Stage Of Impaired Glucose Tolerance Research Articles

A Study to Evaluate the Role of Secreted Frizzled-Related Protein 4 (SFRP4) as a Potential Novel Biomarker of Type 2 Diabetes Mellitus

ABSTRACT Background: A new inflammation mediator called secreted frizzled-related protein 4 (SFRP4), was recently found, the secretion of which is regulated by interleukin-1β. SFRP4 as a potential biomarker of early β-cell dysfunction can help to identify high-risk individuals who are going to develop diabetes in the future. It is highly expressed in β-cells of islets and its levels increase several years before diabetes diagnosis. Objectives: This study was conducted with an objective to estimate and correlate SFRP4 in pre-diabetes, type 2 diabetes, and non-diabetes persons, and evaluate the predictive risk assessment of SFRP4 as a novel biomarker. Materials and Methods: In this cross-sectional observational study, a total of 300 human participants were included among which 100 were prediabetic, 100 were diabetic, and 100 were age- and gender-matched control individuals from a community, all of whom were selected through a predesigned screening questionnaire and inclusion and exclusion criteria from January 2020 to January 2022 in Banke district, Nepal. Serum SFRP4 and IL-1β levels were determined by ELISA. Results: There was a statistically significant difference in body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), fasting insulin, fasting plasma glucose (FPG), two-hour post-load plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), insulin resistance (HOMA-IR), Homeostasis model assessment of β cell function (HOMA-β%), high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) between the three groups, with a progressive increase from the normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) groups and with the highest value in the type 2 diabetes mellitus (T2DM) groups (P < 0.05). However, diastolic blood pressure (DBP) and IL-1β showed a significant difference between the NGT and T2DM groups (P < 0.001) and the NGT and IGT groups (P < 0.001). The median serum SFRP4 concentrations showed a significant difference among three groups (all P < 0.05) and were positively correlated with FPG, HbA1c, hs-CRP, and IL-1 β (P < 0.05). Conclusion: Our study presumes importance as we report increased SFRP4 levels in Asian Nepalis even at the stage of IGT. These findings propose that the increased serum SFRP4 may be a good biomarker of decline in β-cell function and insulin resistance.

Do gene-environment interactions have implications for the precision prevention of type 2 diabetes?

The past decades have seen a rapid global rise in the incidence of type 2 diabetes. This surge has been driven by diabetogenic environmental changes that may act together with a genetic predisposition to type 2 diabetes. It is possible that there is a synergistic gene-environment interaction, where the effects of the diabetogenic environment depend on the genetic predisposition to type 2 diabetes. Randomised trials have shown that it is possible to delay, or even prevent the development of type 2 diabetes in individuals at elevated risk through behavioural modification, focusing on weight loss, physical activity and diet. There is wide heterogeneity between individuals regarding the effectiveness of these interventions, which could, in part, be due to genetic differences. However, the studies of gene-environment interactions performed thus far suggest that behavioural modifications appear equally effective in reducing the incidence of type 2 diabetes from the stage of impaired glucose tolerance, regardless of the known underlying genetic predisposition. Recent studies suggest that there may be several subtypes of type 2 diabetes, which give new opportunities for gaining insight into gene-environment interactions. At present, the role of gene-environment interactions in the development of type 2 diabetes remains unclear. With many puzzle pieces missing in the general picture of type 2 diabetes development, the available evidence of gene-environment interactions is not ready for translation to individualised type 2 diabetes prevention based on genetic profiling.

Retinal Neuropathy in IGT Stage of OLETF Rats: Another Characteristic Change of Diabetic Retinopathy.

