Effects Of Type 2 Diabetes Research Articles

Hippocampal Neurochemical Profile and Glucose Transport Kinetics in Patients With Type 1 Diabetes.

Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical profile. Upregulation of hippocampal glucose transport as a result of recurrent exposure to hypoglycemia may preserve cognitive function during future hypoglycemia in subjects with T1D and impaired awareness of hypoglycemia (IAH). The effect of T1D on hippocampal neurochemical profile and glucose transport is unknown. To test the hypothesis that hippocampal neurochemical composition is altered in T1D and glucose transport is upregulated in T1D with IAH. Hippocampal neurochemical profile was measured with single-voxel magnetic resonance spectroscopy at 3T during euglycemia in 18 healthy controls (HC), 10 T1D with IAH, and 12 T1D with normal awareness to hypoglycemia (NAH). Additionally, 12 HC, 8 T1D-IAH, and 6 T1D-NAH were scanned during hyperglycemia to assess hippocampal glucose transport with metabolic modeling. University medical center. Concentrations of hippocampal neurochemicals measured during euglycemia and ratios of maximal transport rate to cerebral metabolic rate of glucose (Tmax/CMRGlc), derived from magnetic resonance spectroscopy-measured hippocampal glucose as a function of plasma glucose. Comparison of hippocampal neurochemical profile revealed no group differences (HC, T1D, T1D-IAH, and T1D-NAH). The ratio Tmax/CMRGlc was not significantly different between the groups, T1D-IAH (1.58 ± 0.09) and HC (1.65 ± 0.07, P = 0.54), between T1D-NAH (1.50 ± 0.09) and HC (P = 0.19), and between T1D-IAH and T1D-NAH (P = 0.53). Subjects with T1D with sufficient exposure to recurrent hypoglycemia to create IAH did not have alteration of Tmax/CMRglc or neurochemical profile compared with participants with T1D-NAH or HC.

Hydrogen sulfide potentiates the favorable metabolic effects of inorganic nitrite in type 2 diabetic rats

ObjectiveDecreased nitric oxide (NO) bioavailability and hydrogen sulfide (H2S) deficiency have been linked with the pathophysiology of type 2 diabetes (T2D). Restoration of NO levels by nitrite have been associated with favorable metabolic effects in T2D. Moreover, H2S can potentiate the effects of NO in the cardiovascular system. The aim of this study was to determine the effects of long-term co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on carbohydrate metabolism in type 2 diabetic rats. MethodsT2D was induced using chronic high fat diet (HFD) feeding combined with low dose streptozotocin (STZ) regimen. Rats were divided into 5 groups (N = 10/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite + NaSH. Nitrite (50 mg/L in drinking water) and NaSH (0.28 mg/kg, daily i. p. injection) were administered for 9 weeks. Fasting serum glucose, insulin, lipid profile, liver function tests, and oxidative stress indices were measured. Intraperitoneal glucose tolerance test (GTT) was performed at the end of the eighth week, and three days later, intraperitoneal pyruvate tolerance test (PTT) was done. Protein levels and mRNA expression of glucose transporter type 4 (GLUT4) in soleus muscle and epididymal adipose tissue as well as mRNA expression of H2S-producing enzymes in the liver, soleus muscle, and epididymal adipose tissue were measured at the end of the study. ResultsCompared to the controls, HFD and STZ treated rats developed metabolic dysfunction. Nitrite treatment improved carbohydrate metabolism, liver function, and oxidative stress indices whereas NaSH treatment per se had no significant effects. However, co-administration of NaSH and nitrite resulted in further improvement in serum insulin level, GTT, PTT, liver function, oxidative stress, protein level and mRNA expression of GLUT4, as well as mRNA expression of H2S-producing enzymes in diabetic rats. ConclusionLow dose of NaSH per se had no effect on carbohydrate metabolism while it potentiated the favorable metabolic effects of inorganic nitrite in type 2 diabetic rats. These favorable effects were associated with decreased oxidative stress and increased GLUT4 expression in insulin-sensitive tissues as well as improvement of liver function.

Type 2 diabetes induced oxidative brain injury involves altered cerebellar neuronal integrity and elemental distribution, and exacerbated Nrf2 expression: therapeutic potential of raffia palm (Raphia hookeri) wine.

