes Conditions and Microalbuminuria 
Nephro-urology Monthly  2013;5(2):741-744.
Impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) are two prediabetes conditions which have some correlation with macrovascular disorders. The risk of microvascular complications in these groups is not clear.
The prevalence of albuminuria in subjects with IFG and IGT was evaluated in the present study.
Patients and Methods
In this study three groups of subjects were entered (45 subjects in each group): IFG, IGT, and normal glucose tolerance as control. The urine albumin-creatinine ratio was studied in morning spot urine samples to detect microalbuminuria. The subjects were followed up for two years, and blood sugar and urine albumin and glycosylated hemoglobin (HbA1C) were measured every 6 months.
The prevalence rate of microalbuminuria was 15.5% in the prediabetic groups, while no one had microalbuminuria in the control group (P = 0.005). The prevalence of microalbuminuria in patients with IFG or IGT was not significantly different (17.8% vs. 13.3%) (P = 0.4). Fourteen subjects (4 in IFG group and 10 in IGT group) developed diabetes mellitus within a 2-year follow-up period (P = 0.1). Thirty six percent of subjects with albuminuria, and twelve percent of subjects without albuminuria progressed to diabetes mellitus during a 2-year follow-up (P = 0.02, odd ratio = 4.1; CI95%, 1.13-15.1).
The risk of microalbuminuria in prediabetic subjects is high, and probably prediabetic subjects are at higher risk of progression to diabetes mellitus. We suggest periodically evaluation of albuminuria in prediabetic patients after the diagnosis.
PMCID: PMC3703132  PMID: 23841037
Glucose Tolerance; Diabetic Nephropathies; Diabetes Mellitus, Type 2
9.  The rs1142345 in TPMT Affects the Therapeutic Effect of Traditional Hypoglycemic Herbs in Prediabetes 
Therapeutic interventions in prediabetes are important in the primary prevention of type 2 diabetes (T2D) and its chronic complications. However, little is known about the pharmacogenetic effect of traditional herbs on prediabetes treatment. A total of 194 impaired glucose tolerance (IGT) subjects were treated with traditional hypoglycemic herbs (Tianqi Jiangtang) for 12 months in this study. DNA samples were genotyped for 184 mutations in 34 genes involved in drug metabolism or transportation. Multinomial logistic regression analysis indicated that rs1142345 (A > G) in the thiopurine S-methyltransferase (TPMT) gene was significantly associated with the hypoglycemic effect of the drug (P = 0.001, FDR P = 0.043). The “G” allele frequencies of rs1142345 in the healthy (subjects reverted from IGT to normal glucose tolerance), maintenance (subjects still had IGT), and deterioration (subjects progressed from IGT to T2D) groups were 0.094, 0.214, and 0.542, respectively. Binary logistic regression analysis indicated that rs1142345 was also significantly associated with the hypoglycemic effect of the drug between the healthy and maintenance groups (P = 0.027, OR = 4.828) and between the healthy and deterioration groups (P = 0.001, OR = 7.811). Therefore, rs1142345 was associated with the clinical effect of traditional hypoglycemic herbs. Results also suggested that TPMT was probably involved in the pharmacological mechanisms of T2D.
PMCID: PMC3657408  PMID: 23737827
10.  Insufficient Sensitivity of Hemoglobin A1C (A1C) Determination in Diagnosis or Screening of Early Diabetic States 
An International Expert Committee made recommendations for using the hemoglobin A1C (A1C) assay as the preferred method for diagnosis of diabetes in nonpregnant individuals. A concentration of ≥ 6.5% was considered as diagnostic. It is the aim of this study to compare the sensitivity of A1C with that of plasma glucose concentrations in subjects with early diabetes or IGT. We chose two groups of subjects who had A1C of ≤ 6.4%. The first group of 89 subjects had family histories of diabetes (MODY or T2DM) and had OGTT and A1C determinations. They included 36 subjects with diabetes or IGT and 53 with normal OGTT. The second group of 58 subjects was screened for diabetes in our Diabetes Clinic by FPG or 2HPG or OGTT and A1C and similar comparisons were made. Subjects with diabetes or IGT, including those with fasting hyperglycemia, had A1C ranging from 5.0 – 6.4%, mean 5.8%. The subjects with normal OGTT had A1C of 4.2 – 6.3%, mean 5.4% or 5.5% for the two groups. A1C may be in the normal range in subjects with diabetes or IGT, including those with fasting hyperglycemia. Approximately one third of subjects with early diabetes and IGT have A1C <5.7%, the cut-point that ADA recommends as indicating the onset of risk of developing diabetes in the future. The results of our study are similar to those obtained by a large Dutch epidemiological study. If our aim is to recognize early diabetic states to apply effective prophylactic procedures to prevent or delay progression to more severe diabetes, A1C is not sufficiently sensitive or reliable for diagnosis of diabetes or IGT. A combination of A1C and plasma glucose determinations, where necessary, are recommended for diagnosis or screening of diabetes or IGT.