Aims We investigated the changes of retinal structure in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), diabetes mellitus (DM), and diabetic kidney disease (DKD) stages in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods We assigned OLETF rats to four groups based on their OGTT results and 24 h urinary microalbumin (24 h UMA) levels: NGT, IGT, DM, and DKD groups. We observed the structural and the corresponding pathological changes and quantified the expression of HIF-1α, iNOS, NF-κB, VEGF, ICAM-1, and occludin in the retina. Results Significant damage to the retinal structure, especially in retinal ganglion cells (RGCs), was observed in the IGT stage. The expression of HIF-1α, iNOS, NF-κB, VEGF, and ICAM-1 was significantly upregulated, while that of occludin was downregulated. Conclusion Significant retinal neuropathy occurs in the IGT stage. Inflammation and hypoxia may damage the blood retina barrier (BRB), leading to diabetic retinopathy.

Prevalance of Prediabetes among Adults and Evaluation of Indian Diabetes Risk Score ( IDRS Score) in a Tertiary Care Hospital

Background: Status of diabetes mellitus has changed in the recent years and now is one of the major cause for morbidity in young adults. Prediabetes is an intermediate stage of impaired glucose tolerance in the natural history of diabetes mellitus. Objectives: The present study aims to determine the prevalence of prediabetes in adults (age group 18-35 years) and to calculate the detailed risk score by using IDRS and correlate it with diabetic status. Methods Fasting plasma glucose was estimated by hexokinase method. Results: Prevalence of prediabetes was 2%. Based on IDRS scoring 40% of the subjects had low risk, 58 % of the subjects had moderate risk and 2% of the subjects had high risk of developing diabetes mellitus. Interpretation and conclusion: Screening for diabetes mellitus should be considered for individuals above 18 years for the presence of risk factors including family history of DM, physical activity and obesity using IDRS.

Hyperinsulinemia Can Cause Kidney Disease in the IGT Stage of OLETF Rats via the INS/IRS-1/PI3-K/Akt Signaling Pathway.

Aims We investigated the changes of renal structure and its function in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), diabetes mellitus (DM), and diabetic kidney disease (DKD) stages in OLETF rats and explored the role of the INS/IRS-1/PI3-K/Akt signaling pathway. Methods OLETF rats were assigned into four groups on the basis of OGTT results and 24 h urinary microalbumin: NGT, IGT, DM, and DKD groups. The changes of renal structure and function and the corresponding pathological changes were observed. The absorption of albumin and the expression of megalin, cubilin, IRS-1, PI3-K, and Akt in NRK-52E cells were measured after being stimulated by different concentrations of insulin. Results In the IGT group, the index which reflects the function of renal tubule-like N-acetyl-β-glucosaminidase, neutrophil gelatinase-associated lipocalin, retinol-binding protein, and cystatin C was higher than those in the control group and the NGT group (P < 0.05). Significant renal structure damages, especially in renal tubules, were observed in the IGT group. In the presence of insulin at a high concentration, the IRS-1/PI3-K/Akt signaling pathway in renal tubular epithelial cells was inhibited, and the expression of megalin and cubilin was significantly downregulated which was accompanied by a minimum uptake of albumin. Conclusions In contrast to DKD, the renal structural damage and functional changes in the IGT stage, in which we propose the term “IGT kidney disease,” mainly manifest as renal tubular injury. Insulin resistance and compensatory hyperinsulinemia may be involved in its pathogenesis.

Trajectories of changes in glucose tolerance in a multiethnic cohort of obese youths: an observational prospective analysis

