Glycohemoglobin Levels Research Articles

Commentary: confidentiality of interim trial data-the emerging crisis.

Randomized controlled clinical trials (RCTs) represent the pinnacle of evidence used by clinicians and regulators to determine the effectiveness of therapeutic interventions. The importance of RCTs is so universally accepted that clinical practice guidelines for many fields of medicine assign the highest rating for quality of evidence (Class 1A) to recommendations supported by data derived from multiple RCTs. Similarly, regulators have generally required evidence derived from RCTs for approval of pharmacological interventions. These policies ensure that the therapies approved by regulatory agencies and endorsed by professional societies actually deliver the benefits promised to patients. Now, after decades of application, this paradigm is threatened by a looming crisis related to the ability to conduct cardiovascular safety trials of diabetes drugs using the highest standards of scientific integrity. As described by Fleming in this edition of Clinical Trials, maintaining the confidentiality of data for interim results from ongoing clinical trials is essential to maintaining the feasibility and reliability of these crucial studies. The current threat to clinical trial integrity arises from a regulatory crisis that emerged during the past decade. The US Food and Drug Administration (FDA) and global regulatory authorities traditionally approved diabetes drugs based primarily upon the ability of these agents to lower blood sugar in the absence of any apparent toxicity. Diabetes drugs were typically evaluated based upon short-term trials (6–12 months) showing a reduction in glycohemoglobin levels, a measure of average blood glucose values over the previous 3 months. In actual practice, most sponsors, to mitigate the risk of demonstrating toxicity, conducted relatively small trials (total sample size about 3000 patients) in populations with a predicted low likelihood of adverse clinical outcomes. However, like most surrogate outcomes, the use of average blood glucose values to approve diabetes drugs carried considerable theoretical risks. A therapeutic intervention could lower blood glucose, but worsen other important outcome measures, which would go undetected in the small, short-term trials conducted with glycemic endpoints. That’s exactly what happened. In 2005, the diabetes drug muraglitazar was presented to an FDA Advisory Panel, and a recommendation for approval received nearly unanimous support. A few weeks later, we published a meta-analysis of the clinical data presented to the FDA Panel, which showed an approximate doubling of the risk of major adverse cardiovascular events (MACE) in patients treated with muraglitazar compared with placebo or other glucoselowering therapies. Then, 2 years later, we published a meta-analysis of cardiovascular outcome data for an approved and widely prescribed drug, rosiglitazone, showing evidence for increased MACE. This latter publication resulted in considerable controversy with alarming newspaper headlines, Congressional inquiries, and public outcry. A consensus emerged that approval of diabetes drugs primarily on the basis of glucose lowering (without additional cardiovascular outcome data) was no longer tenable. Accordingly, the FDA assembled an advisory panel in 2008 to consider what changes in regulatory policy, if any, were needed. Two participants in that advisory committee meeting, Dr Fleming as a panel member and me as an invited speaker, proposed a new paradigm for diabetes drug approval. The approach we advocated was carefully designed to balance the need to approve new drugs for diabetes in a timely fashion with the compelling societal interest in making certain such drugs did not increase adverse cardiovascular outcomes. We weighed the risks and benefits of several approaches, including requiring a large-scale RCT prior to approval, but ultimately proposed a strategy that would require sponsors to rule out an upper 95% confidence interval (CI) for the hazard ratio (HR) for MACE of 1.8 prior to approval and an

ECOLOGO-PHYSIOLOGICAL CHARACTERISTICS OF CARBOHYDRATE-LIPID METABOLISM AND THYROID STATUS IN SCHOOLCHILDREN LIVING IN NORTHERN REGION

High body mass and obesity are of interest as a medical and social problem of the XXI century. Already at school age, many children have high body mass and obesity, one can state metabolic abnormalities in the serum lipids, carbohydrates, thyroid status. In the study, there have been examined 112 schoolchildren-nonresidents living in the Khanty-Mansiysk Autonomous Okrug: 44 - with high body mass and obesity, 68 - with normal body mass. In the group of the persons with high body mass and obesity, there have been determined reliably higher indices of general cholesterol, low-density lipoproteins, triglycerides (TG), glucose, glycohemoglobin and thyreotrophin and reliably lower indices of high-density lipoproteins and T3. There has been observed a positive correlation between glucose concentration and content of glycohemoglobin in blood (r = 0.983, p = 0.000), general cholesterol (r = 0.455, p = 0.002), triglycerides (r = 0.389, p = 0.034), free thyroxin (r = 0.314, p = 0.038). The level of glycohemoglobin correlated with the content of general cholesterol (r = 0.477, p = 0.001), triglycerides (r = 0.381, p = 0.038). The schoolchildren with high body mass and obesity had higher indices of carbohydrate-lipid metabolism and the thyroid status compared to the control group, what could cause a cascade of metabolic pathological states in young adult life period in the future.

