Type 2 Diabetes Group Research Articles

182-LB: Cardiovascular Response to Exercise in T2D

Type 2 diabetes (T2D) confers a greater likelihood of heart failure (HF) and hospitalization due to HF. Our group has reported sub-clinical cardiac dysfunction and aortic stiffness in youth and adults with uncomplicated T2D. As aortic stiffening is reported to precede HF and is common in people with uncomplicated T2D, we tested the hypothesis that aerobic exercise training will improve cardiac function and central arterial stiffness in people with T2D compared to participants of similar BMI without T2D. Sedentary adults with (n = 18, age 48±7, 45% female) and without (n = 20, age 45±7, 46% female) T2D, underwent MRI for cardiac function and aortic compliance (aortic relative area change [RAC] and pulse wave velocity [PWV]) before and after 15 weeks of aerobic exercise training. At baseline, both cohorts exhibit subclinical diastolic dysfunction, however, those with T2D had lower end-diastolic volume (EDVN,47.2±9.9 vs. 52.3±9.1 mL/m2) and end-systolic volume (ESVN,21.1±5.4 vs. 23.6±5.2 mL/m2), than controls. The T2D group had higher max thickness of the left ventricular (LV) septal wall (LVMTs, 10.5±1.8 vs. 9.3±1.6 mm) and LV lateral wall (LVMTl, 8.4±1.6 vs. 7.6±1.3 mm) than controls. Those with T2D also had lower RAC (12.7±1.6 vs. 20.2±1.6%) and higher PWV (7.4±1.3 vs. 3.9±0.6 m/s) than controls. Preliminary data in a subset post exercise intervention (n=7 with and n=8 without T2D), revealed increased EDVN(42.8±7.9 to 51.5±11.3 mL/m2) and ESVN(19.7±4.0 to 24.3±6.5 mL/m2) and decreased LVMTs(11.35±1.5 to 9.96±1.3 mm) and LVMTl(8.42±0.81 to 7.74±0.89 mm) in the T2D group, but cardiac endpoints were unchanged in controls. Post-intervention in both groups, ascending aorta RAC increased (control: 16.2±4 % to 18.5±1.7 and T2D: 10.6±1.7 % to 19.6±2.2 %) and PWV decreased (control: 6.3±2.0 to 3.4±0.3 and T2D: 8.0±1.4 to 2.9±0.7). Data from this study in progress suggest that adults with T2D have a greater degree of cardiac dysfunction and arterial stiffness than controls of similar BMI, which improve to a greater degree with exercise than in controls. Disclosure D. Enge: None. J.E. Reusch: None. J.G. Regensteiner: None. M. Schäfer: None. K.S. Hunter: None. A.J. Barker: None. K.J. Nadeau: None. R.L. Scalzo: None. I.E. Schauer: None. L. Abushamat: None. M.O. Whipple: None. D. Rafferty: None. Funding U.S. Department of Veterans Affairs (CX001532)

679-P: Endothelial and Hematopoietic Progenitor Cells Are Reduced at Rest and Have an Attenuated Mobilization Response to Exercise in People with Type 1 Diabetes

Aims: Endothelial and Hematopoietic Progenitor Cells (EPCs and HPCs) promote vascular health through secreting proangiogenic factors and replacing damaged cells. Exercise has been shown to be a mobiliser of these rare cells in healthy individuals, however, the response in chronic diseases such as type 1 diabetes (T1D) is unclear. We compared EPC and HPC counts at rest and after acute exercise in people with and without T1D. Methods: Thirty T1D participants (38±12 years, HbA1c 58.5±9.3 mmol/mol-1, diabetes duration 20±13 years) and 30 age, sex, BMI and fitness matched non diabetes controls were recruited. After a maximal exercise test, participants attended a second visit to complete 45mins of walking at 60%VO2peak. Blood samples were taken at rest, immediately and 1 hour post exercise. Circulating levels of two HPCs and five EPC phenotypes were enumerated by flow cytometry. Data (mean±SD) were analysed by mixed model ANOVA and t-test with significance accepted at p≤0.05. Results: The T1D group had significantly lower rest count of HPCs and EPCs, ranging from 21 to 41% lower across all samples compared to the control. Exercise mobilized all cell phenotypes in both groups, with significant increases from rest to post exercise, while HPCs and CD34+CD31+ EPCs remained elevated 1hr post exercise. However, the change (Δ) in HPCs and EPCs from rest to post exercise was greater in the control versus T1D group, with higher CD34+CD45dim HPCs (p=0.03, Δ 48±65 vs. 24±33 cells/ml), as well as CD34+CD31+ (p=0.04, Δ 23±19 vs. 15±25 cells/ml) and CD34+VEGFR2+ EPCs (p=0.02, Δ 24 ±24 vs. 15±31 cells/ml). Conclusion: People with T1D have reduced numbers of HPCs and EPCs at rest and also display a blunted exercise induced increase in these rare blood vessel protecting cells. Further research is needed to understand the clinical significance of an attenuated exercise mobilization of these EPCs and HPCs phenotypes in predicting future cardiovascular complications in T1D. Disclosure G.S. Taylor: None. K. Smith: None. J. Scragg: None. A. Bashir: None. A. Flatt: None. E.J. Stevenson: None. J.A. Shaw: Advisory Panel; Self; Medtronic. Speaker’s Bureau; Self; Novo Nordisk A/S. M.D. Ross: None. D.J. West: None. Funding Diabetes Research & Wellness Foundation (to D.J.W.)