Type 2 diabetes is preceded by a prediabetic stage of impaired glucose tolerance that affects 10-23% of youth and is expected to double over the next decade. The natural history of impaired glucose tolerance and the determinants of β-cell dynamic response have never been investigated longitudinally in young people. We aimed to investigate the clinical and metabolic determinants of longitudinal glucose tolerance changes and β-cell function in a multiethnic cohort of obese youth. We followed up prospectively a multiethnic cohort of overweight and obese (body-mass index >85th percentile) adolescents with baseline normal glucose tolerance (plasma glucose <140 mg/dL) or impaired glucose tolerance (plasma glucose 140-199 mg/dL) at the Yale Pediatric Obesity Clinic (CT, USA). All participants underwent a 3-h oral glucose tolerance test at baseline and after 2 years to estimate insulin secretion (oral disposition index) in the context of body insulin sensitivity. As part of standard care at the clinic, all participants received dietary advice and underwent dietary assessment every 5-6 months. No structured lifestyle or pharmacological intervention was administered. Between January, 2010, and December, 2016, 526 adolescents (mean age 12·7 years, range 10·6-14·2) were enrolled to our study. At baseline, 364 had normal and 162 had impaired glucose tolerance. Median follow-up was 2·9 years (IQR 2·7-3·1). 105 (65%) of 162 with impaired glucose tolerance at baseline reverted to normal glucose tolerance at follow-up, 44 (27%) had persistent impaired glucose tolerance, and 13 (8%) progressed to type 2 diabetes. A feature of reversion to normal glucose tolerance was a roughly four-fold increase in the oral disposition index (from median 0·94 [IQR 0·68-1·35] at baseline to 3·90 [2·58-6·08] at follow-up; p<0·0001) and a significantly higher oral disposition index at follow-up compared with participants who maintained normal glucose tolerance across the study period (median 3·90 [IQR 2·58-6·08] vs 1·59 [1·12-2·23]; p<0·0001). By contrast, a decrease in insulin secretion was seen in participants who had persistent impaired glucose tolerance (median 1·31 [IQR 1·01-1·85]; p<0·0001) or who progressed to type 2 diabetes (0·20 [0·12-0·58]; p<0·0001), compared with participants who maintained normal glucose tolerance across the study period. Non-Hispanic white ethnic origin conferred five times the odds of reversion to normal glucose tolerance compared with non-Hispanic black ethnic origin (OR 5·06, 95% CI 1·86-13·76; p=0·001), with a two times greater annual increase in the oral disposition index (β 2·32, 95% CI 0·05-4·60; p=0·045). Impaired glucose tolerance is highly reversible in obese adolescents. Ethnic origin is the main clinical modifier of the dynamic β-cell response to prediabetic hyperglycaemia and, thus, determines the reversibility of impaired glucose tolerance, or its persistence. Therapeutic interventions for impaired glucose tolerance should target the specific mechanisms underpinning glucose tolerance changes in high-risk ethnic groups. National Institutes of Health (National Institute of Child Health and Human Development, National Center for Research Resources, and National Institute of Diabetes and Digestive and Kidney Diseases), American Diabetes Association, International Society for Pediatric and Adolescent Diabetes, Robert Leet Patterson and Clara Guthrie Patterson Trust, European Society for Pediatric Endocrinology, American Heart Association, and the Allen Foundation.

Prediabetes and risk of diabetes and associated complications: impaired fasting glucose versus impaired glucose tolerance: does it matter?

The purpose of this review is to summarize the distinct metabolic and pathophysiologic phenotype of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and the subsequent clinical implications with regard to future type 2 diabetes mellitus (T2DM) and cardiovascular risk. Both IFG and IGT manifest the two core defects of T2DM, that is, insulin resistance and β-cell dysfunction. However, the site of insulin resistance and shape of β-cell dysfunction differ. These distinct metabolic and pathophysiologic phenotypes explain the greater cardiovascular disease (CVD) risk associated with an increase in the 2-h plasma glucose concentration, that is, IGT compared with an increase in the fasting plasma glucose (FPG) concentration, that is, IFG. Moreover, the increase in future T2DM risk in IFG study participants is, at least in part, explained by the strong correlation between the increase in FPG and the increase in 2-h plasma glucose concentration. Last, recent studies have reported the presence of diabetic microvascular complications, that is, retinopathy and neuropathy, at the IGT stage.Thus, a glucose load (e.g. oral glucose tolerance test) is required in study participants with elevated FPG concentration to accurately assess their future risk for T2DM, as well as their risk for CVD to identify the subgroup of IFG who are at greater risk and subject them to an intervention program to decrease their future T2DM and CVD risk.

Long-term clinical effect of Tangyiping Granules () on patients with impaired glucose tolerance.