Diabetes mellitus is an independent risk for gastroesophageal reflux disease among urban African Americans

An association between gastroesophageal reflux disease (GERD) and diabetes mellitus (DM) has been reported. Studies have not been population-based and have failed to include a representative sample of African American subjects. The aim of the study was to determine if DM is independently associated with GERD among urban African Americans. Single-center, population-based survey utilizing a complex, stratified sampling design. To obtain a simple random sample of the entire African American community, targeted survey zones and hand-delivered invitations were identified. Participating subjects had to be self-described African American, age ≥18. Surveys were completed at a computer terminal assisted by a research coordinator. Four hundred nineteen subjects (weighted sample size of 21 264 [20 888-23 930]). GERD prevalence was 23.7% (95% confidence interval [CI] 23.2-23.9). GERD prevalence was 41.5 % in those with DM versus 20.6 % for those without (P < 0.001). Those with GERD had DM longer but had lower glycohemoglobin levels. The prevalence of ≥2 DM comorbidities was higher in those with GERD (odds ratio [OR] = 2.06; 95% CI 1.71-2.48). In the final model, age >40, DM, increasing body mass index, harmful drinking, and increasing smoking dependence were independently associated with GERD. For DM, there was significant effect modification by gender. In males, the risk was (OR = 4.63; 95% CI 3.96-5.40), while in females, the risk was markedly attenuated (OR = 1.79; 95% CI 1.61-2.00). Among urban African Americans, there is an independent association between DM and GERD that appears to be stronger in men. More information is needed to understand this association.

Urinary polycyclic aromatic hydrocarbon biomarkers and diabetes mellitus

ObjectiveThe aim of the current study is to investigate the association of polycyclic aromatic hydrocarbons (PAHs), a group of environmental pollutants, with diabetes mellitus. Animal studies link PAHs to inflammation...

ADAPTIVE OPTICS IMAGING OF PARAFOVEAL CONES IN TYPE 1 DIABETES

To evaluate the parafoveal cone density in patients with Type 1 diabetes mellitus (DM1). Adaptive optics retinal images of the photoreceptor mosaic were acquired from 11 DM1 patients (study group) and 11 age-matched healthy subjects (control group). Cone density was analyzed, along the horizontal and vertical meridian, at 230-µm, 350-µm, and 460-µm eccentricity from the fovea. Central retinal thickness was measured using a Spectralis spectral-domain optical coherence tomography. A multiple regression model was performed to determine the relationships between the explanatory variables (age, glycohemoglobin level, presence of diabetic retinopathy, duration of diabetes, and central retinal thickness) and cone density. Patients had a diagnosis of DM1 in the past 9 years to 21 years. Of these, five patients had a diagnosis of no diabetic retinopathy and six had mild nonproliferative diabetic retinopathy. On average, cone density was 10% lower in the study than in the control group at each retinal eccentricity along the horizontal and vertical meridians (analysis of variance, P < 0.001). The central retinal thickness was thicker in DM1 eyes than in the control eyes (278 ± 20 µm and 260 ± 13 µm; P < 0.05). The model explained 61% (P < 0.01) of the variance of cone density in the population, with the variables representing an abnormal glucose metabolism, that is, a higher glycohemoglobin level, the presence of diabetic retinopathy, and a chronic diabetes, having the highest influence on cone density decline. A subtle decrease of parafoveal cone density was found in DM1 patients in comparison with age-matched control subjects via high-resolution adaptive optics retinal imaging. The cone density decline was moderately associated with a disturbance in the glucose metabolism.