1283-P: Multicenter Assessment of the Pancreas in Type 1 Diabetes (MAP-T1D)

Individuals both at risk for and newly diagnosed with type 1 diabetes (T1D) have a reduced pancreas volume as assessed by MRI. Furthermore, multiparametric quantitative MRI techniques have detected focal alterations in the T1D pancreas. However, performing quantitative MRI techniques in multi-site trials is challenging due to differences in MRI hardware and software. To determine if quantitative MRI measurements in T1D can be performed at different institutions, 5 academic centers (see author affiliation) have established the Multicenter Assessment of the Pancreas in T1D (MAP-T1D) group to develop harmonized MRI acquisition and image processing protocols. We established and implemented an MRI protocol for pancreas imaging on both Siemens and Philips MRI platforms at 5 imaging centers, consisting of T1- and T2-weighted anatomical images, diffusion-weighted MRI, magnetization transfer MRI, and longitudinal relaxation (T1) mapping. Imaging phantoms assessing volume, diffusion, magnetization transfer ratio, and T1 were created and imaged at each institution to test the reproducibility of multiparametric MRI. Measurement of phantom volume yielded an average error of 1.5% from the true volume. The apparent diffusion coefficient, magnetization transfer ratio, and T1 phantoms had coefficients of variation of 6.0%, 10.0%, and 9.5%, respectively, between sites. To assess the reproducibility of human MRI scanning, we recruited 5 healthy subjects to travel to 4 sites for imaging using the standardized MRI protocol. Pancreas volume measured at multiple sites had an average coefficient of variation between scans of 8.3% with a maximum difference of 17% (n = 9 MRIs). This study demonstrates the feasibility of quantitative pancreas MRI across multiple sites. Standardization of pancreas MRI acquisition and processing will accelerate integration of pancreas volume and other quantitative MRI measurements in future multi-center clinical trials of T1D. Disclosure J. Virostko: None. J.M. Williams: None. M.A. Hilmes: None. L. Du: None. H. Kang: None. W.E. Russell: None. T.M. Triolo: None. L.H. Philipson: None. E.K. Sims: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. H.E. Thomas: None. T. Kay: None. S.W. Greeley: None. A. Steck: None. A.C. Powers: None. D.J. Moore: None. Funding JDRF (3-SRA-2019-759-M-B, 3-SRA-2015-102-M-B)

SUN-381 Cortical Porosity Is Associated with Peripheral Small Vessel Disease in Adult Patients with Type 2 Diabetes

Patients with Type 2 Diabetes (T2D) are at higher fracture risk despite having relatively normal or even increased BMD by DXA. Increased cortical porosity has emerged as a potential factor contributing to fragility fractures in T2D. However, there is conflicting evidence whether T2D patients have increased cortical porosity. We hypothesized that microvascular complications have an important role in cortical porosity. Thus, we performed high-resolution peripheral quantitative computed tomography imaging at the distal radius and tibia to evaluate bone microarchitecture in men with T2DM age ≥ 50 yrs or postmenopausal women with T2DM and nondiabetic controls. Comprehensive diabetic complications were assessed in all patients including urine microalbuminuria, retinopathy, neuropathy (touch, temperature, and vibration sensation), ankle brachial index (ABI) and transcutaneous oxygen tension (TcPO2). Percent differences between groups were obtained from linear regression models adjusting for age, BMI, and sex. Relationships between variables were assessed using adjusted Spearman correlations. A total of 164 T2D patients (mean age 68.9 ±7.8 yrs.; 56.7% men; HbA1C=7.7 ±0.9%; mean diabetes duration 15.2 yrs.) and 107 nondiabetic controls (mean age 67.3±8.8 yrs.; 42.1% men; HbA1C =5.4 ±0.3%) were recruited to the study. Overall, there was a trend for increased cortical porosity at the distal tibia in the T2D group (+12.2%; p=0.063) compared with nondiabetic controls. Of note, TcPO2 was negatively correlated with cortical porosity at the distal radius (r= -0.17; p= 0.039) and distal tibia (r= -0.15; p= 0.073). In particular, the Low TcPO2 (≤40 mmHg) group (n=29) had greater cortical porosity at the distal tibia (+19.6 %; p=0.037) compared with the High TcPO2 (>40 mmHg) group (n=133). In addition, the low TcPO2 group had a significant increase in cortical porosity in the distal tibia (+24.8% p=0.020) compared with nondiabetic controls. In conclusion, this is the first evidence in humans indicating that TcPO2, a measure of microvascular blood flow, is linked to cortical porosity in the distal radius and tibia in T2D patients. Our findings may explain the conflicting findings regarding cortical porosity in T2D because only T2D patients with impaired microvascular blood flow have increased cortical porosity. Collectively, our data indicate that cortical porosity is a microvascular complication of longstanding T2D.