PMCID: PMC2998594  PMID: 20723948
Hemoglobin A1C; Diagnosis; Diabetes
11.  Should the first degree relatives of type 2 diabetic patients with isolated impaired fasting glucose be considered for a diabetes primary prevention program? 
The aim of this study is to investigate the need for diabetes primary prevention program in isolated impaired fasting glucose (i-IFG) of the first degree relatives of type 2 diabetics.
In a cross sectional study, 793 individuals with prediabetes [543 with i-IFG and 250 with isolated impaired glucose tolerance (i-IGT)] who were the first degree relatives of type 2 diabetic patients, were enrolled. Isolated IFG was considered as fasting plasma glucose between 100-125 mg/dl and 2 hour plasma glucose < 140 mg/dl and isolated IGT as FPG < 100 mg/dl and 2 hour plasma glucose between 140-199 mg/dl during an overnight fasting 75 g oral glucose tolerance test. Mean of the age, weight, waist circumference, body mass index, systolic and diastolic blood pressure, plasma glucose, HbA1C, and lipid profile were compared between two groups (i-IFG and i-IGT). The prevalence of cardiometabolic risk factors (BMI ≥ 25 kg/m2, hypertension, cholesterol ≥ 200 mg/dl, LDL-C ≥ 100 mg/dl, HDL-C ≤ 40 mg/dl, and triglyceride ≥ 150 mg/dl) adjusted by age, sex and BMI were compared.
The prevalence of cardiometabolic risk factors is higher in i-IFG group than i-IGT. The mean level of LDL-C is significantly higher in i-IFG than i-IGT group.
First degree relatives of T2DM with isolated impaired fasting glucose should probably be included in the primary preventive program for diabetes. However, longitudinal cohort study is required to show high progression of i-IFG to T2DM.
PMCID: PMC3082819  PMID: 21526094
Prediabetic States; Diabetes Mellitus; Type II; Oral Glucose Tolerance Test; Primary Prevention; Dyslipidemia; Risk Factor; Iran
12.  Prevalence of Type 2 Diabetes and Impaired Glucose Regulation with Associated Cardiometabolic Risk Factors and Depression in an Urbanizing Rural Community in Bangladesh: A Population-Based Cross-Sectional Study 
Diabetes & Metabolism Journal  2012;36(6):422-432.
To determine the prevalence of type 2 diabetes (T2DM) and impaired glucose regulation (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]) in an urbanizing rural population of Bangladesh and associated cardiometabolic risk indicators and depression.
A total of 2,293 subjects aged ≥20 years in an urbanizing rural Bangladeshi community were investigated. Socio-demographic and anthropometric details, blood pressure, fasting plasma glucose (FPG), 2 hours after 75 g plasma glucose (2hPG), glycosylated hemoglobin, fasting serum insulin and lipid profiles were studied. Presence of depressive symptoms using Montogomery-Asberg Depression Rating Scale was also assessed.
The prevalence of IFG, IGT, IFG+IGT, and T2DM were 3.4%, 4.0%, 1.2%, and 7.9%, respectively. The prevalence of T2DM and impaired glucose regulation differed between males and females, but, both increased with age in both sexes. FPG and 2hPG had positive correlation. Employing logistic regression, it was found that increased age, waist to hip ratio, systolic blood pressure, total cholesterol, triglycerides, and depression were independent risk indicators for diabetes. Both insulin resistance and β-cell deficiency were significantly related for causation of diabetes. Among the study population, 26.2% had general obesity, 39.8% central obesity, 15.5% hypertension, 28.7% dyslipidemia, 17.6% family history of diabetes, and 15.3% had depression. Physical inactivity and smoking habits were significantly higher in male.