An Attempt to Predict the Present Glycohemoglobin Level Based on the Glycated Albumin Level Measured Eight Years Earlier in Non-diabetic Individuals Evaluated at Health Checkups

An Attempt to Predict the Present Glycohemoglobin Level Based on the Glycated Albumin Level Measured Eight Years Earlier in Non-diabetic Individuals Evaluated at Health Checkups

The hyperglycemic and hyperinsulinemic combo gives you diabetic kidney disease immediately. Focus on “Combined acute hyperglycemic and hyperinsulinemic clamp induced profibrotic and proinflammatory responses in the kidney”

diabetic kidney disease (DKD) is the leading cause of end-stage kidney failure in the United States (11). Clinically, nephropathy induced by diabetes is characterized by albumin in the urine and declining glomerular filtration rate. On histological examination, diabetic kidney disease is a glomerular disease defined by mesangial expansion, nodular sclerosis, arterial hyalinosis (arteriolar thickening by deposition of pink hyaline material) leading to glomerulosclerosis and tubulointerstitial fibrosis. DKD is caused by hyperglycemia (HG) as reducing the glycohemoglobin levels from 9 to 7% in patients with type 1 diabetes resulted in a greater than 50% decrease in nephropathy development (3). However, recent studies of patients with type 2 diabetes failed to show a significant reduction in DKD progression when the glycohemoglobin target was reduced below 7% (4). Many of us would like to understand the reason for this surprising difference in nephropathy development and progression. One interpretation is that hyperglycemia is just one of the factors that play a role in the development of diabetic complications in type 2 diabetes and that hyperinsulinemia (HI), insulin resistance, and adiponectin could be equally important. In the current edition of the journal, Mariappan et al. (8) examine the effect of acute (7 h) combined hyperglycemia and hyperinsulinemia on profibrotic and proinflammatory gene expression in rat kidneys (8). The authors describe an approximately twofold increase in urinary isoprostane levels indicative of increased renal oxidative stress under these conditions. They observed a significant increase in renal TGF-β expression and its downstream mediator phospho-Smad3 (8). The expression of fibronectin and β1-laminin was also increased even after this short period of HI/HG. Increased expression of phosphorylated mTOR, S6 kinase, ERK, eIF4E, eIF4A are likely responsible for the increased matrix protein synthesis and kidney enlargement. The authors went on to identify the TLR4/Myd88 and NF-κB pathways as responsible for the increased cytokine expression in the context of hyperglycemia and hyperinsulinemia. In summary, the authors provide compelling evidence that acute HI combined with HG regulate the expression of multiple pathways known to play roles in DKD development. Unfortunately, the authors neglected to provide results from control rats exposed to hyperglycemia or hyperinsulinemia alone; thus, we cannot fully conclude whether these effects are mediated by glucose or the increased insulin levels. For example, we are left to wonder whether reactive oxygen species release is higher in HG/HI animals or lower compared with HG rats. In addition, the length of the “acute” treatment warrants further scrutiny of the time course of these changes. Do changes occur only acutely or are they still evident after prolonged hyperglycemia? Are changes reversible after periods of normoglycemia or are changes sustained? Acute changes in cellular metabolism can cause changes in the epigenome by providing more or less substrate for the key histone or DNA modifying enzymes (7). Cells cultured in high glucose-containing medium sustain changes in their histone modification patterns, for example, at the NF-κB locus, that are likely responsible for its sustained increased expression (5, 6, 9). Future studies will be necessary to determine whether the observed changes are reversible or sustained once euglycemic environment is reestablished. The study by Mariappan et al. is significant as it highlights the critical role of hyperinsulinemia in the development of diabetic kidney disease. Indeed, on a cellular level, it is possible that in the setting of both HI and HG, insulin shifts even more glucose into the intracellular compartment providing substrate for the mitochondria and increasing the reactive oxygen species release. Furthermore, the study provides experimental evidence for the notion that acute fluctuations of glucose and insulin levels may be just as damaging to cells as chronic elevated glucose levels (2). For example, in animal models of diabetes, increased reactive oxygen species release and podocyte apoptosis are observed right around the time when hyperglycemia develops and neither of these changes is sustained (10). As we do not routinely treat the hyperglycemia in diabetic mouse models, glucose levels are relatively constant in these animals, which could contribute to the fact that the diabetic mouse models do not develop progressive renal function decline (1). Clinical studies also support the notion that glycemic variability is a critical factor in the development of complications. In summary, this study provides the first description of acute HI/HG-induced kidney damage. In the future, this new model can be used to examine the patho-mechanism of DKD and develop new therapeutic interventions.