2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD)

It has been demonstrated that diabetic dyslipidaemia is the chief bridge between diabetes and incremental risk of cardiovascular disease in patients with diabetes. However, the characteristics of lipoprotein subfractions distribution in patients with type 2 diabetes (T2D) have not been fully investigated. The aim of present study was to evaluate the distributions of lipoprotein subfractions in T2D patients.A total of 920 patients, who have not received lipid-lowering drug treatment previously, were consecutively enrolled in this study. Based on the evidence of diabetes, patients were divided into T2D group (n=204) and non-T2D group (n=716). Both low- and high-density lipoprotein cholesterol (LDL- and HDL-C) subfractions were analysed using the Quantimetrix Lipoprint System. The distributions of lipoprotein subfractions were evaluated in patients with and without T2D.Compared with non-T2D individuals, the T2D group manifested significantly lower large HDL-C concentration/HDL subfraction percentage, smaller mean LDL particle size but higher small HDL-C and LDL-C concentrations as well as small HDL and LDL subfraction percentages. Moreover, the data indicated that the small HDL-C/ LDL-C concentrations, the small and large HDL subfraction percentages along with the mean LDL particle size were independently related to the existence of T2D (95% CI=1.009–1.067, p=0.009; 95% CI=0.938-0.983, p=0.001; 95% CI=1.023–1.135, p=0.005; 95% CI= 1.005–1.048, p=0.014; 95% CI=0.940-0.999, p=0.040; respectively) assessed by logistic regression analysis.The present study indicated that the changes of lipid profile in patients with T2D are characterised by abnormal distributions of lipoprotein subfractions apart from clinically atherogenic dyslipidaemia.

Exogenous spermine attenuates myocardial fibrosis in diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress and the canonical Wnt signaling pathway.

Myocardial fibrosis is one of the main pathological manifestations of diabetic cardiomyopathy (DCM). Spermine (SPM), a product of polyamine metabolism, plays an important role in many cardiac diseases including hypertrophy, ischemia, and infarction, but its role in diabetic myocardial fibrosis has not been clarified. This study aimed to investigate the role of polyamine metabolism, specifically SPM, in diabetic myocardial fibrosis and to explore the related mechanisms. We used intraperitoneal injection of streptozotocin (STZ, 60 mg/kg) in Wistar rats and high glucose (HG, 40 mM) stimulated cardiac fibroblasts (CFs) to established a type 1 diabetes (T1D) model in vivo and in vitro, which were pretreated with exogenous SPM (5 mg/kg per day and 5 μM). The results showed that hyperglycemia induced the expression of the key polyamine synthesis enzyme ornithine decarboxylase (ODC) decreased and the key catabolic enzyme spermidine/spermine N1 -acetyltransferase (SSAT) increased compared with those in the control group. The body weight, blood insulin level, and cardiac ejection function were decreased, while blood glucose, heart weight, the ratio of heart weight to body weight, myocardial interstitial collagen deposition, and endoplasmic reticulum stress (ERS)-related protein (glucose-regulated protein-78, glucose-regulated protein-94, activating transcription factor-4, and C/EBP homology protein) expression in the T1D group were all significantly increased. HG also caused an increased expression of Wnt3, β-catenin (in cytoplasm and nucleus), while Axin2 and phosphorylated β-catenin decreased. Exogenous SPM improved the above changes caused by polyamine metabolic disorders. In conclusion, polyamine metabolism disorder occurs in the myocardial tissue of diabetic rats, causing myocardial fibrosis and ERS. Exogenous SPM plays a myocardial protective role via inhibiting of ERS and the canonical Wnt/β-catenin signaling pathway.

Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes.

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton MRS, we measured glutamate concentrations in ACC and occipital lobe cortex (OCC) in 13 subjects with T1D without major depression (HbA1c 7.1 ± 0.7% [54 ± 7 mmol/mol]) and 11 healthy control subjects without diabetes (HbA1c 5.5 ± 0.2% [37 ± 3 mmol/mol]) during fasting euglycemia followed by a 60-min +5.5 mmol/L hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level-dependent functional MRI to measure the fractional amplitude of low-frequency fluctuations in slow-4 band (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (emotional Stroop task, self-referent encoding task [SRET]) and clinical ratings (Hamilton Depression Rating Scale [HAM-D], Symptom Checklist-90 Revised [SCL-90-R]), respectively. During HG, ACC glutamate increased (1.2 mmol/kg, 10% P = 0.014) while ACC fALFF4 was unchanged (-0.007, -2%, P = 0.449) in the T1D group; in contrast, glutamate was unchanged (-0.2 mmol/kg, -2%, P = 0.578) while fALFF4 decreased (-0.05, -13%, P = 0.002) in the control group. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative word response times (P = 0.017) and higher depression rating scores (HAM-D P = 0.020, SCL-90-R depression P = 0.008). Higher glutamate change tended to associate with longer emotional Stroop response times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia because of the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations among chronic hyperglycemia, cortical thinning, and depressive symptoms in T1D.

Liraglutide protects pancreatic β cells from endoplasmic reticulum stress by upregulating MANF to promote autophagy turnover

AimsThis study was conducted to determine the relationship between mesencephalic astrocyte-derived neurotrophic factor (MANF), autophagy and endoplasmic reticulum (ER) stress, and whether liraglutide (LRG) can protect β cells, promote autophagy and alleviate ER stress by regulating MANF expression. Main methodsHuman serum samples were collected from healthy controls (NC), simple hyperlipidemia (HLD), and newly diagnosed type 2 diabetes (T2D). The MANF levels were detected using ELISA. In vitro, after the mouse islet MIN6 cells were treated with glucose (GLU), palmitate (PA), thapsigargin (TG), LRG, and chloroquine (CQ), cell proliferation was detected using cell counting kit-8 (CCK-8), apoptosis-related protein cleaved caspase 3 (C-cas-3), ER stress, and autophagy-related proteins were detected by Western blotting, MANF, insulin, and C-cas-3 proteins were detected via immunofluorescence. Subcellular structures and autophagosomes were examined using electron microscopy. Key findingsCompared with the NC group, the MANF levels in the HLD and T2D groups increased significantly. After ER stress induced by GLU, PA, and TG, cell viability decreased, while MANF, c-cas3, ERS, and autophagy-related proteins increased, which was related to the concentration of GLU, PA, and TG. Compared with the BSA group, the number of mitochondria and autophagosomes in the PA group increased and the mitochondria were damaged. In the PA and TG plus CQ groups, the effect was further exaggerated. But after co-treatment with LRG, the effects of GLU, PA, and TG were attenuated. SignificanceLRG protects islet β cells from ER stress by upregulating MANF to promote autophagy turnover.

Low-Dose Decitabine Assists Human Umbilical Cord-Derived Mesenchymal Stem Cells in Protecting β Cells via the Modulation of the Macrophage Phenotype in Type 2 Diabetic Mice.

Background Progressive β-cell dysfunction, a major characteristic of type 2 diabetes (T2D), is closely related to the infiltration of inflammatory macrophages within islets. Mesenchymal stem cells (MSCs) have been identified to alleviate β-cell dysfunction by modulating macrophage phenotype in T2D, but the restoration of β-cells by a single MSC infusion is relatively transient. Decitabine (DAC) has been reported to polarize macrophages towards the anti-inflammatory phenotype at low doses. We therefore investigated whether low-dose decitabine could enhance the antidiabetic effect of MSCs and further promote the restoration of β-cell function. Methods We induced a T2D mice model by high-fat diets and streptozotocin (STZ) injection. Mice were divided into five groups: the normal group, the T2D group, the DAC group, the MSC group, and the MSC plus DAC group (MD group). We examined the blood glucose and serum insulin levels of mice 1, 2, and 4 weeks after MSC and/or DAC treatment. Dynamic changes in islets and the phenotype of intraislet macrophages were detected via immunofluorescence. In vitro, we explored the effect of MSCs and DAC on macrophage polarization. Results The blood glucose and serum insulin levels revealed that DAC prolonged the antidiabetic effect of MSCs to 4 weeks in T2D mice. Immunofluorescence staining demonstrated more sustainable morphological and structural amelioration in islets of the MD group than in the MSC group. Interestingly, further analysis showed more alternatively activated macrophages (M2, anti-inflammatory) and fewer classically activated macrophages (M1, proinflammatory) in islets of the MD group 4 weeks after treatment. An in vitro study demonstrated that DAC together with MSCs further polarized macrophages from the M1 to M2 phenotype via the PI3K/AKT pathway. Conclusion These data unveiled that DAC prolonged the antidiabetic effect of MSCs and promoted sustainable β-cell restoration, possibly by modulating the macrophage phenotype. Our results offer a preferable therapeutic strategy for T2D.