Rising prevalence of diabetes and impaired glucose regulation in this urbanizing rural population exist as a significant but hidden public health problem. Depression and other cardiometabolic risk indicators including obesity, hypertension, and dyslipdemia were also prevalent in this population.
PMCID: PMC3530713  PMID: 23275936
Bangladesh; Diabetes mellitus; Impaired glucose regulation; Prevalence
13.  Different Pathophysiology of Impaired Glucose Tolerance in First Degree Relatives of Individuals with Type 2 Diabetes 
To assess whether an increased genetic predisposition for type 2 diabetes (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an OGTT and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) that had normal glucose homeostasis and no first degree T2DM relative (NGH; N=133), IGT with a first degree T2DM relative (IGT/FH+; N=74) or IGT without a first degree T2DM relative (IGT/FH−; N=50). Compared to NGH, first and second phase plasma insulin responses were reduced ~45% and 30%, respectively (both P<0.001) in IGT/FH+, whereas insulin sensitivity was only ~20% reduced (P=0.011). In contrast, in IGT/FH−, first phase plasma insulin responses were only ~20% reduced (P=0.016), second phase plasma insulin responses were not reduced, but insulin sensitivity was ~40% reduced (P<0.001). IGT/FH+ differed significantly from IGT/FH− by having 25–30% lower first phase plasma insulin responses (P=0.026) and 25–30% greater insulin sensitivity (P=0.027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first phase plasma insulin responses were ~30% lower in IGT/FH+ with a BMI ≥27 kg/m2 (P=0.018) but similar in IGT/FH+ with a BMI <27 kg/m2 compared to the corresponding IGT/FH− subgroups. We conclude that in IGT an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity.
PMCID: PMC2713184  PMID: 19375581
impaired glucose tolerance; insulin resistance; insulin secretion
14.  Prevalence of Abnormal Glucose Tolerance and Risk Factors in Urban and Rural Malaysia 
Diabetes Care  2011;34(6):1362-1364.
To determine the prevalence of prediabetes and diabetes among rural and urban Malaysians.
This cross-sectional survey was conducted among 3,879 Malaysian adults (1,335 men and 2,544 women). All subjects underwent the 75-g oral glucose tolerance test (OGTT).
The overall prevalence of prediabetes was 22.1% (30.2% in men and 69.8% in women). Isolated impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were found in 3.4 and 16.1% of the study population, respectively, whereas 2.6% of the subjects had both IFG and IGT. Based on an OGTT, the prevalence of newly diagnosed type 2 diabetes was 12.6% (31.0% in men and 69.0% in women). The prediabetic subjects also had an increased prevalence of cardiovascular disease risk factors.
The large proportion of undiagnosed cases of prediabetes and diabetes reflects the lack of public awareness of the disease.
PMCID: PMC3114358  PMID: 21498788
15.  General effect on high-risk persons when general practitioners are trained in intensive treatment of type 2 diabetes 
Within the frame of a randomized clinical trial to examine whether training of general practitioners (the intervention group) in intensive lifestyle modification and pharmacological treatment of patients with type 2 diabetes has a spillover effect on individuals with impaired fasting glycaemia (IFG) or impaired glucose tolerance (IGT).
A high-risk screening study for type 2 diabetes with an intervention programme, where general practices were randomized to provide standard treatment versus intensive lifestyle modification and pharmacological treatment to newly diagnosed diabetic patients.
General practices in Denmark.
Of 1821 individuals identified with IFG or IGT, results from oral glucose tolerance tests after one and three years were available in 1510 individuals.
Main outcome measures
Progression rates from IFG and IGT to diabetes and effect of intervention were estimated in a regression model using interval censoring.
A total of 442 persons developed diabetes. There was no significant overall effect of intervention on progression rates. For risk factors, no difference in rate of change was found between randomization groups, but a difference was found between general practices within the same randomization groups.