Effect of glycemic control on microalbuminuria development among type 2 diabetes with high-normal albuminuria

This study was aimed at revealing the factors and the interrelationships between factors on microalbuminuria development among type 2 diabetes (T2D) patients. Between 2004 and 2011, 461 T2D patients with a baseline urine albumin-to-creatinine ratio (UACR) of <30 mg/g, and an estimated glomerular filtration rate (eGFR) of >60 mL/min were evaluated retrospectively. Sixty-eight (14.8%) subjects had developed microalbuminuria in a mean follow-up of 6.82 years. Statistical analysis had revealed that the higher baseline UACR (10 mg/g; sensitivity, 80.9%, specificity, 63.6%; AUC = 0.774) and glycohemoglobin level (HbA1c) (8%; sensitivity, 72.1%, specificity, 61.6%; AUC = 0.698) were the two independent microalbuminuria risk factors. When considering the risk of microalbuminuria, the data were normalized with respect to subjects with low-normal UACR (<10 mg/g) and HbA1c < 8%. The adjusted hazard ratio for subjects with low-normal UACR/HbA1c > 8%, high-normal UACR/HbA1c < 8%, and high-normal UACR/HbA1c >8% were 2.59 (p = 0.107), 6.15 (p = 0.001), and 16.96 (p < 0.001), respectively. It was determined that an increase of HbA1c levels (<8, 8–9, 9–10, >10%) showed a progressively increase of the hazard risk in baseline high-normal UACR group. But the same correlation was not shown in the low-normal UACR group. This study identified the relationships of high-normal albuminuria and glycemic control on microalbuminuria development among T2D patients. Glycemic control is especially beneficial for T2D patients with baseline high-normal UACR in preventing microalbuminuria development.

Non–Islet Cell Tumor-Induced Hypoglycemia Associated with Macronodular Pulmonary Metastases from Poorly Differentiated Thyroid Carcinoma

Non-islet cell tumor-induced hypoglycemia (NICTH), a major cause of fasting hypoglycemia, is caused by the overproduction of incompletely processed, high molecular-weight insulin-like growth factor-II (IGF-II), termed "big" IGF-II. To the best of our knowledge, only two cases of thyroid carcinoma associated with NICTH have been documented. We report the case of a 72-year-old woman who was brought to the emergency department with impaired consciousness. The patient had a history of pulmonary metastases from poorly differentiated thyroid carcinoma (PDTC), spanning 12 years since initial treatment. Laboratory tests showed decreased plasma glucose levels even though immunoreactive insulin, IGF-I, and growth hormone (GH) were undetectable. Computed tomography (CT) scan revealed macronodular pulmonary metastases the estimated volume of which was 456 mL. Both the biochemical data and imaging results suggested NICTH. The results of Western blot analysis performed on a fractionated serum sample showed an increased expression of big IGF-II, an important indicator in the diagnosis of NICTH. Because the massive pulmonary metastases were considered inoperable, immunohistochemical analysis of stored formalin-fixed, paraffin-embedded tissues was performed. The analysis revealed that the tumor cells were positive for both IGF-II and thyroglobulin. A whole-body CT excluded extrapulmonary metastatic lesions. A retrospective review revealed a gradual decrease in glycohemoglobin levels accompanied by an increase in the estimated volume of pulmonary metastases. These findings suggested that NICTH had been caused by pulmonary metastases from PDTC. We describe here the third reported case of NICTH associated with thyroid carcinoma. This is also the first case reporting big IGF-II in the serum of a patient with thyroid carcinoma.

