Early Stages Of Glucose Intolerance Research Articles

Glucose intolerance induces anxiety-like behaviors independent of obesity and insulin resistance in a novel model of nutritional metabolic stress

ABSTRACT Objectives: Type 2 diabetes (T2D) is a metabolic disease of major public health concern. It impacts peripheral tissues and the central nervous system, leading to systemic dysmetabolism and neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we sought to address this question by developing a proprietary (P-) high-fat diet (HFD), in which glucose intolerance precedes weight gain and insulin resistance. Methods: The P-HFD model was nutritionally characterized, and tested in vivo in mice that underwent behavioral and metabolic testing. The diet was benchmarked against reference models. . Results: P-HFD has 42% kcal from fat, high monounsaturated/polyunsaturated fatty acid ratio, and 10% (w/v) sucrose in drinking water. When administered, from the early stages of glucose intolerance alone, animals exhibit anxiety-like behavior, without depression nor recognition memory deficits. Long-term P-HFD feeding leads to weight gain, brain glucose hypometabolism as well as impaired recognition memory. Using an established genetic model of T2D (db/db) and of diet-induced obesity (60% kcal from fat) we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. Discussion: Our findings demonstrate that glucose intolerance alone can elicit anxiety-like behavior. Through this study, we also provide a novel nutritional model (P-HFD) to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.

Gut Microbiota Composition in Prediabetes and Newly Diagnosed Type 2 Diabetes: A Systematic Review of Observational Studies.

Evidence of gut microbiota involvement in regulating glucose metabolism and type 2 diabetes mellitus (T2DM) progression is accumulating. The understanding of microbial dysbiosis and specific alterations of gut microbiota composition that occur during the early stages of glucose intolerance, unperturbed by anti-diabetic medications, is especially essential. Hence, this systematic review was conducted to summarise the existing evidence related to microbiota composition and diversity in individuals with prediabetes (preDM) and individuals newly diagnosed with T2DM (newDM) in comparison to individuals with normal glucose tolerance (nonDM). A systematic search of the PubMed, MEDLINE and CINAHL databases were conducted from inception to February 2021 supplemented with manual searches of the list of references. The primary keywords of “type 2 diabetes”, “prediabetes”, “newly-diagnosed” and “gut microbiota” were used. Observational studies that conducted analysis of the gut microbiota of respondents with preDM and newDM were included. The quality of the studies was assessed using the modified Newcastle-Ottawa scale by independent reviewers. A total of 18 studies (5,489 participants) were included. Low gut microbial diversity was generally observed in preDM and newDM when compared to nonDM. Differences in gut microbiota composition between the disease groups and nonDM were inconsistent across the included studies. Four out of the 18 studies found increased abundance of phylum Firmicutes along with decreased abundance of Bacteroidetes in newDM. At the genus/species levels, decreased abundance of Faecalibacterium prausnitzii, Roseburia, Dialister, Flavonifractor, Alistipes, Haemophilus and Akkermansia muciniphila and increased abundance of Lactobacillus, Streptococcus, Escherichia, Veillonella and Collinsella were observed in the disease groups in at least two studies. Lactobacillus was also found to positively correlate with fasting plasma glucose (FPG), HbA1c and/or homeostatic assessment of insulin resistance (HOMA-IR) in four studies. This renders a need for further investigations on the species/strain-specific role of endogenously present Lactobacillus in glucose regulation mechanism and T2DM disease progression. Differences in dietary intake caused significant variation in specific bacterial abundances. More studies are needed to establish more consistent associations, between clinical biomarkers or dietary intake and specific gut bacterial composition in prediabetes and early T2DM.