Neurodegenerative diseases, such as Alzheimer's disease have been recognized as one of the microvascular complications of type 2 diabetes (T2D). In this study, the effect of T2D on neuronal integrity and elemental distribution in the cerebellar cortex, as well as the therapeutic effect of Raffia Palm (Raphia hookeri) wine (RPW) were investigated in male albino rats. T2D was induced in 4 groups of rats using fructose and streptozotocin. One group served as negative control which was administered water, the second and third group were administered 150 and 300mg/kg bodyweight of RPW, while the fourth was administered metformin (200mg/kg bodyweight). Two other groups of normal rats were administered distilled water (control) and of RPW (300mg/kg bodyweight). The rats were sacrificed after 5weeks of treatment, and brains were collected. The cerebellum was removed, and several parts analyzed by immunochemistry, histology and scanning electron microscopy (SEM). Remaining brain tissues were used to analyze for the oxidative stress biomarkers and acetylcholinesterase activity. These analyses revealed oxidative damage with concomitantly increased acetylcholinesterase activity and upregulation of Nrf2 expression in the diabetic brain cerebellar cortexes. Histological and microscopic analysis also revealed altered distribution of neurons and axonal nodes with concomitant elevated levels of several heavy metals. Treatment with RPW significantly elevated glutathione (GSH) level, superoxide dismutase (SOD) and catalase activities, as well as depleted acetylcholinesterase and malondialdehyde (MDA) level and concomitantly inhibited Nrf2 expression. It also improved neuronal integrity and reduced the levels of heavy metals in brain. Taken together, the results of this study suggest that the RPW may afford a novel neuroprotective potential against diabetic neurodegeneration.

1346-P: Longitudinal Evaluation of Cognitive Functioning in Young Children with Type 1 Diabetes: Persistent Effects on IQ and Vocabulary

Background: Subtle but significant cognitive differences between youth with and without type 1 diabetes (T1D) have been observed and found to be related to chronic hyperglycemia. We report continued follow-up of prospectively acquired cognitive data obtained over 4.5 years in a large cohort of young children with and without T1D. Methods: 181 children with T1D and 90 age-matched nondiabetic controls underwent age-appropriate neuropsychological testing at three time points: baseline, 18 months, and approximately 2.9 years after the second visit (T1D group: 11.2 ± 1.9 y, HbA1c: 8.1 ± 1.0%, diabetes duration 6.4 y at the time of latest evaluation; control group: mean age 11.6 ± 1.7 years). Effects of T1D on cognition were estimated based on longitudinal mixed effects modeling after controlling for parental full-scale IQ. Results: The T1D group continued to show significantly lower scores on Full Scale IQ (Cohen’s d=-0.31, p=0.024), Verbal IQ (d=-0.33, p=0.009), and Vocabulary (d=-0.42, p=0.002) compared to nondiabetic controls at last follow-up. Processing speed, memory and learning were similar between the T1D and the control groups. Within the T1D group, there was a significant inverse relationship between HbA1c at last follow-up and Vocabulary (r=-0.307, p=0.001) as well as between HbA1c and VIQ (r=-0.200, p=0.037), controlling for parental IQ. Conclusion: In this large cohort of children with relatively well-controlled T1D followed for 4.5 years, differences in full-scale and verbal IQ persist over time compared to nondiabetic controls, and effects on vocabulary and verbal IQ are related to glycemic control. These findings further support the importance of optimizing glycemic control during this critical period of brain maturation. Disclosure S.A. Weinzimer: Consultant; Self; Eli Lilly and Company, Sanofi. Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Stock/Shareholder; Self; InsuLine Medical Ltd. J.M. Ambrosino: Consultant; Spouse/Partner; Eli Lilly and Company, Sanofi. Consultant; Self; Tandem Diabetes Care. Consultant; Spouse/Partner; Zealand Pharma A/S. Speaker's Bureau; Spouse/Partner; Insulet Corporation, Medtronic, Tandem Diabetes Care. Stock/Shareholder; Spouse/Partner; InsuLine Medical Ltd. A. Cato: None. B. Jo: None. K.A. Englert: Consultant; Self; PicoLife Technologies, LLC. N.H. White: None. A. Arbelaez: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. L.A. Fox: None. E. Tsalikian: None. M. Tansey: Advisory Panel; Self; Daiichi Sankyo Company, Limited. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care. T. Aye: None. D.M. Wilson: Advisory Panel; Self; Tolerion, Inc. Research Support; Self; Beta Bionics, Dexcom, Inc., Medtronic. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. A.L. Reiss: None. N. Mauras: Consultant; Self; Novo Nordisk Inc., PicoLife. Research Support; Self; Medtronic MiniMed, Inc. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (DIRECNET: U01HD-41906, HD-41908, HD-41915, HD-41918, HD-56526, R01HD-078463, U54HD087011); National Center for Advancing Translational Sciences (UL1TR000448)