Glycohemoglobin Levels with Severity of Periodontitis in Non-Diabetic Population

Periodontal disease is closely related to type 2 diabetes and is an important complication of diabetes. There are few studies about the relationship the glycohemoglobin levels with severity of periodontitis in non-diabetic population. We therefore planned this study to evaluate the glycohemoglobin levels with severity of periodontitis in non-diabetic population. This study was conducted on 50 age and gender matched subjects in each of the three groups (according to the grades of mobility in periodontitis), a total of 150 non-diabetic periodontitis patients (Grade 1, Grade 2, and Grade 3 mobility) and 50 non-diabetic periodontitis patients with Grade 0 mobility (controls), in collaboration with the Department of Periodontics of Dental College and Department of Biochemistry, PGIMS, Rohtak, Haryana. After obtaining informed consent, fasting venous blood samples of all the non-diabetic periodontitis patients of all grades were collected aseptically for HbA1c, plasma glucose, and serum C-reactive protein (CRP) estimation. A total of 150 non-diabetic periodontitis patients (Grade 1, Grade 2, and Grade 3 mobility) and 50 age and gender matched controls participated in the study. There was no significant difference in fasting plasma glucose and postprandial plasma glucose in non-diabetic periodontitis patients with Grade 1, Grade 2, and Grade 3 mobility as compared to controls, non-diabetic periodontitis patients with Grade 1 mobility as compared to Grade 2, non-diabetic periodontitis patients with Grade 1 mobility as compared to Grade 3 and non-diabetic periodontitis patients with Grade 2 mobility as compared to Grade 3. Glycohemoglobin and serum C-reactive protein levels were significantly increased in non-diabetic periodontitis patients with Grade 1, Grade 2, and Grade 3 mobility as compared to controls, non-diabetic periodontitis patients with Grade 1 mobility as compared to Grade 3 and non-diabetic periodontitis patients with Grade 2 mobility as compared to Grade 3. The difference of serum C-reactive protein levels were significant. However, glycohemoglobin levels were non-significant between non-diabetic periodontitis patients with Grade 1 and Grade 2 mobility. The evidence of association between periodontitis and increased glycohemoglobin increases attention to the diagnosis and treatment of periodontitis, consequently improving the patient's oral health and prevention of occurrence in future diabetes. An understanding of these correlations is important to allow dental health care providers to inform patients with periodontitis of their increased risks and to counsel such patients to seek additional medical assessment or intervention as indicated.

Coordination chemistry may explain pharmacokinetics and clinical response of vanadyl sulfate in type 2 diabetic patients

Vanadium, abbreviated V, is an early transition metal that readily forms coordination complexes with a variety of biological products such as proteins, metabolites, membranes and other structures. The formation of coordination complexes stabilizes metal ions, which in turn impacts the biodistribution of the metal. To understand the biodistribution of V, V in oxidation state iv in the form of vanadyl sulfate (25, 50, 100 mg V daily) was given orally for 6 weeks to 16 persons with type 2 diabetes. Elemental V was determined using Graphite Furnas Atomic Absorption Spectrometry against known concentrations of V in serum, blood or urine. Peak serum V levels were 15.4 ± 6.5, 81.7 ± 40 and 319 ± 268 ng ml(-1) respectively, and mean peak serum V was positively correlated with dose administered (r = 0.992, p = 0.079), although large inter-individual variability was found. Total serum V concentration distribution fit a one compartment open model with a first order rate constant for excretion with mean half times of 4.7 ± 1.6 days and 4.6 ± 2.5 days for the 50 and 100 mg V dose groups respectively. At steady state, 24 hour urinary V output was 0.18 ± 0.24 and 0.97 ± 0.84 mg in the 50 and 100 mg V groups respectively, consistent with absorption of 1 percent or less of the administered dose. Peak V in blood and serum were positively correlated (r = 0.971, p < 0.0005). The serum to blood V ratio for the patients receiving 100 mg V was 1.7 ± 0.45. Regression analysis showed that glycohemoglobin was a negative predictor of the natural log(ln) peak serum V (R(2) = 0.40, p = 0.009) and a positive predictor of the euglycemic-hyperinsulinemic clamp results at high insulin values (R(2) = 0.39, p = 0.010). Insulin sensitivity measured by euglycemic-hyperinsulinemic clamp was not significantly correlated with ln peak serum V. Globulin and glycohemoglobin levels taken together were negative predictors of fasting blood glucose (R(2) = 0.49, p = 0.013). Although V accumulation in serum was dose-dependent, no correlation between total serum V concentration and the insulin-like response was found in this first attempt to correlate anti-diabetic activity with total serum V. This study suggests that V pools other than total serum V are likely related to the insulin-like effect of this metal. These results, obtained in diabetic patients, document the need for consideration of the coordination chemistry of metabolites and proteins with vanadium in anti-diabetic vanadium complexes.

