Type 2 Diabetes Phenotype Research Articles

Cardiovascular phenotypes in type 2 diabetes: Latent class analysis of the CANVAS Program and CREDENCE trial.

To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05). We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability.

Treatment for type 2 diabetes and diabetic nephropathy by targeting Smad3 signaling.

TGF-β/Smad3 signaling plays a critical role in type 2 diabetes (T2D) and type 2 diabetic nephropathy (T2DN), but treatment by specifically targeting Smad3 remains unexplored. To develop a new Smad3-targeted therapy for T2D and T2DN, we treated db/db mice at the pre-diabetic or established diabetic stage with a pharmacological Smad3 inhibitor SIS3. The therapeutic effect and mechanisms of anti-Smad3 treatment on T2D and T2DN were investigated. We found that anti-Smad3 treatment on pre-diabetic db/db mice largely attenuated both T2D and T2DN by markedly reducing blood glucose levels, and inhibiting the elevated serum creatinine, microalbuminuria, and renal fibrosis and inflammation. Unexpectedly, although SIS3 treatment on the established diabetic db/db mice inhibited T2DN but did not significantly improve T2D. Mechanistically, we uncovered that inhibition of T2DN in SIS3-treated db/db mice was associated with effectively restoring the balance of TGF-β/Smad signaling by inhibiting Smad3 while increasing Smad7, thereby suppressing Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation via lncRNA Erbb4-IR and LRN9884-dependent mechanisms. We also revealed that inhibition of islet β cell injury by preventing the loss of islet Pax 6 could be the mechanism through which the pre-diabetic treatment, rather than the late SIS3 treatment on db/db mice significantly improved the T2D phenotype.

Pregnancy and diabetic ketoacidosis: fetal jeopardy and windows of opportunity.

Diabetic ketoacidosis (DKA) during pregnancy poses significant risks to both the mother and fetus, with an increased risk of fetal demise. Although more prevalent in women with Type I diabetes (T1D); those with Type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) can also develop DKA. A lack of information about DKA during pregnancy exists worldwide, including in South Africa. This study examined the characteristics and outcomes associated with DKA during pregnancy. The study took place between 1 April 2020 and 1 October 2022. Pregnant women with DKA, admitted to Tygerberg Hospital's Obstetric Critical Care Unit (OCCU) were included. Maternal characteristics, precipitants of DKA, adverse events during treatment, and maternal-fetal outcomes were examined. There were 54 episodes of DKA among 47 women. Most DKA's were mild and occurred in the third trimester. Pregestational diabetes dominated (31/47; 60%), with 47% having T1D and 94% requiring insulin. Seven women (7/47, 15%; T2D:6, T1D:1) had two episodes of DKA during the same pregnancy. Most women (32/47; 68%) were either overweight or obese. Yet, despite the T2D phenotype, biomarkers indicated that auto-immune diabetes was prevalent among women without any prior history of T1D (6/21; 29%). Twelve women (26%) developed gestational hypertension during pregnancy, and 17 (36%) pre-eclampsia. Precipitating causes of DKA included infection (14/54; 26%), insulin disruption (14/54; 26%) and betamethasone administration (10/54; 19%). More than half of the episodes of DKA involved hypokalemia (35/54, 65%) that was associated with fetal death (P=0.042) and hypoglycemia (28/54, 52%). Preterm birth (<37 weeks' gestation) occurred in 85% of women. No maternal deaths were recorded. A high fetal mortality rate (13/47; 28%) that included 11 spontaneous intrauterine deaths and two medical terminations, was observed. Women with DKA have a high risk of fetal mortality as well as undiagnosed auto-immune diabetes. There is a strong link between maternal hypokalemia and fetal loss, suggesting an opportunity to address management gaps in pregnant women with DKA.