209-OR: ADA Presidents' Select Abstract: Type 1 Diabetes and the Developing Brain—A Longitudinal Study of Brain Growth by the Diabetes Research in Children Network (DirecNet)

Background: The extent to which glycemic exposure adversely impacts the developing brain in young children with early-onset type 1 diabetes (T1D) is controversial. Methods: As part of the multisite DirecNet Study, we performed structural MRI at three time points (baseline, 18 months and approximately 2.9 years after the second visit) in 137 children with T1D (age: 7.0 ± 1.7 years, lifetime average HbA1c: 8.0 ± 0.7%, and diabetes duration: 2.4 years at study entry) and 66 age-matched nondiabetic controls (7.0 1.8 years old). White matter (WM) and gray matter (GM) volumes in various brain regions-of-interest were determined by voxel-based morphometry (VBM). Total cumulative hyperglycemic exposure was determined as HbA1c area under the curve (lifetime A1c) from the time of diagnosis in T1D children. Results: Children with T1D had slower growth of total cortical and subcortical GM and WM than the nondiabetic controls at all timepoints. Gray matter regions (frontal, temporal, subcortical, and occipital cortex) showed less growth in the T1D compared to the control group (p<0.05 family wise error (FWE)-corrected), as did white matter areas (temporal, parietal, and occipital white matter) (p<0.05 FWE-corrected). The occipital-cerebellar and basal ganglia regions appeared to be most vulnerable to the effects of T1D in children. The regions of slower growth were associated with higher lifetime A1c values (p<0.05 false discovery rate (FDR)-corrected). Conclusion: This study demonstrates that children with early-onset T1D and worse glycemic control have slower cortical and subcortical GM and WM growth than nondiabetic controls, suggesting that hyperglycemia is detrimental to the developing brain during this critical period of rapid brain maturation. The long-term consequences of these early alterations in brain growth require further follow-up. Disclosure A. Arbelaez: None. S. O’Donoghue: None. N. Mauras: Consultant; Self; Novo Nordisk Inc., PicoLife. Research Support; Self; Medtronic MiniMed, Inc. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care. N.H. White: None. S.A. Weinzimer: Consultant; Self; Eli Lilly and Company, Sanofi. Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Stock/Shareholder; Self; InsuLine Medical Ltd. T. Aye: None. E. Tsalikian: None. D.M. Wilson: Advisory Panel; Self; Tolerion, Inc. Research Support; Self; Beta Bionics, Dexcom, Inc., Medtronic. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. M. Tansey: Advisory Panel; Self; Daiichi Sankyo Company, Limited. A. Cato: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. L.A. Fox: None. K.A. Englert: Consultant; Self; PicoLife Technologies, LLC. A.L. Reiss: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (DIRECNET: U01HD-41906, HD-41908, HD-41915, HD-41918, HD-56526, R01HD078463, U54HD087011; National Center for Advancing Translational Sciences (UL1TR000448)

The additive effect of type 2 diabetes on fibrinogen, von Willebrand factor, tryptophan and threonine in people living with HIV.

Chronic immune activation and ensuing inflammation that accompany HIV infection lead to adverse metabolic consequences and an increased risk of type 2 diabetes (T2D). We examined the additive effects of T2D on circulating biomarkers involved in inflammation, coagulation, and vascular function along with plasma amino acids in people living with HIV (PLWH). This cross-sectional study included PLWH with and without T2D (n = 32 total). Analyses involved a multiplex platform for circulating biomarkers and gas chromatography-vacuum ultraviolet spectroscopy for plasma amino acids. In PLWH and T2D, both fibrinogen (2.0 ± 0.6 vs 1.6 ± 0.4µg/mL, p = 0.02) and von Willebrand factor (vWF) (40.8 ± 17.2 vs 26.7 ± 13.8µg/mL, p = 0.02) were increased and tryptophan (47 ± 6 vs 53 ± 8nmol/mL, p = 0.03) and threonine (102 ± 25 vs 125 ± 33nmol/mL, p = 0.03) were decreased. Fibrinogen, as a biomarker of inflammation, and vWF, as a biomarker of endothelial dysfunction, are augmented by the combined effects of HIV and T2D and may contribute to the pathogenesis of T2D in PLWH. Chronic immune activation and inflammation compromise the integrity of the intestinal mucosa, which increases mucus production. Tryptophan metabolism is altered by a loss of intestinal membrane integrity and threonine is consumed in the production of mucus. Metabolic competition arising from increased protein synthesis in the setting of chronic inflammation along with the associated loss in intestinal membrane integrity may be a primary mechanism in the pathogenesis of T2D in PLWH and requires further investigation.