Insulin secretion and action affect glucose variability in the early stages of glucose intolerance

Since it is unknown whether glucose variability (GV) is increased and whether this is related to worsening of insulin secretion and action in prediabetes, we have assessed insulin secretion and sensitivity, and daily GV in early stages of dysglycemia. Twenty subjects with normal glucose tolerance (NGT; age 45.0±9.5years; BMI 31.1±6.4kg/m2), 25 with NGT and 1hrOGTT>8.6mmol/L (1hrOGTT; 45.7±8.5years; 32.4±7.0kg/m2), and 59 with isolated impaired glucose tolerance (iIGT; 47.7±11.2years; 31.3±6.1kg/m2) underwent OGTT and MMTT. CGM was performed with blinded FreeStyle Libre Pro for 24h under standard conditions. Parameters of beta-cell function, insulin sensitivity and GV were calculated. Overall insulin secretion and action as well as GV progressively worsened across glucose tolerance categories. On a matrix analysis, GV parameters were inversely related to ISSI-2; r=-0.37 to -0.52; p<0.0001; and IGI; r=-0.28 to -0.48; p<0.0001 for CV, SD, J-index, LI, HBGI and MAGE. Insulin secretion (IGI) and b-cell function (ISSI-2) emerged as independent contributors to GV in early stage of dysglycemia accounting for about 16%-38% of its variability. Our results show that daily GV worsens already with mild impairment of glucose tolerance. The increase in GV is inversely related to insulin secretion and action.

2025-P: Relation between Serum Uric Acid and Autonomic Function, Blood Pressure, and Visceral Obesity in Prediabetes and Type 2 Diabetes with Short Duration

Aim: The present study assesses the relation between uric acid and cardiovascular autonomic function (CAF), blood pressure (BR) and visceral obesity at early stages of glucose intolerance. Material and Methods: A total of 100 subjects - 50 males, mean age 47.4±14.2years, mean BMI 32.2±7.5kg/m2, divided into 3 groups according to glucose tolerance: 30 subjects with normal glucose tolerance (NGT), 37 with prediabetes and 33 with type 2 diabetes (T2D) with duration ≤5 years were included. Glucose tolerance was assessed by OGTT according to WHO 2006 criteria. Anthropometric indices, BP, HbA1c and plasma glucose were measured. Body fat distribution was estimated by a bioimpedance method (InBody 720, BioSpace). CAF was assessed by ANX-3.0 using frequency-domain analysis during standard clinical tests. Results: Uric acid levels were higher in prediabetes and T2D (p&amp;lt;0.0001 and p=0.004, respectively) as compared to NGT. There was a decreased parasympathetic tone at rest (p=0.026 and p=0.001, respectively), deep breathing (p=0.025 and p=0.003, respectively), Valsalva maneuver (p=0.023 and p=0.003, respectively) and standing (p=0.012 and p=0.002, respectively) test in T2D in comparison to prediabetes and NGT. Sympathetic tone was diminished at rest (p=0.004), deep breathing (p=0.040) and standing (p=0.016) test in T2D as compared to NGT. Uric acid positively correlated with waist circumference (r=44, p&amp;lt;0.0001), visceral fat area (r=24, p=0.022), diastolic BP (r=0.023) and HbA1c (r=22, p=0.030); and negatively with sympathetic activity at rest (r=-23, p=0.024), deep breathing (r=-26, p=0.010) and standing (r=-21, 0=0.039) test and with parasympathetic activity during deep breathing test (r=-21, p=0.033). Conclusions: It seems to be an increase in uric acid levels and a decline in CAF in prediabetes and T2D with short duration. Uric acid is probably associated with CAF, visceral obesity and BP at early stages of dysglycaemia. Disclosure R. Dimova: Consultant; Self; Amgen, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Sanofi, Wörwag Pharma. N. Chakarova: None. G. Grozeva-Damyanova: None. T. Tankova: Board Member; Self; Amgen, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Servier.