To evaluate the long-term clinical effect of Tangyiping Granules (, TYP) on patients with impaired glucose tolerance (IGT) to achieve normal glucose tolerance (NGT) and hence preventing them from conversion to diabetes mellitus (DM). In total, 127 participants with IGT were randomly assigned to the control (63 cases, 3 lost to follow-up) and treatment groups (64 cases, 4 lost to follow-up) according to the random number table. The control group received lifestyle intervention alone, while the patients in the treatment group took orally 10 g of TYP twice daily in addition to lifestyle intervention for 12 weeks. The rates of patients achieving NGT or experiencing conversion to DM as main outcome measure were observed at 3, 12, and 24 months after TYP treatment. The secondary outcome measures included fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2hPG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS), 2-h insulin (2hINS), homeostatic model assessment of insulin resistance (HOMA-IR), blood lipid and patients' complains of Chinese medicine (CM) symptoms before and after treatment. A higher proportion of the treatment group achieved NGT compared with the control group after 3-, 12- and 24-month follow-up (75.00% vs. 43.33%, 58.33% vs. 35.00%, 46.67% vs. 26.67%, respectively, P<0.05). The IGT to DM conversion rate of the treatment group was significantly lower than that of the control group at the end of 24-month follow-up (16.67% vs. 31.67%, P<0.05). Before treatment, FPG, 2hPG, HbA1c, FINS, 2hINS, HOMA-IR, triglyceride (TG), total cholesterol, low- and high-density lipoprotein cholesterol levels had no statistical difference between the two groups (P>0.05). After treatment, the 2hPG, HbA1c, HOMA-IR, and TG levels of the treatment group decreased significantly compared with those of the control group (P<0.05). CM symptoms such as exhaustion, irritability, chest tightness and breathless, spontaneous sweating, constipation, and dark thick and greasy tongue were significantly improved in the treatment group as compared with the control group (P<0.05). No severe adverse events occurred. TYP administered at the IGT stage with a disciplined lifestyle delayed IGT developing into type 2 DM.

T-helper-1, T-helper-17, T-regulatory lymphocytes in hypertensive patients with diabetes mellitus type 2 or impaired glucose tolerance: association with clinical and metabolic parameters in a case control study

Low-grade inflammation plays significant role in the development of diabetes mellitus type 2 (DM2) and impaired glucose tolerance (IGT), but immune regulatory mechanisms involved in these processes are studied incompletely. The purpose of the present study was to characterize the subsets of T-helper-1 (Th1), Th17 and T-regulatory lymphocytes (Treg) in hypertensive patients with DM2 or IGT according to the clinical variant of the disease. Hypertensive patients with DM2 (n = 20) and IGT (n = 7) were recruited in the study. Hypertensive patients without carbohydrate disturbances (n = 7) and healthy volunteers (n = 12) constituted comparison groups. All patients underwent thorough clinical examination. Th1-, Th17- and Th1/Th17-lymphocytes were assessed in peripheral blood mononuclear cells (PBMC) according to intracellular production of interferon (IFN)-γ and interleukin (IL)-17. Expression of receptor to IL-23 (IL-23R) by PBMC was evaluated. Treg-lymphocytes were detected in PBMC by expression of transcription factor FoxP3. Cells were analyzed using flow cytometry. We found that ratio Treg/Th17 was lower and numbers of IL-23R-positive cells were higher in hypertensive patients with IGT. Patients with DM2 were characterized by elevated numbers of Th17-lymphocytes in intact PBMC culture and Th1-lymphocytes after PBMC activation, as well as decreased ratios Treg/Th17 and Treg/Th1, and reduced numbers of Tregs that were inversely related to visceral adiposity index. In hypertensive patients with DM2 glomerular filtration rate was related to numbers of intact Th17- and IL-23R+ cells and FoxP3+ Treg-lymphocytes, while values of Treg/Th1 ratio were interconnected with visceral adiposity index and concentrations of total cholesterol and LDL-cholesterol. Our study underlines the importance of immune imbalance in the development of carbohydrate metabolism perturbations in hypertensive patients even at the stage of impaired glucose tolerance. Further prospective research is needed to elaborate the possible strategy of the risk evaluation for hypertensive DM2 and IGT patients according to their current inflammatory status and propose therapeutic approaches for its correction.