Bilateral asteroid hyalosis revealing a blood imbalance

Asteroid hyalosis is an age related vitreous degeneration of unknown etiology, usually described to be unilateral. It's characterized by aggregation of calcium soaps in vitreous body. This benign condition has been reported to be frequently associated to many systemic disorders including diabetes mellitus, systemic arterial hypertension, atherosclerotic vascular disease, hypercholesterolemia and increased serum calcium levels. We report an unusual case of bilateral asteroid hyalosis revealing a diabetes in a previously healthy man. A 65-year old man presented with 2 years history of increasing bilateral eye floaters. The best corrected visual acuity was 6/10 in the right eye and 3/10 in the left eye. At examination there were dense vitreous clouds of bright white particles in both eyes, with fundus-obscuring; particularly in the left eye (Panel A), an abnormality of the retinal vasculature was suspected in the right eye (arrow). Fluorescein angiography showed bilateral retinal neovascularization (Panel B, arrowheads). A workup was performed revealing high levels of fasting glucose and glycohemoglobin with high levels of serum calcium, arterial pressure was within normal limits. This presentation was consistent with proliferative diabetic retinopathy with bilateral asteroid hyalosis. The patient was then referred to department of diabetology for further investigations and management of his diabetes. Meanwhile, Laser retinal photocoagulation was started in the right eye. However the marked vitreous degeneration in the left eye made photocoagulation with a conventional contact lens difficult; thus, prompt posterior vitrectomy with endolaser photocoagulation was indicated after intravitreal injection of anti-endothelial growth factor (anti VEGF) agents.

Suppression of GLUT1; A new strategy to prevent diabetic complications

High blood glucose results in high glucose levels in retina, because GLUT1, the sole glucose transporter between blood and retina, transports more glucose when blood glucose is high. This is the ultimate cause of diabetic retinopathy. Knockdown of GLUT1 by intraocular injections of a pool of siRNAs directed against SLC2A1 mRNA which codes for GLUT1 significantly reduced mean retinal glucose levels in diabetic mice. Systemic treatment of diabetic mice with forskolin or genistein, which bind GLUT1 and inhibit glucose transport, significantly reduced retinal glucose to the same levels seen in non-diabetics. 1,9-Dideoxyforskolin, which binds GLUT1 but does not stimulate adenylate cyclase had an equivalent effect to that of forskolin regarding lowering retinal glucose in diabetics indicating that cyclic AMP is noncontributory. GLUT1 inhibitors also reduced glucose and glycohemoglobin levels in red blood cells providing a peripheral biomarker for the effect. In contrast, brain glucose levels were not increased in diabetics and not reduced by forskolin. Treatment of diabetics with forskolin prevented early biomarkers of diabetic retinopathy, including elevation of superoxide radicals, increased expression of the chaperone protein β2 crystallin, and increased expression of vascular endothelial growth factor (VEGF). These data identify GLUT1 as a promising therapeutic target for prevention of diabetic retinopathy.

Altered Homeostasis of Systemic Glucocorticoids as Related to Obesity, Glucose Tolerance, and Smoking

The hypothalamic-pituitary-adrenal axis is supposed to be involved in the pathogenesis of the metabolic disorders. Differences in adipose tissues and parameters of insulin resistance are linked to steroid homeostasis. We assessed the correlation of fat tissue distribution, gender, and glucose control with levels of systemic corticosteroid-binding globulin (CBG), free cortisol (FuF), and total cortisol (FuM). Data of 1 114 patients with overweight, lipid disorders, and impaired glucose tolerance were collected. Blood samples were sorted according to gender and anthropometric measures. Variable-association was calculated using the Spearman Rank Correlation coefficient and tested for significance (p<0.05 and p<0.01). CBG and FuF were consistently negatively correlated to each weight parameter. Especially in women, fat mass index (FMI) was significantly negatively correlated with CBG-levels. While CBG levels dropped with increasing age, FuF showed an inverse behavior. Glycohemoglobin levels showed negative correlations with CBG while fasting glucose did not. Both changes were associated with significant increases in FuF. All negative correlations to cortisol and its binding globulin with regards to weigh- and glucose-control parameters were absent in smokers compared to nonsmokers. Our observations suggest that different weight parameters correspond to adrenal steroids and their buffer systems. Especially in women, CBG levels might serve as prognostic marker for the fat mass. In addition, CBG levels may predict long term blood glucose control more reliably than FG. However, the value of CBG as an indirect surrogate-marker for obesity and glucose is limited in smokers.

Abstract 121: Relationship of Vitamin D Level with Cardiovascular Fitness: Does Demography Matter?