Raffia palm (Raphia hookeri) wine extenuates redox imbalance and modulates activities of glycolytic and cholinergic enzymes in hyperglycemia-induced testicular injury in type 2 diabetic rats.

This study investigated the effects of Raffia palm wine (RPW) on redox imbalance, glycolytic and cholinergic enzymes, and ATPase activities in hyperglycemia-induced oxidative testicular injury. Type 2 diabetes (T2D) was induced in male albino rats (Sprague-Dawley) by first administering 10% fructose solution for 14 days, before injecting with an intraperitoneal injection (40mg/kg body weight) of streptozotocin. Raffia palm wine was administered to two diabetic groups at 150 and 300mg/kg body weight (bw), when untreated diabetic group was used as a negative control, and metformin-fed group was served as a positive control. The rats were sacrificed after 5 weeks of treatment, and testes were harvested. Treatment with RPW led to lower levels of nitric oxide, malondialdehyde and myeloperoxidase activity, with concomitant elevation of reduced glutathione level, superoxide dismutase, catalase and ATPase activities. Raffia palm wine also inhibited glycogen phosphorylase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and acetylcholinesterase, while restoring the altered testicular morphology to near-normal. The results of this study suggest the therapeutic potentials of RPW against the effects of T2D on testicular functions and morphology. PRACTICAL APPLICATIONS: Diabetes mellitus is one of the fastest growing global epidemy, with most developing countries being at the receiving end owing to the cost of treatment. Testicular damage has been recognized as one of the complications of diabetes, and if left untreated will lead to erectile dysfunction followed by infertility. Raffia palm wine is among the common natural beverage in West Africa, which is utilized for both social and medicinal purposes. In this study, for the first time we showed its ability to protect diabetes-induced testicular injury in type 2 diabetic rats. This may be of great benefit in managing diabetes associated erectly dysfunction and male infertility, as Raffia palm wine is readily available in all seasons. This study will also improve the medicinal use of this wine, which may also indirectly improve its commercial benefit.

Resistance Bands Training Improved Strength and Glycemic Control: The DARE-Bands Trial

Background: Gym-based resistance training with weights or weight machines improves strength and glycemic control (A1C) in type 2 diabetes (T2D). Resistance training with elastic bands (RBT) is a potential alternative, but its effects in T2D have not previously been evaluated in a high-quality randomized trial. The Diabetes Aerobic and REsistance Bands Exercise (DARE-Bands) trial aimed to determine the effects of RBT on strength and A1C in T2D.

Nonalcoholic Fatty Liver Disease as a High-Value Predictor of Postoperative Hyperglycemia and Its Associated Complications in Major Abdominal Surgery

For patients undergoing major abdominal operations, acute postoperative hyperglycemia (POHG) is associated with suboptimal outcomes and higher costs of care. This study was performed to determine whether CT-derived indices of nonalcoholic fatty liver disease (hepatic steatosis) or visceral adiposity may serve as predictors of POHG and its consequences in such patients. We reviewed records and preoperative abdominal CT images of 129 patients undergoing complex open ventral hernia repair (cVHR) from 2012 to 2016, with 90-day follow-up. Univariate and multivariate regressions were performed to estimate associations between CT-detected steatosis or visceral adiposity with POHG (serum glucose > 140 mg/dL within 48 hours), surgical site occurrence (SSO), and subsequent interventions (SSO-I). Type-2 diabetes (T2D) was present in 23% and POHG in 52%; SSO events occurred in 28% and SSO-I in 21%. Highest-effect associations with POHG were observed for T2D (odds ratio [OR] 21.54; 95% CI 4.85, 95.58), hepatic steatosis (OR 2.20, 95% CI 1.07, 4.52), and waist circumference-to-height ratio (WCHR > 0.65; OR 2.37, 95% CI 1.16, 4.83). After multivariate analysis, the effects of T2D (OR 16.73; CI 5.42, 73.87; p < 0.0001) and steatosis (OR 2.55; CI 1.17, 5.69; p= 0.02) remained independently associated with POHG. Independent associations with SSO were observed for steatosis (OR 3.31; CI 1.41, 8.06; p= 0.007), POHG (OR 2.85; CI 1.17, 7.38; p= 0.024), and WCHR (OR 2.68; CI 1.11, 6.85; p= 0.03). Image-based indices of chronic metabolic disturbance in the liver and adipose tissues may offer novel opportunities for identifying patients at risk for POHG and those who would benefit from preoperative metabolic optimization.