Treatment with DPP-4I Anagliptin or α-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats.

It has been reported that postprandial hyperglycemia from the pre-diabetic stage, especially from the impaired glucose tolerance (IGT) stage, is positively associated with subsequent incidences of cardiovascular diseases (CVD) and type 2 diabetes. In this study, we aimed to investigate whether treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4I) or an α-glucosidase inhibitor (α-GI), either of which suppresses postprandial hyperglycemia, reduces the expression of CVD risk factors in an IGT animal model. A DPP-4I, anagliptin (1,200 ppm), or an α-GI, miglitol (600 ppm), in the diet was administered for 47 wk to Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for spontaneously-developed type 2 diabetes, at the IGT stage. We examined whether each treatment reduced the expression of CVD risk factors such as inflammatory cytokines/cytokine-like factors in peripheral leukocytes and adhesion molecules in the aortic tissues and circulation. Treatment with either drug reduced IGT development and repressed expression of the interleukin-1β, tumor necrosis factor-α, S100a9, and S100a11 genes in peripheral leukocytes in the fasting state at weeks 25 and 39. The mRNA levels of E-selectin in aortic tissues and protein levels of the soluble forms of E-selectin and ICAM-1 in arterial blood were significantly lower in the anagliptin and miglitol groups than in the control group. Our results suggest that long-term treatment with anagliptin or miglitol in OLETF rats at the IGT stage suppresses the expression of inflammatory cytokines in peripheral leukocytes and adhesion molecules in aortic tissues.

Inhibition of Postprandial Hyperglycemia by Either an Insulin-Dependent or -Independent Drug Reduces the Expression of Genes Related to Inflammation in Peripheral Leukocytes of OLETF Rats

Treatment with the dipeptidyl peptidase-4 inhibitor, anagliptin, or with the α-glucosidase inhibitor, miglitol, reduced the oral sucrose load-inducible expression of interleukin (IL)-1β, IL-18, tumor necrosis factor-α, S100a8, S100a9, S100a11, IL-1R2, IL-1Rn and tumor necrosis factor receptor 2 genes in peripheral leukocytes of Otsuka Long-Evans Tokushima fatty (OLETF) rats at the stage of impaired glucose tolerance. Inhibiting postprandial hyperglycemia reduced the expression of genes related to inflammation in peripheral leukocytes of OLETF rats.

Diazoxide inhibits aortic endothelial cell apoptosis in diabetic rats via activation of ERK

Endothelial cell (EC) survival is critical in the maintenance of endothelial function as well as in the regulation of angiogenesis and vessel integrity since endothelial dysfunction is the initial lesion of atherosclerosis. The goal of this study was to examine the effect of diazoxide, a mitochondrial ATP-sensitive K(+)(mito K(ATP)) channel opener, on aorta ECs apoptosis and its potential mechanism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats at prediabetic stage. Diazoxide (25 mg kg(-1) day(-1)) was administered intraperitoneally from age 8 weeks to age 30 weeks. Thoracic aorta and cultured thoracic aortic ECs were used. The thickening of thoracic aortic wall and apoptosis of ECs were markedly increased in OLETF rats early from the age of 16 weeks, at the impaired glucose tolerance stage, compared with Long-Evans Tokushima Otsuka rats, in conjunction with intimal hyperplasia and perivascular fibrosis. In contrast, diazoxide treatment inhibited these changes. Further study strongly demonstrated that extracellular signal-regulated kinases (ERKs) are key regulatory proteins in protecting ECs from apoptosis. Diazoxide could significantly enhance phosphorylation of ERK via opening mito K(ATP) channels. This role was reversed by both 5-hydroxydecanoate, selectively closing mito K(ATP) channels, and PD-98509, MEK inhibitors. The present studies demonstrate that diazoxide prevents the onset and development of macrovascular disease in OLETF rats by inhibiting apoptosis directly via phosphorylated ERK increase in aorta ECs. Our findings establish the basis for the therapeutic potential of diazoxide in atherosclerotic disease.