Insights into Insulin Resistance and Calcification in the Myocardium in Type 2 Diabetes: A Coronary Artery Analysis

Type 2 diabetes (T2D) is responsible for high incidence of cardiovascular (CV) complications leading to heart failure. Coronary artery region-specific metabolic and structural assessment could provide deeper insight into the extent of the disease and help prevent adverse cardiac events. Therefore, in this study, we aimed at investigating such myocardial dynamics for the first time in insulin-sensitive (mIS) and insulin-resistant (mIR) T2D patients. We targeted global and region-specific variations using insulin sensitivity (IS) and coronary artery calcifications (CACs) as CV risk factor in T2D patients. IS was computed using myocardial segmentation approaches at both baseline and after an hyperglycemic-insulinemic clamp (HEC) on [18F]FDG-PET images using the standardized uptake value (SUV) (ΔSUV = SUVHEC - SUVBASELINE) and calcifications using CT Calcium Scoring. Results suggest that some communicating pathways between response to insulin and calcification are present in the myocardium, whilst differences between coronary arteries were only observed in the mIS cohort. Risk indicators were mostly observed for mIR and highly calcified subjects, which supports previously stated findings that exhibit a distinguished exposure depending on the impairment of response to insulin, while projecting added potential complications due to arterial obstruction. Moreover, a pattern relating calcification and T2D phenotypes was observed suggesting the avoidance of insulin treatment in mIS but its endorsement in mIR subjects. The right coronary artery displayed more ΔSUV, whilst plaque was more present in the circumflex. However, differences between phenotypes, and therefore CV risk, were associated to left descending artery (LAD) translating into higher CACs regarding IR, which could explain why insulin treatment was effective for LAD at the expense of higher likelihood of plaque accumulation. Personalized approaches to assess T2D may lead to more efficient treatments and risk-prevention strategies.

Establishing a Type 2 Diabetes phenotype in APPxhQC transgenic mice expressing N‐terminally modified pGlu Aβ peptides.

AbstractBackgroundAlzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Aβ peptides are commonly subjected to post‐translational modifications like truncation known to play pivotal role in Aβ plaque aggregation. N‐terminally truncated Aβ peptides containing pyroglutamatic acid (pGlu) catalyzed by glutaminyl cyclase (QC) e.g., pGlu3‐Aβ (3‐40/42) are the major Aβ peptide fragments within the core of the neuritic plaques and correlate with disease severity and progression. Type 2 diabetes (T2D) is one of the major risk factors associated with AD and compelling evidence supports the notion that insulin resistance, a key feature of T2D, is involved in AD‐type neurodegeneration. Hence, in this study, we aim to establish a T2D phenotype in APPxhQC transgenic using low‐dose Streptozocin injection in combination with high fat diet (HFD).MethodsAPPxhQC mice, crossbreds of APPSL and hQC mice, were used. APPSL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice on B6CBAF1/J background express human glutaminyl cyclase (QC) enzyme. The cross‐breeding results in an increased generation of N‐terminal modified pGlu Aβ peptides. To establish a T2D phenotype, 8‐9 months old APPxhQC transgenic mice were allocated to 4 treatment groups receiving: standard chow diet, HFD, standard chow diet in combination with streptozocin injections and HFD in combination with streptozocin injections. The intraperitoneal glucose tolerance test (ipGTT) and intraperitoneal insulin tolerance test (ipITT) were performed at 6 and 7 weeks after the initiation of the diet, as a relevant parameter of T2D progression.ResultsStreptozocin‐injected mice maintained on HFD had the least tolerance to injected glucose as shown by ipGTT. Impaired glucose clearance was observed at 15, 30, 60 and 120 mins after intraperitoneal glucose injection (2g/kg). Also, impaired glucose clearance at 15 mins after intraperitoneal insulin injection (0.75U/kg) was observed in the same group.ConclusionCombination of high‐fat diet and streptozocin injections leads to the development of robust T2D symptoms in APPxhQC transgenic mice. Current experiments are focusing on combinational effects of T2D and post‐translationally modified amyloid peptides in AD progression and pathophysiology.

Epigenetic Reprogramming of the Inflammatory Response in Obesity and Type 2 Diabetes.