Causal associations between risk factors and common diseases inferred from GWAS summary data

Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer’s disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative).

Effect of verbal task complexity in a working memory paradigm in patients with type 1 diabetes. A fMRI study.

Type 1 diabetes (T1D) is commonly diagnosed in childhood and adolescence, and the developing brain has to cope with its deleterious effects. Although brain adaptation to the disease may not result in evident cognitive dysfunction, the effects of T1D on neurodevelopment could alter the pattern of BOLD fMRI activation. The aim of this study was to explore the neural BOLD activation pattern in patients with T1D versus that of healthy matched controls while performing two visuospatial working memory tasks, which included a pair of assignments administered through a block design. In the first task (condition A), the subjects were shown a trial sequence of 3 or 4 white squares positioned pseudorandomly around a fixation point on a black background. After a fixed delay, a second corresponding sequence of 3 or 4 red squares was shown that either resembled (direct, 50%) or differed from (50%) the previous stimulation order. The subjects were required to press one button if the two spatial sequences were identical or a second button if they were not. In condition B, the participants had to determine whether the second sequence of red squares appeared in inverse order (inverse, 50%) or not (50%) and respond by pressing a button. If the latter sequence followed an order distinct from the inverse sequence, the subjects were instructed to press a different button. Sixteen patients with normal IQ and without diabetes complications and 16 healthy control subjects participated in the study. In the behavioral analysis, there were no significant differences between the groups in the pure visuo-spatial task, but the patients with diabetes exhibited poorer performance in the task with verbal stimuli (p < .001). However, fMRI analyses revealed that the patients with T1D showed significantly increased activation in the prefrontal inferior cortex, subcortical regions and the cerebellum (in general p < .001). These different activation patterns could be due to adaptive compensation mechanisms that are devoted to improving efficiency while solving more complex cognitive tasks.

Does type 2 diabetes mellitus promote intervertebral disc degeneration?

PurposeLDD is an important cause of low back pain. Many people believe there is an adverse influence of type 2 diabetes (T2D) on lumbar intervertebral disc degeneration (LDD). We examined a population sample for epidemiological evidence of association.MethodsTwin volunteers from the TwinsUK cohort having spine magnetic resonance (MR) scans coded for LDD and information about T2D were investigated in two ways. First, as a population sample and second as a cotwin case control study in twin pairs discordant for T2D. Other risk factors for LDD considered were age, body-mass index (BMI), smoking, and alcohol.ResultsIn 956 twin volunteers T2D had a prevalence of 6.6 %. LDD score was higher in T2D twins (14.9 vs 13.1 p = 0.04) but was not an independent risk factor if the influence of age and BMI were included in the model. Discordant twin analysis (n = 33 pairs) showed no significant difference in LDD between twins having T2D and their unaffected cotwins.ConclusionsTwins having T2D did manifest higher LDD scores but the effect was abrogated once BMI was included in multivariable analysis, showing it is not an independent risk factor for LDD. The population study had 80 % power at 0.1 significance level to detect a difference of 1.8 in LDD score (range of 0–60), so if there is an effect of T2D on LDD, it is likely to be small.

Assessment of whole-genome regression for type II diabetes.