Background: Recent studies have suggested association of vitamin D with cardiovascular events. The relationship of vitamin D deficiency with cardiovascular fitness level (CVF) has not been studied in current literatures. Demographic variation of this association is also unclear. The primary objective of our study was to assess the relationship of vitamin D level to CVF and evaluate the demographic variation of this association in young adults. The secondary objective of this study was to assess the relationship of vitamin D level with the other cardiovascular risk factors. Methods: We evaluated 5388 adults from National Health and Nutrition Examination Survey 2001-2004. The associations of serum 25-hydroxy vitamin D level with CVF and cardiovascular risk factors such as systolic/diastolic blood pressure (SBP/DBP), low density lipoprotein (LDL), high density lipoprotein (HDL), and glycohemoglobin (HbA1c) levels in young adults aged 20-49 years were evaluated. Adults with vitamin D deficiency (≤30 mg/dL) and normal vitamin D level (&gt;30 mg/dL) were compared. The CVF was assessed with peak oxygen uptake on treadmill test (VO2 max &lt;20 percentile= low CVF, VO2 max ≥60 percentile= high CVF). Chi square analysis and odds ratio were calculated to assess the association of vitamin D deficiency with CVF. Pearson correlation was measured for the secondary analysis of association of vitamin D level with cardiovascular risk factors. The alpha error ≤0.05 was used as a level of significance. Results: Total of 85.4% (n=4603/5388) young adults had vitamin D deficiency. Vitamin D level was positively associated with CVF (p&lt;0.001). In comparison to normal vitamin D level, vitamin D deficiency was significantly associated with low CVF (Odds ratio 2.01, confidence interval 1.64-2.46, p&lt;0.001). In contrast to normal vitamin D level, vitamin D deficiency was significantly associated with low CVF in subgroups of males (p&lt;0.01), females (p&lt;0.01), age group of 20-29 years (p&lt;0.01) and age group of 30-49 years (p&lt;0.01). In contrast to normal vitamin D level, vitamin D deficiency was significantly associated with low CVF only in Caucasians (p=0.001). This association was not significant in Mexican-Hispanics (p=0.35), other Hispanics (p=0.095), African Americans (p=0.061) and other races (p=0.206). In comparison to normal vitamin D level, vitamin D deficiency was significantly associated with low CVF among normal BMI (p&lt;0.001), overweight BMI (p&lt;0.001) and obese adults (p=0.019) but not in underweight BMI adults (p=0.48). Vitamin D level was inversely associated with SBP (p&lt;0.001), and HbA1c (p&lt;0.001) and positively associated with HDL (p&lt;0.001). There was no significant association found between vitamin D level and DBP (p=0.66) or LDL (p=0.79). Conclusions: The results of our study demonstrate that vitamin D deficiency may decrease CVF in Caucasian young adults. Surprisingly it may not affect CVF in other races and underweight adults. Vitamin D deficiency is also associated with increase in cardiovascular risk factors such as low HDL, high SBP and HbA1c. The large population based clinical trials are needed for evaluation of this relationship and long-term consequences on cardiovascular outcomes.

Ischemic Stroke After Low-voltage Electric Injury in a Diabetic and Coagulopathic Woman

Electric injury is a common physical injury in daily life. Because of the low resistance of vascular tissue, vascular injury and thrombosis are frequently found in cases of high-voltage electric injury but are rarely reported in low-voltage conditions. We present the case of a diabetic woman who suffered symptomatic brainstem stroke after a short duration of 60 Hz/110 V alternate current electric contact with a home washer socket. A stroke risk factor survey did not reveal remarkable cardiac or vascular abnormality, except increased glycohemoglobin levels and decreased protein C activity. In contrast to a direct and adequate energy transfer in high-voltage electric injury, a pre-existing vasculohemostatic deficit, such as coagulopathy, has been proposed to provide a predisposition to thrombosis in low-voltage electric injury. Nevertheless, the findings in this patient remind the possibility of physical triggering factor for stroke occurrence in our environment as new technology and product generates rapidly enough for understanding their safety and biologic effect.

Association of Metabolic Dysregulation With Volumetric Brain Magnetic Resonance Imaging and Cognitive Markers of Subclinical Brain Aging in Middle-Aged Adults

OBJECTIVEDiabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer’s disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.RESEARCH DESIGN AND METHODSFramingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998–2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).RESULTSWe observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).CONCLUSIONSMetabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.