Investigation of early change of endothelial function and related factors in individuals with hyperglycemia

ObjectiveTo evaluate early change of endothelial function by color Doppler ultrasound and pulse wave velocity in hyperglycemia people, and probe the effect of related factors. MethodsFrom March to December 2009, 115 subjects (40 subjects with type 2 diabetes, 45 subjects with impaired glucose tolerance and 30 healthy individuals) aged 35–45 without cardio-cerebral-vascular disease and other disease were recruited into the study. Height, weight, blood pressure were measured, and fasting blood glucose, postprandial blood glucose, adiponectin, endothelin and lipid profile were tested. Then, pulse wave velocity and color Doppler ultrasound test was processed in all subjects. ResultsThe abnormality of pulse wave velocity and endothelium-dependent dilatation was found both in impaired glucose tolerance stage and early stage of type 2 diabetes. Systolic blood pressure, pulse pressure, endothelin, fasting blood glucose and postprandial blood glucose were positively correlated with pulse wave velocity and endothelium-dependent dilatation. Whereas, adiponetin was negatively correlated with pulse wave velocity and endothelium-dependent dilatation. ConclusionEndothelial dysfunction exits in individuals with impaired glucose tolerance as well as in type 2 diabetes. Pulse wave velocity and endothelium-dependent dilatation are associated with adiponectin and endothelin.

Accumulation of renin and imidazolone in peritubular capillary endothelial cells in insulin-resistant hypertensive rats

Peritubular endothelium plays a key role in the development and progression of diabetic and nondiabetic chronic kidney disease. Renal injury in disorders of glucose metabolism may appear as early as in the stage of impaired glucose tolerance (IGT) and is accelerated by hypertension. The aim of our study was to investigate renal histology in rats with hypertension and IGT, with special emphasis on the peritubular endothelium. Hypertension and IGT (H/IGT) were provoked in adult male Wistar rats by bilateral administration of methylglyoxal into the ventromedial hypothalamus. Immunohistochemistry with anti-renin and anti-imidazolone antibodies and immunoelectron microscopy with anti-renin antibody were performed. H/IGT rats showed tubulointerstitial fibrosis as well as renin and imidazolone staining in the papillary region. The patterns of immunostaining for renin and imidazolone were similar to that of endothelium. On electron microscopy, peritubular capillary endothelial cells and to a less extent, tubular epithelial cells showed renin positivity. Impaired glucose tolerance complicated with hypertension leads to tubulointerstitial fibrosis in rat kidney. Imidazolone deposition and renin production in peritubular capillary endothelial cells may play a role in the development of tubulointerstitial fibrosis.

The Effect of Plasminogen Activator Inhibitor-1 −675 4G/5G Polymorphism on PAI-1 Gene Expression and Adipocyte Differentiation