Lifestyle and genetic factors play a large role in the development of Type 2 Diabetes (T2D). Despite the important role of genetic factors, genetic information is not incorporated into the clinical assessment of T2D risk. We assessed and compared Whole Genome Regression methods to predict the T2D status of 5,245 subjects from the Framingham Heart Study. For evaluating each method we constructed the following set of regression models: A clinical baseline model (CBM) which included non-genetic covariates only. CBM was extended by adding the first two marker-derived principal components and 65 SNPs identified by a recent GWAS consortium for T2D (M-65SNPs). Subsequently, it was further extended by adding 249,798 genome-wide SNPs from a high-density array. The Bayesian models used to incorporate genome-wide marker information as predictors were: Bayes A, Bayes Cπ, Bayesian LASSO (BL), and the Genomic Best Linear Unbiased Prediction (G-BLUP). Results included estimates of the genetic variance and heritability, genetic scores for T2D, and predictive ability evaluated in a 10-fold cross-validation. The predictive AUC estimates for CBM and M-65SNPs were: 0.668 and 0.684, respectively. We found evidence of contribution of genetic effects in T2D, as reflected in the genomic heritability estimates (0.492±0.066). The highest predictive AUC among the genome-wide marker Bayesian models was 0.681 for the Bayesian LASSO. Overall, the improvement in predictive ability was moderate and did not differ greatly among models that included genetic information. Approximately 58% of the total number of genetic variants was found to contribute to the overall genetic variation, indicating a complex genetic architecture for T2D. Our results suggest that the Bayes Cπ and the G-BLUP models with a large set of genome-wide markers could be used for predicting risk to T2D, as an alternative to using high-density arrays when selected markers from large consortiums for a given complex trait or disease are unavailable.

Differential Telomere Shortening in Blood versus Arteries in an Animal Model of Type 2 Diabetes.

Vascular dysfunction is an early feature of diabetic vascular disease, due to increased oxidative stress and reduced nitric oxide (NO) bioavailability. This can lead to endothelial cell senescence and clinical complications such as stroke. Cells can become senescent by shortened telomeres and oxidative stress is known to accelerate telomere attrition. Sirtuin 1 (SIRT1) has been linked to vascular health by upregulating endothelial nitric oxide synthase (eNOS), suppressing oxidative stress, and attenuating telomere shortening. Accelerated leukocyte telomere attrition appears to be a feature of clinical type 2 diabetes (T2D) and therefore the telomere system may be a potential therapeutic target in preventing vascular complications of T2D. However the effect of T2D on vascular telomere length is currently unknown. We hypothesized that T2D gives rise to shortened leukocyte and vascular telomeres alongside reduced vascular SIRT1 expression and increased oxidative stress. Accelerated telomere attrition was observed in circulating leukocytes, but not arteries, in T2D compared to control rats. T2D rats had blunted arterial SIRT1 and eNOS protein expression levels which were associated with reduced antioxidant defense capacity. Our findings suggest that hyperglycemia and a deficit in vascular SIRT1 per se are not sufficient to prematurely shorten vascular telomeres.

SERUM OSTEOCALCIN LEVEL IN TYPE II DIABETES MELLITUS AS AMARKER FOR EARLY DETECTION OF OSTEOPROSIS

Background: Diabetic osteoporosis is caused by reduced bone mineral content due to the abnormal levels of sugar, protein, fat, and macroelements, such as calcium and phosphorus. Beside metabolic bone diseases, these changes at times lead to pathological fractures. Still, the effect of type 2diabetes (T2DM) on bone mineral density remains controversial. There are potential mechanisms behind the increased fracture risk that occurs in patients with diabetes, even those with increased bone mineral density. One potential link between diabetes and bone is the osteoblast-produced factor, osteocalcin. Objective: The aim of this study was to determine the level of osteocalcin in type 2 diabetic patients as a marker for early detection of osteoporosis. This may help early prediction and treatment of osteoporosis before bone mass density (BMD) affected. Subjects and Methods: Sixty diabetic patients (30 males and 30 females) aged33 –61years were recruited and classified by DEXA into three equal groups: patients with type 2 diabetes mellitus with osteoporosis, patients with osteopenia, and patients with normal bone, as well as twenty apparently healthy controls. The inclusion and exclusion criteria were applied for both patients and controls. All subjects included in this study were subjected to the following : Full history taking and clinical examination , laboratory investigations including complete blood picture (CBC) , fasting and post prandial serum glucose levels, serum creatinine, lipid profile (LDL, HDL, total cholesterol and triglycerides) and complete urine analysis. Serological test for osteocalcin by ELISA technique was used. Results: The results of the present study showed that serum osteocalcin level significantly decreased in diabetic patients with osteoporosis, osteopenia and normal bone as compared to healthy control subjects. Also, there was significant decrease in serum osteocalcin level in type 2 diabetic patients with osteoporosis as compared to those with osteopenia and normal bone density groups. Significant negative correlation was found between osteocalcin and HbA1c, LDL, duration of diabetes and TG in all diabetic patients groups, and positive correlation between osteocalcin, HDL, and BMD in all diabetic groups. Conclusion: Osteocalcin may have a role on prediction of osteoporosis in diabetic patients even before bone mineral density affected.