The relationship between glucose variability and insulin sensitivity and oxidative stress in subjects with prediabetes

AimThe present study assessed the relationship between glucose variability (GV) and insulin levels, insulin resistance and oxidative stress at early stages of glucose intolerance. Material and methodsA total of 50 subjects – 12 males and 38 females, mean age 55.6 ± 9.7 years, mean BMI 28.4 ± 6.4 kg/m2, divided into 2 groups according to glucose tolerance: 32 with prediabetes and 18 with normal glucose tolerance were included. Glucose tolerance was assessed by OGTT according to WHO 2006 criteria. Plasma glucose and serum insulin were measured at fasting, 120-minute and 180-minute during the test; and oxLDL and 3-Nitrotyrosine – at fasting and 120-minute. HOMA-IR and OGIS indexes were calculated. HbA1c and lipid levels was assessed. Continuous glucose monitoring was performed with a blind sensor (FreeStyle Libre Pro) for a mean period of 13.6 ± 2.3 days. ResultsOur results demonstrate significantly increased insulin resistance in subjects with prediabetes, whereas there is no difference in oxidative stress markers between the two groups. OxLDL and 3-NT correlate positively with insulin levels and HOMA-IR and negatively with OGIS in both groups. There is a positive association between oxidative stress markers and 120-minute glucose in the prediabetes group. Insulin levels and HOMA-IR are positively related to plasma glucose and reciprocally to CV and M-Value in prediabetes, since the latter association is with borderline significance after adjustment for hypertension and smoking. ConclusionsOur results demonstrate a significant correlation between oxidative stress and insulin resistance at early stages of glucose intolerance. Both chronic hyperglycemia and GV seem to be related to insulin levels and insulin resistance, and just postload glycaemia to oxidative stress in prediabetes.

Impaired glucose tolerance and albuminuria in patients with chronic heart failure: a subanalysis of the SUPPORT trial.

AimsThe study aims to evaluate the prognostic significance of impaired glucose tolerance (IGT) with reference to albuminuria in patients with chronic heart failure (CHF).Methods and resultsWe examined 535 CHF patients (mean 66 years, women 25%) in the control arm of our SUPPORT trial, in which we examined additive impact of olmesartan in hypertensive patients with symptomatic CHF treated with β‐blockers and/or angiotensin‐converting enzyme inhibitors. We examined the association between glycaemic abnormality (assessed by 75 g of oral glucose tolerance test) and albuminuria for a composite outcome of all‐cause death, myocardial infarction, stroke, and HF hospitalization. IGT patients (N = 113, mean 67.2 years) were older and more frequently treated with β‐blockers compared with those with normal glucose regulation (N = 142, mean 64.0 years) and those with diabetes mellitus (N = 280, mean 65.7 years). Multivariable Cox proportional hazard models revealed that, as compared with normal glucose regulation (NGR), IGT was associated with increased risk of the outcome when complicated by albuminuria [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.14–4.42; P = 0.019] but not when uncomplicated by albuminuria (HR 0.76; 95% CI 0.35–1.60, P = 0.47) (P for interaction = 0.041). This was also the case for diabetes mellitus and albuminuria (HR 2.06; 95% CI 1.17–3.61; P = 0.012). Among IGT patients without albuminuria, 21 (29%) developed albuminuria at 1‐year visit, which was again associated with poor prognosis (HR 7.36; 95% CI 1.39–38.98, P = 0.019).ConclusionsThese results indicate that IGT is associated with poor prognosis when complicated by albuminuria in CHF patients, demonstrating the importance of combined early stages of glucose intolerance and renal dysfunction in the management of CHF.

Endothelial and Autonomic Dysfunction at Early Stages of Glucose Intolerance and in Metabolic Syndrome.