For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these conditions are accompanied by major abnormalities in fuel metabolism, evidence indicates that altered immune cell functions also play an important role in shaping of obesity and T2D phenotypes. Interestingly, these events have been shown to be determined by epigenetic mechanisms. Consistently, recent epigenome-wide association studies have demonstrated that immune cells from obese and T2D individuals feature specific epigenetic profiles when compared to those from healthy subjects. In this work, we have reviewed recent literature reporting epigenetic changes affecting the immune cell phenotype and function in obesity and T2D. We will further discuss therapeutic strategies targeting epigenetic marks for treating obesity and T2D-associated inflammation.

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

Latent autoimmune diabetes in youth shows greater autoimmunity than latent autoimmune diabetes in adults: Evidence from a nationwide, multicenter, cross-sectional study.

To investigate the prevalence and clinical features of latent autoimmune diabetes in youth (LADY) diagnosed between 15 and 29 years old as a component of an age-related autoimmune diabetes spectrum. This nationwide, multicenter, cross-sectional study continuously included 19,100 newly diagnosed diabetes patients over 15 years old across China. LADY patients were screened from 1803 subjects aged between 15 and 29 years old, with the type 2 diabetes (T2D) phenotype and positive autoantibodies against glutamic acid decarboxylase (GADA), insulinoma-associated-2 (IA-2A) or zinc transporter-8 (ZnT8A). The clinical features of LADY, including metabolic status, β-cell function and insulin resistance, were investigated and compared with those of latent autoimmune diabetes in adults (LADA) identified from 17,297 other subjects over 30 years old. The age-related characteristics of the latent autoimmune diabetes spectrum were explored. A total of 135 subjects were diagnosed as LADY, accounting for 9.0% of the T2D phenotypic youth. Compared with autoantibody-negative T2D patients, LADY patients had fewer metabolic syndrome, less insulin resistance and poorer β-cell function, which were closely related to their autoantibody status (all p < 0.05). After stratifying LADA according to age, the GADA titer decreased across the LADY, "Y-LADA" (young LADA, onset age < 60 years old) and "E-LADA" (elderly LADA, onset age ≥ 60 years old) groups, while the prevalence of metabolic syndrome and level of β-cell function increased (all p < 0.05). A high prevalence of LADY exists in youth with T2D phenotype. Latent autoimmune diabetes forms a continuous age-related spectrum from LADY to LADA, in which LADY shows greater autoimmunity.

Type 2 diabetes classification: a data-driven cluster study of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort

IntroductionA Swedish data-driven cluster study identified four distinct type 2 diabetes (T2D) clusters, based on age at diagnosis, body mass index (BMI), hemoglobin A1c (HbA1c) level, and homeostatic model assessment...

Maternal low protein diet and fetal programming of lean type 2 diabetes.

Maternal nutrition is found to be the key factor that determines fetal health in utero and metabolic health during adulthood. Metabolic diseases have been primarily attributed to impaired maternal nutrition during pregnancy, and impaired nutrition has been an immense issue across the globe. In recent years, type 2 diabetes (T2D) has reached epidemic proportion and is a severe public health problem in many countries. Although plenty of research has already been conducted to tackle T2D which is associated with obesity, little is known regarding the etiology and pathophysiology of lean T2D, a variant of T2D. Recent studies have focused on the effects of epigenetic variation on the contribution of in utero origins of lean T2D, although other mechanisms might also contribute to the pathology. Observational studies in humans and experiments in animals strongly suggest an association between maternal low protein diet and lean T2D phenotype. In addition, clear sex-specific disease prevalence was observed in different studies. Consequently, more research is essential for the understanding of the etiology and pathophysiology of lean T2D, which might help to develop better disease prevention and treatment strategies. This review examines the role of protein insufficiency in the maternal diet as the central driver of the developmental programming of lean T2D.