General practitioners identify a high number of incident diabetes cases in individuals with IFG or IGT found by high-risk screening. Intervention at the general practitioner's level in intensive treatment type 2 diabetes does not have a significant spillover effect reducing the risk of diabetes from pre-diabetic conditions. This could indicate that intervention strategies should be specifically targeted at individuals with IFG or IGT, either by training general practitioners or directly at the individual level.
PMCID: PMC3409605  PMID: 18677673
Clustering; family practice; general practice; impaired fasting glucose; impaired glucose tolerance; intervention studies; risk management; type 2 diabetes
16.  Reduced Progression to Type 2 Diabetes From Impaired Glucose Tolerance After a 2-Day In-Hospital Diabetes Educational Program 
Diabetes Care  2008;31(10):1949-1954.
OBJECTIVE—We assessed the effects of a 2-day in-hospital diabetes educational program in preventing or delaying progression of impaired glucose tolerance (IGT) to type 2 diabetes, including analysis of changes in serum lipids, body weight, and blood pressure after the program.
RESEARCH DESIGN AND METHODS—A total of 426 subjects (51 ± 9 years, BMI 24.6 ± 3.9 kg/m2) with newly diagnosed IGT were randomly assigned to three groups, 143 as the short-term hospitalization with diabetes education and support (STH) group, 141 as the nonhospitalization but diabetes education and support (DES) group, and 142 as the neither hospitalization nor education (control) group.
RESULTS—The average follow-up was 3.1 years. The incidence of diabetes was 8.0, 10.7, and 13.2 cases per 100 person-years for STH, DES, and control groups, respectively. The incidence of diabetes was 42% lower (95% CI 33–51%) in the STH group and 27% lower (15–37%) in the DES group than in the control group. The incidence of diabetes was 21% lower (10–31%) in the STH group than in the DES group.
CONCLUSIONS—The 2-day in-hospital program with diabetes education and support every 3 months was more effective in preventing or delaying the progression from IGT to diabetes than only diabetes education and support every 3 months.
PMCID: PMC2551633  PMID: 18591401
17.  The relationship between the level of glutathione, impairment of glucose metabolism and complications of diabetes mellitus 
Objective: To investigate whether there is a difference between the subjects with new-onset type 2 diabetes mellitus (DM), impaired glucose tolerance (IGT) and normal fasting blood glucose levels with respect to the level of glutathione (GSH) and the relationship between the presence of complication of diabetes and the level of GSH.
Methods: Oral Glucose Tolerance Test (OGTT) was performed in IFG patients, with no episode of drug use, who were admitted to hospital. According to the results of the application 30 subjects with type 2 DM, 30 subjects with IGT and 28 subjects with normal blood glucose level were included in the study. Anthropometric measurements and blood pressure values of all subjects were recorded. The biochemical parameters of subjects were studied in the biochemistry laboratory by utilizing Olympus AV-2700. The subjects with diabetic retinopathy and nephropathy were established subsequent to the examination of the retina and 24-hour urine collection test performed to subjects with diagnosis of DM. Levels of GSH in all subjects were measured by enzymatic recycling method.
Results: The mean levels of GSH in subjects with DM were significantly reduced compared with IGT or normal subjects (respectively p=0.02 and p<0.001). Besides, lower levels of GSH were acquired in subjects with IGT compared to normal subjects (p<0.001). The mean levels of GSH in subjects with diabetic retinopathy were lower than the subjects with no established diagnosis of diabetic retinopathy (p<0.001). Similarly, lower levels of GSH (p<0.001) were obtained in microalbuminuric subjects than normoalbuminuric subjects.
Conclusions: At the end of the study, we came to the conclusion that GSH deficiency was of great significance in the pathogenesis of Diabetes Mellitus.
PMCID: PMC3817774  PMID: 24353663
Complications; Diabetes mellitus; Glutathion
18.  Glucose challenge increases circulating progenitor cells in Asian Indian male subjects with normal glucose tolerance which is compromised in subjects with pre-diabetes: A pilot study 
Haematopoietic stem cells undergo mobilization from bone marrow to blood in response to physiological stimuli such as ischemia and tissue injury. The aim of study was to determine the kinetics of circulating CD34+ and CD133+CD34+ progenitor cells in response to 75 g glucose load in subjects with normal and impaired glucose metabolism.