This study evaluated sE-selectin, Endothelin-1, and cardiovascular autonomic neuropathy (CAN) at early stages of glucose intolerance and in metabolic syndrome (MetS). A total of 87 subjects - 39 males, of mean age 45.7±11.6 years and mean BMI 31.4±6.6 kg/m2, divided according to glucose tolerance and the presence of MetS were enrolled. Glucose tolerance was studied during OGTT. Anthropometric indices, blood pressure, HbA1c, lipids, hsCRP, sE-selectin, Endothelin-1, and immunoreactive insulin were measured. Body composition was assessed by a bioimpedance method (InBody 720, BioSpace). Tissue AGEs accumulation was evaluated by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAN was assessed by ANX-3.0 technology. In the groups, according to glucose tolerance, the prevalence of CAN was 5.7% in normal glucose tolerance (NGT), 8.6% in prediabetes, and 23.5% in newly diagnosed type 2 diabetes (NDD). In the groups, according to the presence of MetS, the prevalence of CAN was 12.3% in those with MetS and 4.8% in those without MetS. Parasympathetic activity was diminished at rest (p=0.048, 0.015, respectively) in NDD as compared to prediabetes and NGT; and there was a numerically elevated heart rate at rest in NDD in comparison to NGT. There was a negative correlation between parasympathetic tone and waist circumference, BMI, and visceral and total fat. There was no difference in the measured endothelial function markers in the groups according to glucose tolerance and MetS. sE-selectin correlated with HOMA-IR (r=0.275, p=0.048). No association between Endothelin-1 levels and assessed metabolic parameters was observed. There is a high prevalence of CAN at early stages of glucose intolerance and in MetS, due to decreased parasympathetic activity. Slight elevation of glycemia and MetS probably do not affect endothelial function, since sE-selectin seems to be related to insulin resistance.

578-P: Evaluation of Autonomic Function and Its Relation to Glucose Variability, Insulin Resistance, and Oxidative Stress in Prediabetes

Aim: The present study assesses the relation between cardiovascular autonomic function and some indexes of glycose variability, insulin resistance and oxidative stress in prediabetes. Material and Methods: A total of 50 subjects - 12 males, mean age 55.6±9.7 years, mean BMI 28.4±6.4 kg/m2, divided into 2 groups according to glucose tolerance: 32 subjects with prediabetes and 18 subjects with normal glucose tolerance (NG) were included. Glucose tolerance was assessed by OGTT in accordance with WHO 2006 criteria. Plasma glucose was measured by hexokinase method and immunoreactive insulin - by immuno-chemiluminescence method at fasting, 120-minute and 180-minute during the test; and also oxLDL and 5-Nitrotyrosine - by ELISA method at fasting and 120-minute during the test. Indirect indexes of insulin resistance - HOMA-IR and insulin sensitivity - OGIS were calculated. HbA1c was assessed by immuno-turbidimetric, NGSP certified method. Continuous glucose monitoring was performed with blind sensor for professional use - FreeStyle Libre Pro - for a mean period of 13.6 ± 2.3 days. Results: There was a significantly decreased parasympathetic tone during deep breathing test (p=0.009) and sympathetic tone at rest (p=0.021) and during Valsalva maneuver test (p=0.026) in prediabetes. Sympathetic activity was related to the standard deviation of glycemic excursions in prediabetes (F [1,31]=7.91, p=0.018); whilst parasympathetic activity was related to J-index and % time spent in glycemic range &amp;gt;7.8 mmol/l in prediabetes (F [1,31]=7.20, p=0.004) and with CONGA index in NGT (F [1,18]=6.75, p=0.025). No significant correlation between autonomic tone and the assessed markers of insulin resistance and oxidative stress was established. Conclusions: The autonomic tone has been found to be declined in prediabetes. Glucose variability is probably an additional risk factor for autonomic dysfunction at these early stages of glucose intolerance. Disclosure R. Dimova: None. N. Chakarova: None. G. Kirilov: None. G. Grozeva: None. T. Tankova: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Novo Nordisk A/S, Servier.

Glutathione S-transferase P deficiency induces glucose intolerance via JNK-dependent enhancement of hepatic gluconeogenesis.

Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, nonalcoholic fatty liver disease, and diabetes. The multifunctional GST pi-isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet in wild-type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver. Genetic deletion of GSTP did not affect body composition, fasting blood glucose levels, or insulin levels in mice maintained on a normal chow diet; however, compared with WT mice, the GSTP-null mice were glucose intolerant. In GSTP-null mice, pyruvate intolerance, reflecting increased hepatic gluconeogenesis, was accompanied by elevated levels of activated JNK, cytokine mRNAs, and glucose-6-phosphatase proteins in the liver. Treatment of GSTP-null mice with the JNK inhibitor 1,9-pyrazoloanthrone (SP600125) significantly attenuated pyruvate-induced hepatic gluconeogenesis and significantly altered correlations between hepatic cytokine mRNAs and metabolic outcomes in GSTP-null mice. Collectively, these findings suggest that hepatic GSTP plays a pivotal role in glucose handling by regulating JNK-dependent control of hepatic gluconeogenesis. Thus, hepatic GSTP-JNK dysregulation may be a target of new therapeutic interventions during early stages of glucose intolerance to prevent the worsening metabolic derangements associated with human obesity and its relentless progression to diabetes.

Cardio-metabolic profile of subjects with early stages of glucose intolerance and cardiovascular autonomic dysfunction.

The present study evaluates the cardio-metabolic profile of subjects with early stages of glucose intolerance and presence of cardiovascular autonomic dysfunction (CAD). 478 subjects, of mean age 49.3±13.7years and mean BMI 31.0±6.2kg/m2, divided according to glucose tolerance: 130 with normal glucose tolerance, 227 with prediabetes, and 121 with newly-diagnosed type 2 diabetes, were enrolled. Glucose tolerance was studied during OGTT applying 2006 WHO criteria. Anthropometric indices, blood pressure, HbA1c, serum lipids, hsCRP, and albumin-to-creatinine ratio (ACR) were measured. Body fat distribution was estimated by a bioimpedance method (InBody720, BioSpace). Tissue AGEs accumulation was assessed by skin autofluorescence (AGE-Reader-DiagnOptics™). CAD was assessed by ANX-3.0 method. CAD was found in 24.1% of subjects with any disorder of glucose tolerance in comparison to 12.3% in NGT, OR 2.0 (95% CI: 1.2-3.2), p=0.005. Sympathetic and parasympathetic tone declined with the progression of glucose intolerance. Age, waist circumference, visceral fat area, fasting and 120-min plasma glucose, HbA1c, AGEs, ACR and QTc interval were higher in subjects with CAD, p<0.05. In a logistic regression analysis the panel of age >53years (76% sensitivity, 61% specificity), HbA1c >6.0% (66% sensitivity, 60% specificity), QTc interval >423ms (65% sensitivity, 61% specificity) and presence of arterial hypertension (83% sensitivity, 55% specificity) was related to the presence of CAD - AUC 0.778 (95% CI: 0.73-0.83), p<0.001. Our results demonstrate a high prevalence of CAD in early stages of glucose dysmetabolism. Age, HbA1c, QTc interval and presence of arterial hypertension are related to the presence of CAD in this population.

Insulin, Glucagon and Growth Hormone and CIMT in Glucose Intolerance

Objective: There is an increasing evidence that glucagon and growth hormone (GH)-insulin-like growth factor (IGF) axis may play an important role in glucose metabolism since early stages of glucose intolerance. Carotid intima media thickness is a marker for subclinical atherosclerosis. We aimed to evaluate glucagon, GH and IGF-1 in prediabetic states and their relationship with carotid intima media thickness. Methods: One hundred subjects underwent a 75 gr oral glucose tolerance test and were divided into 4 groups according to their state of glucose tolerance: (i) normal glucose tolerance (NGT)/Controls (n=21), (ii) impaired glucose tolerance (IGT) (n=35), (iii) impaired fasting glucose (IFG) (n=22), (iv) type 2 diabetes mellitus (n=22). Insulin, glucagon and GH were measured at 0, 60 and 120. minutes of OGTT and their area under the curve (AUC) were calculated. Fasting IGF-1 levels and carotid intima media thickness were determined in all participants. Results: AUC for Glucagon was significantly higher in subjects with IGT, IFG and type 2 diabetes mellitus compared to NGT subjects. AUC for GH was significantly higher in subjects with IFG compared to subjects with IGT, type 2 diabetes mellitus and NGT. Plasma IGF-1 levels were significantly lower in subjects with abnormal glucose tolerance. CIMT was significantly higher in IFG group and CIMT was found to be negatively correlated with IGF-1 levels in subjects with IFG. Conclusion: There are pathological alterations of glucagon, GH-IGF-1 and insulin in prediabetic stages. Among these alterations insulin resistance and IGF-1 are associated with CIMT. Further studies needed to investigate the role of treatments targeting insulin sensitivity will have an impact on the association between insulin and early atherogenesis

Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance

AimThe present study evaluates autonomic and somatic nerve function in different stages of glucose tolerance and its correlation with different cardio-metabolic parameters. Material and methodsFour hundred seventy-eight subjects, mean age 49.3±13.7years and mean BMI 31.0±6.2kg/m2, divided according to glucose tolerance: 130 with normal glucose tolerance (NGT), 227 with prediabetes (125 with impaired fasting glucose (IFG) and 102 with isolated impaired glucose tolerance (iIGT)), and 121 with newly-diagnosed T2D (NDT2D), were enrolled. Glucose tolerance was studied during OGTT. Antropometric indices, blood pressure, HbA1c, serum lipids, hsCRP and albumin-to-creatinine ratio were assessed. Body composition was estimated by a bioimpedance method (InBody 720, BioSpace). Tissue AGEs accumulation was assessed by skin autofluorescence (AGE-Reader-DiagnOpticsTM). Electroneurography was performed by electromyograph Dantec Keypoint. Cardiovascular autonomic neuropathy (CAN) was assessed by ANX-3.0 method applying standard clinical tests. ResultsCAN was found in 12.3% of NGT, 19.8% of prediabetes (13.2% of IFG and 20.6% of iIGT), and 32.2% of NDT2D. The prevalence of diabetic sensory polyneuropathy (DSPN) was 5.7% in prediabetes and 28.6% in NDT2D. The panel of age, QTc interval, waist circumference, diastolic blood pressure, and 120-min plasma glucose was related to sympathetic activity (F [5451]=78.50, p<0.001). The panel of age, waist circumference, and QTc interval was related to parasympathetic power (F [3453]=132.26, p<0.001). HbA1c and age were related to sural SNAP (F [2454]=15.12, p<0.001). HbA1c and AGEs were related to sural SNCV (F [2454]=12.18, p<0.001). ConclusionsOur results demonstrate a high prevalence of autonomic and sensory nerve dysfunction in early stages of glucose intolerance. Age, postprandial glycemia, central obesity, diastolic blood pressure and QTc interval outline as predictive markers of CAN; hyperglycemia, glycation and age of DSPN.

Is vaspin related to cardio-metabolic status and autonomic function in early stages of glucose intolerance and in metabolic syndrome?

BackgroundThis study aims to assess serum vaspin in early stages of glucose intolerance and in the presence of metabolic syndrome (MetS); and to evaluate vaspin correlation to different cardio-metabolic parameters and autonomic tone in these subjects.Methods185 subjects (80 males and 105 females) of mean age 45.8 ± 11.6 years and mean BMI 31.2 ± 6.3 kg/m2, divided into groups according to: glucose tolerance, presence of MetS and cardio-vascular autonomic dysfunction (CAD), were enrolled. Glucose tolerance was studied during OGTT. Anthropometric indices, blood pressure, HbA1c, serum lipids, hsCRP, fasting immunoreactive insulin and serum vaspin were measured. Body composition was estimated by impedance analysis. AGEs were assessed by skin fluorescence. CAD was assessed by ANX-3.0.ResultsThere was no difference in vaspin levels between the groups according to glucose tolerance, presence of MetS, and CAD. Regression analysis revealed independent association between serum vaspin and total body fat in newly diagnosed type 2 diabetes (NDT2D) group, and between serum vaspin and age and total body fat in MetS group. Vaspin negatively correlated with both sympathetic and parasympathetic activity in normal glucose tolerance (NGT) and just with parasympathetic tone in NGT without MetS.ConclusionOur results demonstrate no overt fluctuations in vaspin levels in the early stages of glucose intolerance and in MetS. Total body fat seems to be related to vaspin levels in MetS and NDT2D. Our data show negative correlation between vaspin and autonomic function in NGT, as vaspin is associated with parasympathetic activity even in the absence of MetS.