Taurine and N‐acetylcysteine supplementation prevents memory impairment in high‐fat diet‐fed female mice

AbstractBackgroundThe risk to develop memory impairment in has been widely investigated in type 2 diabetes (T2D). There are several mechanisms proposed for T2D‐associated cognitive impairment, such as brain insulin resistance, synaptic dysfunction, inflammation, gliosis, or disruption of neuron‐astrocyte interactions (Garcia‐Serrano &amp; Duarte, 2020). On the other hand, supplementation with the antioxidants taurine and N‐acetylcysteine (NAC) have been suggested to have benefits on reducing T2D phenotype and enhancing memory performance in diabetic mice models (Inam‐U‐Ilah et al, 2018). We aimed at studying mechanisms by which taurine and NAC improve memory in obesity‐associated T2D.MethodTen‐week‐old female C57Bl/6J mice were divided in 6 groups (n=10): control diet (CD 10%‐fat diet), high‐fat diet (HFD; 60% fat diet), CD/HFD supplemented with 3% taurine in drinking water (CD+T or HFD+T) or 3% N‐acetylcysteine (CD+NAC or HFD+NAC). After 2 months, hippocampal metabolic profiles were analysed by magnetic resonance spectroscopy (MRS) under isoflurane anaesthesia, memory performance was evaluated by behavioural testing with the novel location recognition (NLR) and novel object recognition (NOR) tasks, and diabetes phenotype was measured by monitoring weight, glucose tolerance test and HOMA insulin resistance.ResultHFD group was overweight compared to CD group (p&lt;0.01), with no effects of taurine or NAC. HFD‐fed mice showed glucose intolerance compared to CD mice (p&lt;0.001). Although HFD+T and HFD+NAC groups were glucose intolerant but to a lesser degree than untreated HFD mice (p&lt; 0.05 and p&lt;0.01, respectively). None of the experimental groups displayed insulin resistance, neither memory impairment in the NOR test. The NLR test showed memory impairment in the HFD‐fed mice compared to controls (p&lt;0.037), which was prevented by taurine and NAC treatments. The metabolic profile showed decreased concentration of the neuronal marker N‐acetylaspartate and lactate in the hippocampus of HFD‐fed mice compared to controls (p&lt;0.01). While N‐acetylaspartate concentrations were recovered to control levels in both HFD+T and HFD+NAC mice, only HFD+NAC group recovered lactate concentration in the hippocampus.ConclusionMemory impairment in HFD‐fed mice was restored by taurine and NAC treatments, through mechanisms that involve metabolism in mitochondria, which is the organelle responsible for producing N‐acetylaspartate in neurons.Garcia‐Serrano &amp; Duarte, 2020. https://doi.org/10.1177/0271678X20942397 Inam‐U‐Ilah et al, 2018. https://doi.org/10.1007/s00726‐018‐2544‐4

Transcriptomics of type 2 diabetic and healthy human neutrophils

ObjectivesChronic inflammatory diseases, including diabetes and cardiovascular disease, are heterogeneous and often co-morbid, with increasing global prevalence. Uncontrolled type 2 diabetes (T2D) can result in severe inflammatory complications. As neutrophils are essential to normal and aberrant inflammation, we conducted RNA-seq transcriptomic analyses to investigate the association between neutrophil gene expression and T2D phenotype. As specialized pro-resolving lipid mediators (SPM) act to resolve inflammation, we further surveyed the impact of neutrophil receptor binding SPM resolvin E1 (RvE1) on isolated diabetic and healthy neutrophils.MethodsCell isolation and RNA-seq analysis of neutrophils from N = 11 T2D and N = 7 healthy individuals with available clinical data was conducted. Additionally, cultured neutrophils (N = 3 T2D, N = 3 healthy) were perturbed with increasing RvE1 doses (0 nM, 1 nM, 10 nM, or 100 nM) prior to RNA-seq. Data was evaluated through a bioinformatics pipeline including pathway analysis and post hoc false discovery rate (FDR)-correction.ResultsWe observed significant differential expression of 50 genes between T2D and healthy neutrophils (p < 0.05), including decreased T2D gene expression in inflammatory- and lipid-related genes SLC9A4, NECTIN2, and PLPP3 (p < 0.003). RvE1 treatment induced dose-dependent differential gene expression (uncorrected p < 0.05) across groups, including 59 healthy and 216 T2D neutrophil genes. Comparing T2D to healthy neutrophils, 1097 genes were differentially expressed across RvE1 doses, including two significant genes, LILRB5 and AKR1C1, involved in inflammation (p < 0.05).ConclusionsThe neutrophil transcriptomic database revealed novel chronic inflammatory- and lipid-related genes that were differentially expressed between T2D cells when compared to controls, and cells responded to RvE1 dose-dependently by gene expression changes. Unraveling the mechanisms regulating abnormalities in diabetic neutrophil responses could lead to better diagnostics and therapeutics targeting inflammation and inflammation resolution.