Obesity is a complex, multifactorial chronic disease frequently associated with cardiovascular risks, hypertriglyceridemia, low high-density lipoprotein-cholesterol, high blood pressure, and the insulin resistance that appears to be central to the pathogenesis of Type II diabetes. Plasminogen activator inhibitor-1 expression induced in differentiating adipose tissue, but its role in adipogenesis and obesity is poorly understood. Circulating plasminogen activator inhibitor-1 levels are elevated at an early stage of impaired glucose tolerance, resulting in diabetes and metabolic syndrome. Plasminogen activator inhibitor-1 levels are also significantly elevated in the plasma of obese individuals and in adipose tissues of obese mice and humans. Some investigators proposed that the -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter caused overexpression of this gene and predisposed carriers to obesity. In this study, we investigated the role of -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter in the expression of this gene and the contribution of plasminogen activator inhibitor-1 to adipogenesis. Using a dual-luciferase promoter assay, we determined that the -675 4G/5G polymorphism contributes significantly to overexpression of plasminogen activator inhibitor-1 in the course of adipogenesis. The antidiabetic agents troglitazone and ciglitazone inhibited reporter gene expression driven by wild-type and -675 4G/5G mutant promoter, as well as the expression of endogenous plasminogen activator inhibitor-1, indicating that suppression of plasminogen activator inhibitor-1 expression may contribute to antidiabetic effects of these agents. The results indicate that absence of plasminogen activator inhibitor-1 in adipocytes may protect the cells against insulin resistance by promoting glucose uptake and adipocyte differentiation via a decrease in the peroxisome proliferator activated receptor-gamma expression that modulates the adipocyte differentiation.

Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy

Objective Shortening of telomere length has been reported in several conditions including Type 2 diabetes and atherosclerosis. The aims of this study were (1) to assess whether telomere shortening occurs at the stage of pre-diabetes, i.e., impaired glucose tolerance (IGT) and (2) whether telomere shortening was greater in Type 2 diabetic subjects with atherosclerotic plaques. Methods Subjects with impaired glucose tolerance (IGT) ( n = 30), non-diabetic control subjects ( n = 30), Type 2 diabetic patients without ( n = 30) and with atherosclerotic plaques ( n = 30) were selected from the Chennai Urban Rural Epidemiology Study (CURES), an ongoing epidemiological population-based study. Southern-blot analysis was used to determine mean terminal restriction fragment (TRF) length, a measure of average telomere size, in leukocyte DNA. Levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCO) and high sensitive C-reactive protein (hs-CRP) were measured by standard methodologies. Carotid intima-media thickness (IMT) was assessed by high resolution B-mode ultrasonography. Results The mean (±S.E.) TRF lengths were significantly lower in IGT subjects (6.97 ± 0.3 kb; p = 0.002) and lower still in Type 2 diabetic subjects without plaques (6.21 ± 0.2; p = 0.0001) and lowest in Type 2 diabetic subjects with atherosclerotic plaques (5.39 ± 0.2; p = 0.0001) when compared to control subjects (8.7 ± 0.5). In IGT subjects, TRF length was positively correlated to HDL cholesterol and negatively correlated to glycated hemoglobin (HbA 1c), TBARS, PCO, HOMA-IR and IMT. In multiple linear regression analysis, presence of diabetes, HDL cholesterol and increased TBARS levels appear as significant determinants of telomere shortening. Conclusion Telomere shortening is seen even at the stage of IGT. Among subjects with Type 2 diabetes, those with atherosclerotic plaques had greater shortening of telomere length compared to those without plaques.

Effect of Metformin and Rosiglitazone in a Prepubertal Boy with Alström Syndrome

Alström syndrome (AS) is an autosomal recessive disorder characterized by progressive pigmentary retinopathy, sensorineural hearing loss, fatty liver infiltration, obesity, insulin resistance and early-onset type 2 diabetes mellitus (DM2). Early onset of insulin resistance and DM2 are key components of this syndrome. To study the effect of early initiation of the insulin sensitizer metformin combined with rosiglitazone in a patient with AS with impaired glucose tolerance. An 8 year-old boy with AS presented with acanthosis nigricans and insulin resistance at the age of 6 years. He had progressive excessive weight gain from 9 months of age. By the age of 1 year he developed photosensitivity, blindness and nystagmus. At the age of 5.5 years, his body mass index (BMI) was above the 95th percentile. He developed impaired glucose tolerance at 6 years of age and treatment with metformin was initiated. After 8 months of treatment with metformin he developed DM2. The dose of metformin was increased, and rosiglitazone added. A 2-hour oral glucose tolerance test (OGTT) and a rapid intravenous glucose tolerance test (IVGTT) were performed before treatment was initiated, after treatment with metformin and at the end of 1 year of combination therapy with metformin and rosiglitazone to calculate quantitative insulin sensitivity check index (QUICKI) and acute insulin response (AIR). For mutation analysis, all exons and splice site sequences of the ALMS1 gene were amplified and sequenced. Metformin treatment alone at the stage of impaired glucose tolerance did not prevent progression to DM2. However, metformin at a higher dose and in combination with rosiglitazone resulted in improvement of pancreatic beta-cell function, shown by markedly improved first-phase insulin response to glucose measured by AIR. The patient was found to have two heterozygous nonsense mutations in ALMS1, 8008 C-->T Ter, R2670X, and 11449 C-->T Ter, Q3817X. These alterations cause premature stops and result in a truncated ALMS1 protein. We suggest that early initiation of combined therapy comprising a high dose of metformin plus rosiglitazone may be valuable in managing insulin resistance and DM2 in children with AS.