Type 2 diabetes induced microbiome dysbiosis is associated with therapy resistance in pancreatic adenocarcinoma

Resistance to therapy is one of the major factors that contribute to dismal survival statistics in pancreatic cancer. While there are many tumor intrinsic and tumor microenvironment driven factors that contribute to therapy resistance, whether pre-existing metabolic diseases like type 2 diabetes (T2D) contribute to this has remained understudied. It is well accepted that hyperglycemia associated with type 2 diabetes changes the gut microbiome. Further, hyperglycemia also enriches for a “stem-like” population within the tumor. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to gemcitabine/paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group. Additionally, we also observed an increase in the CD133+ tumor cells population in the T2D model. These observations indicated that in an animal model for T2D, microbial dysbiosis is associated with increased resistance to chemotherapeutic compounds.

Clinical and laboratory characteristics of the patterns of chronic kidney disease in patients with type 2 diabetes

BACKGROUND: A growing body of evidence demonstrates increasing prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in subjects with type 2 diabetes (T2D), while proportion of albuminuric pattern is decreasing.
 AIMS: To determine the clinical and laboratory parameters associated with different patterns of CKD in patients with T2D.
 METHODS: This observational, single-center, cross-sectional study included 360 patients with T2D duration 10 years. Patients with urinary albumin/creatinine ratio (UACR) 3 mg/mmol and estimated glomerular filtration rate (eGFR) 60 ml/min/1.73 m2 were classified as no-CKD group (n=89). Patients with UACR 3 mg/mmol and eGFR 60 ml/min/1.73 m2 formed NA-CKD group (n=111). Individuals with eGFR 60 ml/min/1.73 m2 and UACR mg/mmol 3 were recorded as albuminuric with preserved renal function (A-CKD, n=87). Patients with eGFR 60 ml/min/1.73 m2 and UACR mg/mmol 3 mg/mmol were considered as albuminuric CKD group (A-CKD+, n=73). Urinary nephrin and podocin, the podocyte injury markers, and whey acidic protein four-disulfide core domain protein 2 (WFDC-2), a marker of tubulointerstitial involvement, was assessed by ELISA and compared to control (20 non-diabetic subjects).
 RESULTS: Age 65 years (p=0.0001), duration of T2D 15 years (p=0.0009), female sex (p=0.04), and therapy with diuretics (p=0.0005) were found as risk factors for NA-CKD. The risk factors for A-CKD were male sex (p=0.01), smoking (p=0.01), waist-to-hip ratio 1 (p=0.01) and HbA1c levels 8% (p=0.005). The duration of T2D 15 years (p=0.01) and the use of dihydropyridine calcium channel blockers (p=0.01) were associated with A-CKD+. In T2D groups, the urinary excretion of nephrin and podocin was increased (all p0.001), more markedly in albuminuric individuals (p0.01 vs. NA-CKD). WFDC-2 excretion was increased in men from all diabetic groups (p0.05) and in women with decreased eGFR only (p0.05 vs. the control and NA-CKD).
 CONCLUSIONS: The CKD patterns in T2D are heterogeneous according to their clinical and laboratory characteristics. The changes in the excretion of nephrin and podocin indicate the association of albuminuric patterns with podocyte injury. A decrease in eGFR in women with T2D is associated with an increase in urinary excretion of WFDC-2, tubulointerstitial fibrosis marker.

Prevalence of elevated liver enzymes and its association with type 2 diabetes: A cross-sectional study in Bangladeshi adults.