Asian Indian male subjects (n = 50) with no prior history of glucose imbalance were subjected to 2 hour oral glucose tolerance test (OGTT). 24 subjects had normal glucose tolerance (NGT), 17 subjects had impaired glucose tolerance (IGT) and 9 had impaired fasting glucose (IFG). The IGT and IFG subjects were grouped together as pre-diabetes group (n = 26). Progenitor cell counts in peripheral circulation at fasting and 2 hour post glucose challenge were measured using direct two-color flow cytometry.
The pre-diabetes group was more insulin resistant (p < 0.0001) as measured by homeostasis assessment model (HOMA-IR) compared to NGT group. A 2.5-fold increase in CD34+ cells (p = 0.003) and CD133+CD34+ (p = 0.019) cells was seen 2 hours post glucose challenge in the NGT group. This increase for both the cell types was attenuated in subjects with IGT. CD34+ cell counts in response to glucose challenge inversely correlated with neutrophil counts (ρ = -0.330, p = 0.019), while post load counts of CD133+CD34+ cells inversely correlated with serum creatinine (ρ = -0.312, p = 0.023).
There is a 2.5-fold increase in the circulating levels of haematopoietic stem cells in response to glucose challenge in healthy Asian Indian male subjects which is attenuated in subjects with pre-diabetes.
PMCID: PMC3027185  PMID: 21219665
19.  Impaired Glucose Tolerance and Obesity as Effect Modifiers of Ethnic Disparities of the Progression to Diabetes 
Diabetes Care  2012;35(12):2548-2552.
The Diabetes Prevention Program (DPP) reported no racial/ethnic differences in the incidence of diabetes in individuals with impaired glucose tolerance (IGT). Therefore, it has been hypothesized that factors associated with racial/ethnic disparities act prior to the development of IGT. Because impaired fasting glucose (IFG) and obesity were also very prevalent in the DPP, we examined IGT, IFG, and obesity as effect modifiers of ethnic disparities in the San Antonio Heart Study.
Participants were 3,015 Mexican Americans and non-Hispanic whites aged 25–64 years. The median follow-up period was 7.8 years. IGT, IFG, and diabetes were defined by the 2003 American Diabetes Association criteria, and obesity was defined as BMI ≥30 kg/m2.
Mexican Americans had an excess risk of incident IGT (odds ratio 1.48 [95% CI 1.16–1.89]) and incident IFG (1.71 [1.31–2.23]) compared with non-Hispanic whites. Mexican Americans also had a higher incidence of diabetes among individuals who had normal 2-h glucose (2.20 [1.48–3.29]) and IGT (1.72 [1.08–2.74]) at baseline. There was an interaction of obesity on the relationship between ethnicity and progression to IGT or diabetes (P = 0.034), with Mexican Americans having a greater risk among the nonobese (1.73 [1.36–2.21]) and a comparable risk among the obese (1.08 [0.75–1.56]).
Ethnic differences can be detected at both the early and later stages of the diabetes disease process. However, non-Hispanic whites lose much of the ethnic advantage once they have developed obesity.
PMCID: PMC3507579  PMID: 22923668
20.  Prevention of type 2 diabetes in a primary healthcare setting: Three-year results of lifestyle intervention in Japanese subjects with impaired glucose tolerance 
BMC Public Health  2011;11:40.
A randomized control trial was performed to test whether a lifestyle intervention program, carried out in a primary healthcare setting using existing resources, can reduce the incidence of type 2 diabetes in Japanese with impaired glucose tolerance (IGT). The results of 3 years' intervention are summarized.
Through health checkups in communities and workplaces, 304 middle-aged IGT subjects with a mean body mass index (BMI) of 24.5 kg/m2 were recruited and randomized to the intervention group or control group. The lifestyle intervention was carried out for 3 years by public health nurses using the curriculum and educational materials provided by the study group.