Combined therapy for type 2 diabetes mellitus

The development of diabetes is preceded by a number of stages of impaired carbohydrate tolerance. From the state of normal through the stage of impaired glucose tolerance, the development of type 2 diabetes mellitus, diabetes complications, the disease leads to death. With this understanding of the disease, the question arises: is it possible to prevent diabetes and its complications? With regard to type 2 diabetes, the answer is yes. Primary disease prevention involves exposure before the onset of the disease; the presence of a specific target, i.e., an etiological determinant; continued effect after discontinuation of therapy.The results of many studies have been published, which convincingly proved that drug and non-drug effects can prevent the transition of the stage of impaired glucose tolerance into diabetes mellitus.

2型糖尿病におけるナテグリニド適応症例についての検討

Nateglinide is a novel rapid- and short-acting insulin secretagogue that ameliorates postprandial hyperglycemia by improving insulin secretory dynamics to a near normal level more effectively than sulfonylureas. Recent epidemiological studies have demonstrated that postprandial hyperglycemia can result in arteriosclerosis, and that advanced arteriosclerosis is present in the initial stage of impaired glucose tolerance. Since postprandial hyperglycemia could be well treated by nateglinide, we examined the background factors of type 2 diabetic patients to determine the optimal indication for nateglinide. Our results indicate that nateglinide is most effective in young and obese patients. Furthermore, fewer responders had microangiopathy or were previously on oral hypoglycemic agents or sulfonylureas compared with non-responders. Although nateglinide is generally indicated for patients with mild HbA1c level, the present findings indicate that the drug was effective in the aforementioned patients regardless of pretreatment HbA1c levels. In one obese patient, nateglinide improved late hyperinsulinemia to near normal secretory dynamics. Our findings suggest that nateglinide is a physiologically preferable and useful drug for early type 2 diabetes without microangiopathy.

OVERVIEW OF CURRENT THERAPY IN DIABETES MELLITUS

Diabetes mellitus can be found world wide and is a disease effecting carbohydrate metabolism. An increase in the number of diabetic patients from 189 billion today to 324 billion worldwide in 2025 is predicted. More than ninety percent suffer from type 2 diabetes. Similar numbers are mentioned for the pre-diabetic stage of impaired glucose tolerance (IGT) and metabolic syndrome. It is an important task for the future to use adequate diagnosis-finding methods and therapies to discern and treat the disturbance of carbohydrate metabolism as early as possible and perhaps slow down further progress in the case of IGT or metabolic syndrome. This should minimize the risk of cardiovascular or organic damage. In contrast to the treatment of type 1 diabetes with intensive insulin regimens, therapy for type 2 diabetes has changed noticeably in the last years. All treatment forms have to account for the results of recent studies which show evidence that long- and short-dated elevation of blood glucose, mostly postprandial appearing peaks can lead to vascular damage with all consequences. The main goal should be to adapt treatment individually, estimating the stage of the disease, the risk of developing or progression of micro- or/and macrovascular complications, present risk factors, age and abilities. Non-pharmacologic and pharmacologic approaches are available.