BackgroundType 2 diabetes (T2D) is a major public health concern affecting millions of people worldwide. The relationship between liver enzymes and T2D has been reported in limited studies; however, there is still a lack of evidence for the Bangladeshi population. This study aimed to evaluate the prevalence of elevated liver enzymes and examine its association with the prevalence of T2D in Bangladeshi adults.MethodsA total of 270 individuals (110 diabetic and 160 nondiabetic) were enrolled in the study. Alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase (ALP) and γ‐glutamyltransferase (GGT) activities were measured in blood serum collected from them. T2D was defined as fasting blood glucose (FBG) ≥126 mg/dL or self‐reported recent use of insulin or antidiabetic medications. Association between liver enzymes and T2D was evaluated by multinomial logistic regression analysis.ResultsOverall, 61.2% of participants in T2D and 37.1% of participants in the nondiabetes group had at least one or more elevated liver enzymes. The mean concentrations of serum ALT, AST, ALP and GGT were significantly higher in the T2D group compared to the nondiabetes group. The prevalence of elevated liver enzymes was significantly higher in the diabetes group compared to the nondiabetes group (P < .01). In regression analysis, serum GGT activity showed an independent association with the prevalence of T2D.ConclusionsA high prevalence of elevated liver enzymes was observed in subjects having diabetes. Increased serum GGT activity was independently associated with the prevalence of T2D among Bangladeshi adults. More studies of this nature should be carried out in developing countries to get proper insights into the involvement of liver enzymes in T2D.

Association of adiponectin gene polymorphisms and their haplotypes with type 2 diabetes and related metabolic traits in an Iranian population

Adiponectin is an adipocyte-secreted protein that contributes to glucose homeostasis. Contradictory reports are available on single nucleotide polymorphisms (SNPs) in the adiponectin gene and the risk of type 2 diabetes (T2D). We investigate the association of adiponectin gene SNPs (+45T/G and +276G/T) with serum adiponectin, insulin resistance, lipid profile, and T2D risk in an Iranian population. The +45T/G and +276G/T SNPs were genotyped in 211 non-familial T2D patients and 202 non-diabetic subjects by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and TaqMan probe, respectively. T2D was associated with a decrease in serum adiponectin level. The G allele and the GG and TG genotypes of +45T/G SNP were more abundant than the T allele and the TT genotype in T2D patients compared with controls (p < 0.001). The risk of T2D in individuals with the GG and TG genotypes of +45T/G SNP was 4 and 2 times more than that with the TT genotype, respectively. There was no statistically significant difference in the frequencies of allele and genotype of +276G/T SNP between the control and T2D groups. The presence of +45G/+276G haplotype was associated with an increased risk of T2D (OR = 2.01, 95% CI = 1.34–3.03, p = 0.04). Therefore, our results showed that +45T/G SNP is associated with the risk of T2D higher than +276G/T SNP in the studied population.

The effects of (a combined exercise programme aerobic and resistance) on blood glucose and incretin hormone that could control the diabetes in type 2 diabetes.

Aim: An excessive number of calories consumed daily, in addition to a sedentary lifestyle, are the main causes of increasing Type 2 Diabetes (T2D) prevalence worldwide. Diabetes is usually accompanied by hypertension, lipid disorders, and obesity. The aim of this study is to show that the combination exercise is effective. It will compare T2D and Non-Diabetes (ND) volunteer doing combination exercise consisting of resistance and cycling. The interventions are minor and fairly short consisting of 12 episodes of exercise over 6 weeks, yet this was enough to produce measurable change and improvement. This included the re-categorization of two T2D volunteers to being ND, using normal metrics. A literature search was conducted by using electronic databases (Science direct, google scholar, Medline, Embase, Sports medicine, PubMed, CINAHL, Cochrane library, and Scopus) from April 2015 until January 2019. Results show that changes in primary and secondary outcomes are significant between the different groups. The primary outcome is HbA1c, and the secondary outcomes are weight, waist, BMI, lipid, BP, HR, lactate and body fitness. Moreover, this study focuses on the changes in incretin level in the T2D group for effects of exercise on the secretion of this hormone and compare within T2D who are using a different medication for diabetes Results: After just six weeks, there was a reduction in the HbA1c level for the T2D volunteers which is significant (P=0.000). Moreover, in ND the reduction was also significant (P=0.000). In the T2D group who are using (Metformin and SGT2-I group), their result shows elevation in GLP-1 in the assessment of the both acute and chronic effect of the programme. GLP-1 in this group was (3.9 ± 1.5) and increased to (8.4 ± 1.2), (P=0.345) after S1 and then increased more to (11.0 ± 0.8), (P=0.196) after 6 weeks of exercise. This was of interest because of the inference that incretins and exercise were linked. The crucial factor is metformin. Conclusion: In T2D and ND combination exercise has a beneficial effect on HbA1c, the improvement was higher in T2D. The anthropometric variables (weight, waist, BMI and lung capacity) improved significantly as well in T2D and ND. Exercise is also important to improve GLP-1 secretion. Despite the range of studies on incretin undertaken here, still, there is a need to compare the effect of exercise and different types of pharmacological therapy on GLP1. This study compared the effect of exercise on T2D plus medication in volunteers. It has been found that within the T2D group only Metformin and SGT2-I group was improved. Both SGLT2 inhibitors and metformin have been found to affect body weight and this may explain the improvement of GLP-1 level, suggesting an area for future investigation.