Markers of endothelial and autonomic dysfunction in early stages of glucose intolerance and in metabolic syndrome

Markers of endothelial and autonomic dysfunction in early stages of glucose intolerance and in metabolic syndrome

Correlation between baseline serum 1,5-anhydroglucitol levels and 2-hour post-challenge glucose levels during oral glucose tolerance tests

Since there is increasing evidence that postprandial hyperglycemia is a risk factor for the development of macrovascular complications, it is important to predict postprandial hyperglycemia in the early stages of glucose intolerance, and routine medical checkups provide a good opportunity to do so. The aim of this study was to evaluate the usability of 1,5-anhydroglucitol (1,5-AG) in routine medical checkups. The subjects were 77 Japanese men who participated in a routine medical checkup. First, we performed 75 g oral glucose tolerance tests (OGTTs), and examined the changes in glucose and 1,5-AG levels measured at 0, 30, 60, 90, 120, and 180 minutes (min). 1,5-AG levels did not significantly change until 90 min after the glucose load. Second, a linear regression analysis showed an inverse correlation between the 2-hour post-challenge glucose (2h-PG) and baseline 1,5-AG levels during the OGTT (P = 0.001, r(2) = 0.13), and the correlation was still significant after adjustment for age (2h-PG = 170 + 0.83 × (age in years) - 3.23 × (1,5-AG), P = 0.002, adjusted r(2) = 0.12). Finally, to investigate the test characteristics of 1,5-AG levels as a predictor of a 2h-PG level ≥200 mg/dL, we plotted a receiver operating characteristic (ROC) curve. The area under the ROC curve was 0.78, and the maximal sum of sensitivity and specificity (78% and 72%, respectively) was obtained at a 1,5-AG cutoff level of <14.2µg/mL. We conclude that 1,5-AG values may provide an ancillary predictor of 2h-PG of 75 g OGTTs in routine medical checkups.

Natural History of Cardiovascular Disease in Patients With Diabetes

Atherosclerotic vascular disease is more common in diabetic than in nondiabetic individuals. Diabetic macrovascular disease also has a more severe course with greater prevalence of multiple-vessel coronary artery disease and more diffuse elongated atheromas in affected blood vessels. In this review, we discuss possible reasons for increased incidence of cardiovascular (CV) events in individuals with diabetes. Although an increased prevalence of standard CV risk factors has been clearly documented in association with diabetes, diabetes-related abnormalities, particularly hyperglycemia, also play an important role. Epidemiological studies suggest that the effect of hyperglycemia on CV risk is independent of other known risk factors, but no data from primary interventional trials are available yet. Analysis of datasets from populations that included individuals with impaired glucose tolerance and impaired fasting glucose suggest that the pathogenic role of hyperglycemia on the blood vessel wall already exists in the early stages of glucose intolerance. The effect of postprandial or postchallenge hyperglycemia seems to be greater than the effect of fasting blood glucose abnormalities. The relationship of postprandial glycemia, fasting blood glucose, and CV risk in individuals with diagnosed (or overt) diabetes is less clear, although most reports indicate a greater pathogenic potential of postprandial hyperglycemia rather than fasting hyperglycemia. Based on the results of epidemiological reports, the most appropriate targets in interventional trials are postprandial hyperglycemia or A1C.