High-intensity Exercise Training Attenuates Diabetes-induced Muscle Capillary Regression In Non-obese NIDDM Rats

Exercise has been shown to be an effective non-pharmacological treatment in the prevention of some disease complications due to type 2 diabetes mellitus (T2DM). PURPOSE: The purpose of this study was to explore the effects of high-intensity running exercise on the 3-D microangiopathic structural changes of the capillary networks and associated angiogenic factors in the soleus muscle of non-obese T2DM rats. METHODS: Male Goto-Kakizaki (6 weeks old) spontaneously non-obese diabetic rats were used as a model of non-insulin dependent diabetes mellitus (NIDDM). Three groups of rats were studied: sedentary diabetic (T2DM), exercised diabetic (T2DM+Ex), and age-matched sedentary non-diabetic control (Con, wild-type Wistar) rats. The exercised rats were run at a relatively high-intensity (lactate > 9 mmol/L) on a treadmill. This protocol consisted of running at 20 m/min at a 20° incline for 30 min /session, 5 sessions /week for 3 weeks. The capillary network of the soleus muscle was visualized using confocal laser microscopy. The mRNA expression levels of several angiogenic factors (VEGF, KDR, Flt-1, Ang-1, Ang-2, Tie-2, and HIF-1 alpha) were determined in the soleus by TaqMan probe-based real-time PCR. RESULTS: Both T2DM and T2DM+Ex rats had higher levels of plasma glucose and glycohemoglobin compared to Con rats. The level of reactive oxygen species was higher in T2DM+Ex than Con and T2DM rats. The capillary volume of the soleus was lower in T2DM than Con rats. In contrast, the capillary volume was higher in T2DM+Ex than Con and T2DM rats. In addition the expression levels of all angiogenic factors in the soleus were lower in T2DM than Con and T2DM+Ex rats, except for VEGF and Ang-1 which were similar to Con rats. Furthermore, all values were higher in the T2DM+Ex than Con and T2DM rats. CONCLUSIONS:The present results indicate that high-intensity running exercise training reduces muscle circulatory complications associated with NIDDM in rats.

Relevance of the serum apolipoprotein ratio to diabetic retinopathy

To determine the correlations among apoA-1, apoB, and apoB/A-1, the ratio of the first two and their relation to the severity of diabetic retinopathy (DR). A total of 116 patients with type 2 diabetes, 34 with nonproliferative diabetic retinopathy (NPDR) and 82 with proliferative diabetic retinopathy (PDR), were included. The serum levels of apoA-1, apoB, and the apoB/A-1 ratio were compared. We performed multiple regression analyses to determine whether age, diabetes duration, glycohemoglobin level, estimated glomerular filtration rate, body mass index, or hypertension contribute to PDR. The apoB levels were lower in the NPDR group than in the PDR group (90.8 ± 21.4 versus 102.5 ± 25.3 mg/dl) (P = 0.02). The apoA-1 levels did not differ between the groups. The apoA-1 was lower in the PDR group than in the NPDR group (136.9 ± 24.9 versus 145.6 ± 21.2 mg/dl) mg/dl (P = 0.08). The apoB/A-1 ratio differed significantly between groups (NPDR versus PDR, 0.64 ± 0.20 versus 0.77 ± 0.24) (P = 0.004). Age, apoB/A-1, and diabetes duration were independent risk factors for PDR (R = -3.49, 3.06, and 2.44; standard regression coefficient, -0.33, 0.28, and 0.23; P = 0.0007, P = 0.003, and P = 0.02, respectively). The PDR group had significantly higher serum levels of apoB and apoB/A-1 than the NPDR group. The apoB/A-1 ratio may contribute to PDR progression in patients with DR. High apoB and apoB/A-1 values may be related to PDR development.

Factors Associated with Cognitive Decline in Elderly Diabetics

Background/Aims: Although recent evidence has indicated that type 2 diabetes mellitus (T2DM) in the elderly is a risk factor for cognitive dysfunction or dementia, few studies have prospectively observed this potential cognitive decline. In the current study, we performed cognitive assessments at baseline and after 3 years in the same patient group in an attempt to reveal the contributions of diabetes-related factors to the increased decline in cognitive function in elderly patients with T2DM. Methods: We recruited 55 consecutive T2DM patients with a Mini-Mental State Examination (MMSE) score ≧24 from the Diabetic Center at the Chubu Rosai Hospital. These patients ranged in age from 65 to 85 years. Cognitive and clinical assessments, including brain MRI, were performed at baseline and at the 3-year follow-up. Results: The higher plasma insulin and HbA_1c levels observed at baseline were significantly associated with a worse cognitive performance at baseline and a more neurocognitive decline at the follow-up visit. Conclusion: The current prospective study suggests that higher insulin and glycohemoglobin levels may be associated with diabetes-related cognitive dysfunction.