Association between growth differentiation factor-15 and cardiovascular risk in patients with type 2 diabetes mellitus

Background and aim As most diabetic patients have high risk of cardiovascular hazards, the aim was to assess an indicator biomarker that can help us to estimate these hazards in patients with type 2 diabetes (T2D). Patients and methods A total of 80 participants were examined for T2D and divided into two groups: T2D group and control group. To estimate the 10-year risk of atherosclerotic cardiovascular disease, we utilized the Framingham risk score (FRS), the New Pooled Cohort Equation score, Tch/high-density lipoprotein (HDL) ratio, HDL/low-density lipoprotein (LDL) ratio, and serum growth differentiation factor-15 (GDF15). Results The T2D group had higher levels of systolic blood pressure and diastolic blood pressure and lower levels of weight and BMI than control. The T2D group had higher levels of random blood glucose (RBG), glycosylated hemoglobin, and urea. Both the total cholesterol/HDL and LDL/HDL were high significantly in the T2D, whereas FRS was high in the T2D group than control group. The level of serum GDF15 was higher in the T2D group (P=0.000). We found a positive correlation between level of serum GDF15 and BMI (r=0.336, P=0.017), systolic blood pressure (r=0.622, P=0.000), diastolic blood pressure (r=0.572, P=0.000), RBG (r=0.298, P=0.035), and FRS (r=0.415, P=0.003). Conclusion GDF15 can be used as an indicator for measuring cardiovascular hazards in patients with T2D.

Diabetes is a risk factor for high-dose methotrexate-associated AKI in lymphoma patients

Purpose The aim of the study was to investigate the incidence of acute kidney injury (AKI) occurring after high-dose methotrexate (HDMTX) administration and the role of type 2 diabetes (T2D) playing in the occurrence of AKI. Methods We assessed associations between T2D along with other confounding factors mainly including baseline estimated glomerular filtration rate (eGFR), methotrexate (MTX) elimination and urine pH, and AKI occurrence. Patients who were diagnosed as primary central nervous system lymphoma with treatment of HDMTX and with eGFR ≥60 mL/min/1.73 m2 were enrolled in this study. Results Of the 507 courses enrolled in this study, 132 courses have T2D. Lower baseline eGFR, delayed MTX elimination, lower urine pH, and higher incidence of AKI were observed in T2D group. Using univariate logistic regression, several confounding factors including baseline eGFR, hypertension, MTX elimination, and urine alkalinization statistically and clinically important were screened out. After adjusting for these factors, T2D remained an independent association with AKI occurrence. AKI outcome had no significant relationship with severe hematological toxicity or hepatotoxicity. AKI was associated with faster eGFR decline after a series of HDMTX treatment courses. Conclusions Patients with T2D have a higher sensitivity to AKI when administrated with HDMTX. This conclusion addresses safety concerns for making chemotherapy regimen for this population.

Link between ACE I/D Gene Polymorphism and Dyslipidemia in Diabetic Nephropathy: A Case-control Study from Hyderabad, India.

Introduction:Diabetic nephropathy (DN) is the commonest single cause of end-stage renal failure, and dyslipidemia is a critical risk factor in the occurrence of DN. In the light of recent reports emphasizing the importance of angiotensin I-converting enzyme (ACE) in the modulation of plasma lipids, we sought to evaluate the influence of ACE I/D gene polymorphism with dyslipidemia status among type 2 diabetic (T2D) patients with and without nephropathy in the genetic predisposition and the progression to DN.Method:This study comprised of 600 subjects, which include patients with DN, T2D, and healthy controls (HC). Polymerase chain reaction based genotyping of ACE I/D polymorphism was performed and appropriate statistical analysis was done.Results:Out of the 600 subjects, 20 (10%) of the HC, 73 (36.5%) of the T2D group, and 125 (62.5%) of the DN subjects had dyslipidemia. The D allele (0.62) and DD (42.5) genotype frequencies were higher in the DN group in comparison with T2D and HC (P < 0.05). The genotypes also varied among patients with dyslipidemia (χ2 5.04; P < 0.05) but not in the non-dyslipidemia group. Under the co-dominant model, DD genotype conferred a risk of 1.26 (P < 0.001) toward DN, whereas the ID genotype offered protection from DN among the dyslipidemic subjects (OR = 0.05; P < 0.01). In addition, genotype-dependent difference was seen in the plasma lipid levels among study groups. A multiple logistic regression analysis revealed male gender, BMI, HbA1c, TG, HDL, and ACE DD genotype as independent risk factors for the development of DN.Conclusion:The study showed a significant predisposing association of ACE DD genotype with DN and protective effect of ID genotype on DN in the dyslipidemia subgroup.