Effect of enhanced iron chelation therapy on glucose metabolism in patients with β‐thalassaemia major

Recently introduced chelation regimens that combine deferoxamine (DFO) and deferiprone have been shown to have greater efficacy in promoting iron excretion than either chelator alone and have been associated with rapid reduction of the iron load in the heart and liver, and with reversal of cardiac dysfunction. It is unclear whether this combined therapy could be associated with a reduction in iron load or decline in the severity of iron-induced endocrinopathies. Starting in January 2001, 42 patients with beta-thalassaemia major, previously maintained on subcutaneous DFO only, were switched to combined treatment with DFO and deferiprone. The primary endpoint was to investigate the effects of this therapy on the glucose metabolism characteristics of this population. Combination therapy markedly decreased ferritin levels (638 +/- 1345 vs. 2991 +/- 2093 microg/l, P < 0.001). Glucose responses were improved at all times during an oral glucose tolerance test, particularly in patients in early stages of glucose intolerance. Glucose quantitative secretion also decreased significantly with combined therapy, while no significant change occurred in insulin levels in any group. Insulin secretion, according to the homeostasis assessment model, markedly increased in all groups, while overall reduction in insulin sensitivity did not reach statistical significance. This study showed that the combination of DFO and deferiprone was associated with an improvement in liver iron deposition and glucose intolerance.

Disturbances in beta-cell function in impaired fasting glycemia.

In a cross-sectional study, we assessed beta-cell function and insulin sensitivity index (ISI) with hyperglycemic clamps (10 mmol/l) in 24 subjects with impaired fasting glycemia (IFG, fasting plasma glucose [FPG] between 6.1 and 7.0 mmol/l), 15 type 2 diabetic subjects (FPG >7.0 mmol/l), and 280 subjects with normal fasting glycemia (NFG, FPG <6.1 mmol/l). First-phase insulin release (0-10 min) was lower in IFG (geometric mean 541 pmol/l.10 min; 95% confidence interval [CI] 416-702 pmol/l.10 min) and in type 2 diabetes (geometric mean 376 pmol/l.10 min; 95% CI 247-572 pmol/l.10 min) than NFG (geometric mean 814 pmol/l.10 min; 95% CI 759-873 pmol/l.10 min) (P < 0.001). Second-phase insulin secretion (140-180 min) was also lower in IFG (geometric mean 251 pmol/l; 95% CI 198-318 pmol/l; P = 0.026) and type 2 diabetes (geometric mean 157 pmol/l; 95% CI 105-235 pmol/l; P < 0.001) than NFG (geometric mean 295 pmol/l; 95% CI 276-315 pmol/l). IFG and type 2 diabetic subjects had a lower ISI (0.15 plus minus 0.02 and 0.16 plus minus 0.02 micromol/kg fat-free mass [FFM]/min/pmol/l, respectively) than NFG (0.24 plus minus 0.01 micromol/kg FFM/min/pmol/l, P < 0.05). We found a stepwise decline in first-phase (and second-phase) secretion in NFG subjects with progressive decline in oral glucose tolerance (P < 0.05). IFG subjects with impaired glucose tolerance (IGT) had lower first-phase secretion than NFG subjects with IGT (P < 0.02), with comparable second-phase secretion and ISI. NFG and IFG subjects with a diabetic glucose tolerance (2-h glucose >11.1 mmol/l) had a lower ISI than their respective IGT counterparts (P < 0.05). We conclude that the early stages of glucose intolerance are associated with disturbances in beta-cell function, while insulin resistance is seen more markedly in later stages.

Clinical and biochemical studies in the prediabetic phase of tropical calcific pancreatitis.

The frequency of diabetes is much higher in tropical calcific pancreatitis (TCP) as compared with alcoholic chronic pancreatitis. We report 97 patients with tropical calcific pancreatitis and compare the profile of 21 patients without diabetes (called TCP for the purpose of this report) with that of 76 patients with diabetes, called fibrocalculous pancreatic diabetes (FCPD) according to the World Health Organization (WHO) study group classification of diabetes. TCP patients were a decade younger and had marginally higher body mass indices (BMIs) as compared with the FCPD group. Of the TCP patients, 13 had abnormal glucose tolerance tests (GTT) and the others had normal GTT. Immunoreactive insulin (IRI) responses to glucose load in the TCP group did not differ significantly from that of the control group. This study shows the existence of early stages of glucose intolerance in TCP.