After 1 year, the intervention had significantly improved body weight (-1.5 ± 0.7 vs. -0.7 ± 2.5 kg in the control; p = 0.023) and daily non-exercise leisure time energy expenditure (25 ± 113 vs. -3 ± 98 kcal; p = 0.045). Insulin sensitivity assessed by the Matsuda index was improved by the intervention during the 3 years. The 3-year cumulative incidence tended to be lower in the intervention group (14.8% vs.8.2%, log-rank test: p = 0.097). In a sub-analysis for the subjects with a BMI > 22.5 kg/m2, a significant reduction in the cumulative incidence was found (p = 0.027).
The present lifestyle intervention program using existing healthcare resources is beneficial in preventing diabetes in Japanese with IGT. This has important implications for primary healthcare-based diabetes prevention.
Trial registration number
PMCID: PMC3037863  PMID: 21235825
21.  Postchallenge Hyperglycemia Is Positively Associated With Diabetic Polyneuropathy 
Diabetes Care  2012;35(9):1891-1893.
To assess the prevalence of distal sensorimotor polyneuropathy (DSPN) in an older population and to examine its relationship with prediabetes.
Glucose tolerance status was determined in 61- to 82-year-old participants (n = 1,100) of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 Survey (2006–2008). Clinical DSPN was defined as bilaterally impaired foot-vibration perception and/or foot-pressure sensation.
Prevalence of clinical DSPN was similar in subjects with known diabetes (22.0%) and subjects with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (23.9%). Among prediabetic subgroups, IFG-IGT, but not isolated-IFG and -IGT, was associated with a higher risk of clinical DSPN, compared with normal glucose tolerance. A J-shaped association was observed between clinical DSPN and quartiles of 2-h postchallenge glucose, but not with fasting glucose and HbA1c levels.
Subjects with IFG-IGT and known diabetes had a similar prevalence of clinical DSPN. Elevated 2-h postload glucose levels appeared important for disease risk.
PMCID: PMC3424984  PMID: 22751964
22.  Evaluation of a diabetes patient education program consisting of a three-day hospitalization and a six-month follow-up by telephone counseling for mild type 2 diabetes and IGT 
The purpose of this study was to evaluate the efficacy and feasibility of a newly developed diabetes patient education program consisting of a three-day hospitalization and a six-month follow-up by telephone counseling for patients with mild type 2 diabetes or impaired glucose tolerance (IGT) by a randomized controlled trial (RCT) method. Fifty-two patients with mild type 2 diabetes or IGT (HbAlc<8) were randomly assigned to either an intervention group or a control group. The current care was continued for the control group and the new education program was provided in addition to the current care for the intervention group. Changes in weight, blood glucose in a 75g-oral glucose tolerance test (75g-OGTT), and HbAlc were measured in June 1997 as baseline data and again in Dec. 1997. Scores for knowledge of diabetes, dietary habits, physical activity, health practice index, diabetes quality of life (DQOL), and self-efficacy were also obtained. After six months, the intervention group showed a statistically significant weight loss and blood glucose reduction in the 75g-OGTT test, but the control group did not. A significant improvement in lifestyle was observed in the intervention group, especially in terms of dietary habits and physical activity. The knowledge test scores increased in both groups. There were no significant differences in HbAlc, DQOL, or self-efficacy between the two groups. The results of this study show that the combination of a three-day hospitalization and a six-month follow-up by telephone counseling is effective in metabolic control and improvement of lifestyle for patients with mild type 2 diabetes or IGT. The reasons for the effectiveness were considered to be that l)changes in lifestyle were based on autonomous decision-making; 2)regular, consistent counseling was provided by the nurse in charge of each patient; 3)extended follow-up is more effective than initial education in preventing a rebound of weight or metabolic control.
PMCID: PMC2723521  PMID: 21432184
randomized controlled trial; type 2 diabetes; IGT; patient education; telephone counseling
23.  Effect of Progression From Impaired Glucose Tolerance to Diabetes on Cardiovascular Risk Factors and Its Amelioration by Lifestyle and Metformin Intervention 
Diabetes Care  2009;32(4):726-732.
Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program.
A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status.
CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia.
Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.
PMCID: PMC2660486  PMID: 19171717
24.  Pancreatic B-cell function is altered by oxidative stress induced by acute hyperglycaemia 
Diabetic Medicine  2007;24(2):154-160.