Gut Metabolite Trimethylamine N-oxide Protects β Cell Insulin Secretion by Reducing Oxidative Stress and Maintaining Insulin Granule Formation

Abstract Objectives Elevated circulating levels of the dietary metabolite trimethylamine N-oxide (TMAO) is associated with chronic diseases including cardiovascular disease (CVD) and obesity. While TMAO production via the gut microbiome-liver axis and distribution through the circulation is clear, its molecular effects on metabolic tissues are still unclear. Some clinical studies suggest that elevated TMAO levels increase the risk of type 2 diabetes (T2D) where pancreatic β cell insulin secretion is insufficient for blood glucose management. T2D promoting mechanisms limit functional β cell mass by reducing β cell viability and survival, inhibiting proliferation or decreasing insulin secretory function. We hypothesized that TMAO decreases functional β cell mass by one of these mechanisms to aggravate the T2D phenotype. Methods Using the INS-1 832/13 β cell line and primary murine islets, we screened the effect of various TMAO concentrations on cell viability, proliferation, and function. These parameters were measured under standard and glucolipotoxic (GLT) culture conditions to mimic T2D. We investigated TMAO effects, GLT effects and combined effects. Results TMAO minimally affected viability, proliferation or function under standard culture conditions across 96-hours of treatment. Culturing with GLT impaired viability, proliferation and function after 24 hours of treatment, mimicking T2D onset. Interestingly, adding 40–80 μM TMAO protected against GLT mediated functional impairments in cells and islets. Further, GLT increased oxidative stress by 2.5-fold and adding TMAO was significantly protective. Electron microscopy reveals that GLT alters insulin granule density whereas TMAO maintains proper granule structure. Conclusions These results reject our hypothesis. While TMAO has minor effects on β cells in standard culture conditions, TMAO is sufficient to improve GLT mediated β cell damage by decreasing oxidative stress and maintaining insulin granule formation. These results suggest an early compensatory role for TMAO in countering oxidative damage caused by glucolipotoxicity in β cell function during T2D onset. Funding Sources Funding for this study was provided by the Beatson Foundation and the US Department of Agriculture.

Eye-color and Type-2 diabetes phenotype prediction from genotype data using deep learning methods

BackgroundGenotype–phenotype predictions are of great importance in genetics. These predictions can help to find genetic mutations causing variations in human beings. There are many approaches for finding the association which can be broadly categorized into two classes, statistical techniques, and machine learning. Statistical techniques are good for finding the actual SNPs causing variation where Machine Learning techniques are good where we just want to classify the people into different categories. In this article, we examined the Eye-color and Type-2 diabetes phenotype. The proposed technique is a hybrid approach consisting of some parts from statistical techniques and remaining from Machine learning.ResultsThe main dataset for Eye-color phenotype consists of 806 people. 404 people have Blue-Green eyes where 402 people have Brown eyes. After preprocessing we generated 8 different datasets, containing different numbers of SNPs, using the mutation difference and thresholding at individual SNP. We calculated three types of mutation at each SNP no mutation, partial mutation, and full mutation. After that data is transformed for machine learning algorithms. We used about 9 classifiers, RandomForest, Extreme Gradient boosting, ANN, LSTM, GRU, BILSTM, 1DCNN, ensembles of ANN, and ensembles of LSTM which gave the best accuracy of 0.91, 0.9286, 0.945, 0.94, 0.94, 0.92, 0.95, and 0.96% respectively. Stacked ensembles of LSTM outperformed other algorithms for 1560 SNPs with an overall accuracy of 0.96, AUC = 0.98 for brown eyes, and AUC = 0.97 for Blue-Green eyes. The main dataset for Type-2 diabetes consists of 107 people where 30 people are classified as cases and 74 people as controls. We used different linear threshold to find the optimal number of SNPs for classification. The final model gave an accuracy of 0.97%.ConclusionGenotype–phenotype predictions are very useful especially in forensic. These predictions can help to identify SNP variant association with traits and diseases. Given more datasets, machine learning model predictions can be increased. Moreover, the non-linearity in the Machine learning model and the combination of SNPs Mutations while training the model increases the prediction. We considered binary classification problems but the proposed approach can be extended to multi-class classification.