Effect of Peripheral Arterial Disease on Serum Ischemia-Modified Albumin Levels in Type 2 Diabetic Patients

Background: The aim of this study is to evaluate the role of IMA and the effect of Type-2 diabetes in peripheral arterial ischemic patient. Methods: In our study, randomized patient groups to be undergone peripheral surgery, consisting of 16 diabetic and 12 non-diabetic patients diagnosed with peripheral arterial disease, have been examined. After standard anesthesia, the surgery was performed by the same surgical team, blood samples were taken before and after cross-clamp, and the levels of ischemia modified albumin (IMA), which is a new ischemic marker, were studied spectrophotometrically. Demographic data were compared with the type-2 diabetes association. Results: In this study, we found that there were no correlation with the ankle brachial index (ABI) and risk factors of diabetes between postoperative IMA levels (P: 0.47). Preoperative IMA serum blood levels were significantly higher in patients with peripheral arterial disease (P: 0.70), and positively associated with ABI (diabetic group P: 0.04, non-diabetic group P: 00). Also, no correlation was found with X clamp times, ABI, and IMA blood levels (P: 0.30). In diabetic group, ischemia marker increase was high and there was a positive correlation between HbA1c levels (P: 0.002). Conclusion: Our study suggested that, preoperative serum IMA levels were positively associated with ABI. In diabetic group, the increase in IMA levels was high and there was positive correlation between HbA1c levels. IMA was a benefit marker for monitoring and early diagnosis of the peripheral arterial disease.

Impact of type 2 diabetes on cardiac autonomic responses to sympathetic stimuli in patients with coronary artery disease

Type 2 diabetes (T2D) has shown limited impact on cardiac autonomic function in patients with cardiac disease at rest. The effect of T2D on autonomic responses to sympathetic stimuli, such as passive tilt and static exercise, is not well known in patients with coronary artery disease (CAD). Heart rate, arterial pressure, and their variability along with baroreflex sensitivity (BRS) were analyzed at supine rest and during passive head-up tilt (TILT) and static handgrip exercise (HG) in CAD patients with (T2D+, n=68, 61±6 years, 14 women) and without T2D (T2D-, n=68, 62±6 years, 17 women). The effect of T2D at rest and in responses to TILT and HG was examined. In T2D+, the normalized low-frequency (0.04-0.15 Hz) power of R-R intervals was higher at rest (44±17 vs. 38±17 nu, p=0.015) and its response to TILT and HG was lower than that in T2D- (8±21 vs. 2±17 nu, p=0.041 and 3±18 vs. -4±15 nu, p=0.019, respectively). Vagally mediated heart rate variability indices and BRS were not different between T2D+ and T2D-. We concluded that T2D has a specific impact on low-frequency oscillation of R-R interval among patients with angiographically documented CAD. This may indicate increased basal sympathetic modulation of sinoatrial node and lower sympathetic responsiveness to sympathetic activation by baroreceptor unloading and exercise pressor response. Limited effects of T2D on vagally mediated heart rate variability and baroreflex were observed in the patients with CAD.

Effects of thyroid hormone supplementation on ventilation and metabolism in a rat model of Type 2 Diabetes