Moderate intensity exercise in hypoxia increases IGF-1 bioavailability and serum irisin in individuals with type 1 diabetes.

Aim:This study aimed to determine the effect of moderate intensity continuous exercise (Ex) and hypoxia (Hyp) on serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3), irisin and cytokines levels in patients with type 1 diabetes (T1D).Methods:A total of 14 individuals with T1D (age: 28.7 ± 7.3 years) and 14 healthy adults (age: 27.1 ± 3.9 years) performed 40-min continuous Ex at moderate intensity (50% lactate threshold) on a cycle ergometer in normoxia (Nor) and Hyp (FiO2 = 15.1%) Biochemical factors, glucose concentrations and physiological variables were measured at rest, immediately and up to 24 h after both Ex protocols.Results:Patients with T1D had significantly lower pre-Ex serum concentrations of BDNF (p < 0.05, p < 0.01), and total IGF-1 (p < 0.001, p < 0.05) and significantly higher irisin levels (p < 0.05, p < 0.01) in Nor and Hyp, compared with healthy subjects. Ex significantly increased in T1D group serum BDNF (in Nor only p < 0.05) and total IGF-1 levels in Nor and Hyp (p < 0.001 and p < 0.01, respectively). Immediately after Ex in Hyp, freeIGF-1 (p < 0.05) and irisin levels (p < 0.001) were significantly higher compared with the levels induced by Ex alone. Free IGF-1 and irisin serum levels remained elevated in 24 h post-Ex in Hyp. In T1D, significant blood glucose (BG) decrease was observed immediately after Ex in Hyp (p < 0.001) and in 24 h recovery (p < 0.001) compared with pre-Ex level.Conclusion:The study results suggest that moderate intensity continuous Ex has beneficial effect on BDNF and IGF-1 levels. Ex in hypoxic conditions may be more effective in increasing availability of IGF-1. The alterations in the post-Ex irisin levels and IGF-1 system may be contributing to more effective glycaemia control in patients with T1D.

Early identification of cardiac autonomic neuropathy using complexity analysis in children with type 1 diabetes.

In children and adolescents, there are significant limitations to detecting cardiac autonomic neuropathy (CAN), an important contributor to morbidity and mortality in adults with type 1 diabetes (T1D). The analysis of heart rate variability (HRV) is one method available to detect CAN. Some evidence shows traditional linear HRV measures detect abnormalities in youth with T1D. In this study, we aimed to assess whether non-linear complexity analysis of HRV would assist identification of CAN in youth with T1D and to assess contributory factors. We studied 19 youth with T1D and 17 healthy controls. Each had an electrocardiogram recorded continuously for 10 min, at a sampling frequency of 1000 Hz. Using Labview software and an algorithm for complexity analysis, along with standard time-domain and spectral analysis, recordings of the electrocardiogram were analysed to detect differences in HRV between groups. Youth with T1D had significantly higher sample entropy than controls (P = 0.015) suggesting increased complexity in HRV, but similar detrended fluctuation analysis (P = 0.68). Youth with T1D also had increased % high frequency power (P = 0.017) and reduced mid-frequency power (P = 0.019) on spectral analysis. There were no differences in heart rate or blood pressure responses to standing, or time-domain analysis of HRV. Within the T1D group, sample entropy correlated strongly with triglycerides (r = 0.76, P = 0.001) and detrended fluctuation analysis correlated strongly with serum potassium (r = -0.86, P < 0.001). Complexity analysis of HRV, particularly using sample entropy, may aid detection of CAN in youth with T1D.

Executive task-based brain function in children with type 1 diabetes: An observational study.

BackgroundOptimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood.Methods and findingsUsing a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 ± 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 ± 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of “no-go > go” were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct “go” trials; r = −0.36, 95% CI −0.53 to −0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < −0.29, 95% CIs −0.47 to −0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = −0.22, 95% CI −0.41 to −0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI −0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown.ConclusionsThese data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.