Type 2 diabetes is preceded by a symptom-free period of impaired glucose tolerance (IGT). Pancreatic B-cell function decreases as glucose intolerance develops. In many patients with IGT, fasting blood glucose is within normal limits and hyperglycaemia occurs only postprandially. We examined whether pancreatic B-cell function changes during acute hyperglycaemia induced by oral glucose loading.
We calculated the insulinogenic index (I.I.) as an indicator of pancreatic B-cell function and measured serum levels of thioredoxin, a marker of cellular redox state, and 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative stress, during a 75-g oral glucose tolerance test (OGTT) in 45 subjects [24 patients with normal glucose tolerance (NGT), 14 with IGT and seven with Type 2 diabetes].
Thioredoxin levels decreased after glucose loading [66.1 ± 23.7, *59.3 ± 22.4, *49.3 ± 21.2 and *37.7 ± 18.0 ng/mL, fasting (0 min) and at 30, 60 and 120 min, respectively; *P < 0.001 vs. fasting]. In contrast, concentrations of 8-OHdG peaked at 30 min and then gradually decreased (0.402 ± 0.123, *0.440 ± 0.120, †0.362 ± 0.119 and †0.355 ± 0.131 ng/mL, *P < 0.05 vs. fasting, †P < 0.01 vs. 30 min). The insulinogenic index correlated with the change in thioredoxin levels (r = 0.34, P < 0.05). However, there was no relationship with the change in 8-OHdG levels from 0 to 30 min.
Hyperglycaemia in response to oral glucose impairs pancreatic B-cell function with decreasing thioredoxin levels. The augmented oxidative stress induced by hyperglycaemia may affect the cellular redox state. These findings strongly suggest that repeated postprandial hyperglycaemia may play an important role in the development and progression of diabetes mellitus.
PMCID: PMC1974794  PMID: 17257277
blood glucose; impaired glucose tolerance; oxidative stress; postprandial hyperglycaemia
25.  Hypoglycemia Assessed by Continuous Glucose Monitoring Is Associated with Preclinical Atherosclerosis in Individuals with Impaired Glucose Tolerance 
PLoS ONE  2011;6(12):e28312.
Hypoglycemia is associated with increased risk of cardiovascular adverse clinical outcomes. There is evidence that impaired glucose tolerance (IGT) is associated with cardiovascular morbidity and mortality. Whether IGT individuals have asymptomatic hypoglycemia under real-life conditions that are related to early atherosclerosis is unknown. To this aim, we measured episodes of hypoglycemia during continuous interstitial glucose monitoring (CGM) and evaluated their relationship with early manifestation of vascular atherosclerosis in glucose tolerant and intolerant individuals. An oral glucose tolerance test (OGTT) was performed in 79 non-diabetic subjects. Each individual underwent continuous glucose monitoring for 72 h. Cardiovascular risk factors and ultrasound measurement of carotid intima-media thickness (IMT) were evaluated. IGT individuals had a worse cardiovascular risk profile, including higher IMT, and spent significantly more time in hypoglycemia than glucose-tolerant individuals. IMT was significantly correlated with systolic (r = 0.22; P = 0.05) and diastolic blood pressure (r = 0.28; P = 0.01), total (r = 0.26; P = 0.02) and LDL cholesterol (r = 0.27; P = 0.01), 2-h glucose (r = 0.39; P<0.0001), insulin sensitivity (r = −0.26; P = 0.03), and minutes spent in hypoglycemia (r = 0.45; P<0.0001). In univariate analyses adjusted for gender, minutes spent in hypoglycemia were significantly correlated with age (r = 0.26; P = 0.01), waist circumference (r = 0.33; P = 0.003), 2-h glucose (r = 0.58; P<0.0001), and 2-h insulin (r = 0.27; P = 0.02). In a stepwise multivariate regression analysis, the variables significantly associated with IMT were minutes spent in hypoglycemia (r2 = 0.252; P<0.0001), and ISI index (r2 = 0.089; P = 0.004), accounting for 34.1% of the variation. Episodes of hypoglycemia may be considered as a new potential cardiovascular risk factor for IGT individuals.
PMCID: PMC3229545  PMID: 22164268

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