Thyroid hormone supplementation can have beneficial effects in type 2 diabetes (T2D). In this study T2D was induced in thirty young female rats by an intraperitoneal (ip) injection of nicotinamide (200 mg/kg) followed 15 minutes later by an ip injection of streptozotocin (65 mg/kg, STZ/N). Control rats (CR, n=10) received vehicle injections. After 2 months, subgroups of STZ/N rats received either 4 (STZ/N4) or 8ug/kg/day (STZ/N8) of triiodothyronine (T3) in drinking water for one month. Subsequent metabolic and ventilatory studies (during exposure to air or hypoxia, 10% O2 in N2) indicated little effects in the STZ/N group compared to CR. In contrast, STZ/N8 group was clearly hyperthyroid with lower body weights, elevated body temperatures, metabolic rates, and ventilation during exposure to air and hypoxia. Except for changes in inspiratory (increased) and expiratory (decreased) times during air exposure, the ventilation and metabolism of the STZ/N4 group was similar to the CR and STZ/N groups. Importantly, the lower, but not higher dose of T3 attenuated the hyperglycemia observed in both the STZ/N and STZ/N8 groups. Thus, low levels of T3 supplementation may have beneficial effects in T2D, but have subtle effects of ventilatory timing parameters during air exposure. Funded by R01 7R01HL093160‐03 (from NHLBI) and a Clinical Scientist Training Award from the American Diabetes Association (ADA 7‐10‐CST‐01).

Effect of a fatty meal on inflammatory markers in healthy volunteers with a family history of type 2 diabetes

A family history of type 2 diabetes (T2D) confers a high risk of developing the disease, independent of that due to other common risk factors. Postprandial state is a pro-inflammatory condition associated with a transiently impaired endothelial function; an increased oxidative stress is considered as a mediator of such effects in T2D. We evaluated the short-term effect of a lipid meal on markers of early vascular damage in subjects at risk of developing T2D. A total of thirty-two healthy volunteers, divided according to the presence (FHD+) or absence (FHD-) of a family history of T2D, underwent a fatty meal test. We measured the monocyte mRNA expressions of IL-6, IL-8 and IL-1β, and IL-6, soluble CD40 ligand (sCD40L), vascular cellular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and nitrotyrosine plasma concentrations at baseline and in the post-meal phase, relating them to the lipid profile and other biochemical parameters. The basal expression of the cytokines did not differ in FHD- and FHD+ subjects; neither was it modified by the meal ingestion. IL-6 and sCD40L plasma levels, similar in the two groups in the fasting state, did not vary after the meal. VCAM-1 and ICAM-1 increased in FHD+ subjects but not in FHD- subjects. Nitrotyrosine, similar between the FHD- and FHD+ subjects at baseline, increased more in FHD+ subjects than in FHD- subjects after the meal. In conclusion, the presence of a familial history of T2D confers an abnormal endothelial activation after an oral lipid meal, coupled with an increased oxidative stress, supporting the hypothesis of an early endothelial dysfunction already present in healthy individuals prone to develop T2D.

Enhanced inflammatory responses to toll-like receptor 2/4 stimulation in type 1 diabetic coronary artery endothelial cells: the effect of insulin

BackgroundEndothelial inflammatory responses mediated by Toll-like receptors (TLRs), particularly TLR2 and TLR4, play an important role in atherogenesis. While Type 1 diabetes (T1D) promotes the development and progression of atherosclerosis, the effect of T1D on TLR2/4-mediated inflammatory responses in coronary artery endothelial cells (CAECs) remains unclear.MethodsWe tested the hypothesis that diabetic CAECs have enhanced inflammatory responses to TLR2/4 stimulation. Non-diabetic and diabetic CAECs were treated with TLR2 agonist peptidoglycan and TLR4 agonist lipopolysaccharide. The expression of ICAM-1, IL-6 and IL-8 were analyzed by real-time PCR, immunoblotting and ELISA, and NF-κB activation by immunoblotting and immunostaining. In additional experiments, insulin was added before TLR stimulation to determine whether insulin deficiency alone is responsible for the alteration of TLR2/4-mediated inflammatory responses.ResultsStimulation of TLR2 or TLR4 induced NF-κB activation, and the expression of ICAM-1, IL-6 and IL-8. Interestingly, the expression of inflammatory mediators was significantly enhanced in diabetic cells. The enhanced inflammatory responses correlated with augmented NF-κB activation in the absence of a change in TLR2 or TLR4 protein levels. Further, pretreatment of diabetic cells with insulin failed to suppress the enhanced inflammatory responses.ConclusionsDiabetic CAECs have enhanced inflammatory responses to stimulation of TLR2 or TLR4, and insulin alone is insufficient to correct the hyper-inflammatory responses. The mechanism underlying the enhanced inflammatory responses appears to be augmentation of pro-inflammatory signaling, rather than up-regulation of levels of TLR2 and TLR4. These findings suggest that diabetic CAECs adopt a hyper-inflammatory phenotype and that this endothelial phenotypic change may predispose coronary artery to atherogenesis.