Effects of diet, BMP-2 treatment, and femoral skeletal injury on endothelial cells derived from the ipsilateral and contralateral limbs.

Type 2 diabetes (T2D) results in physiological and structural changes in bone, contributing to poor fracture healing. T2D compromises microvascular performance, which can negatively impact bone regeneration as angiogenesis is required for new bone formation. We examined the effects of bone morphogenetic protein-2 (BMP-2) administered locally at the time of femoral segmental bone defect (SBD) surgery, and its angiogenic impacts on endothelial cells (ECs) isolated from the ipsilateral or contralateral tibia in T2D mice. Male C57BL/6 mice were fed either a low-fat diet (LFD) or high-fat diet (HFD) starting at 8 weeks. After 12 weeks, the T2D phenotype in HFD mice was confirmed via glucose and insulin tolerance testing and echoMRI, and all mice underwent SBD surgery. Mice were treated with BMP-2 (5 µg) or saline at the time of surgery. Three weeks postsurgery, bone marrow ECs were isolated from ipsilateral and contralateral tibias, and proliferation, angiogenic potential, and gene expression of the cells was analyzed. BMP-2 treatment increased EC proliferation by two fold compared with saline in LFD contralateral tibia ECs, but no changes were seen in surgical tibia EC proliferation. BMP-2 treatment enhanced vessel-like structure formation in HFD mice whereas, the opposite was observed in LFD mice. Still, in BMP-2 treated LFD mice, ipsilateral tibia ECs increased expression of CD31, FLT-1, ANGPT1, and ANGPT2. These data suggest that the modulating effects of T2D and BMP-2 on the microenvironment of bone marrow ECs may differentially influence angiogenic properties at the fractured limb versus the contralateral limb.

Homocysteine Inhibits Pro-Insulin Receptor Cleavage and Causes Insulin Resistance Via Protein Cysteine-Homocysteinylation

Elevation in homocysteine (Hcy) level is associated with insulin resistance; however, the causality between them, and the underlying mechanism remain elusive. Here, we demonstrated that Hcy induced insulin resistance and caused phenotypes of diabetes via protein cysteine-homocysteinylation (C-Hcy) of the pro-insulin receptor (pro-IR). Mechanistically, Hcy reacted and modified cysteine-825 of pro-IR in the endoplasmic reticulum (ER) and abrogated the formation of the original disulfide bond. C-Hcy impaired the interaction between pro-IR and the Furin protease in the Golgi apparatus, thereby hindering the cleavage of pro-IR. In mouse, increase in Hcy level decreased the mature IR level in various tissues, thereby inducing insulin resistance and type-2 diabetes phenotype. Furthermore, inhibition of C-Hcy in vivo and in vitro by overexpressing protein disulfide isomerase rescued the Hcy-induced phenotypes. Thus, C-Hcy in the ER might be a potential pharmacological target for the development of drugs that prevent insulin resistance and increase insulin sensitivity.

NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity

The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in the liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance, and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased nonesterified fatty acid (NEFA) and triglyceride (TG) in the liver and plasma and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in the liver and circulation and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKα1-dependent phosphorylation of AKT and GSK3β. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in the liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment.

Molecular biomarker profile of heart failure with mid-range and preserved ejection fraction in patients with type 2 diabetes

Aim. To study molecular biomarkers in patients with type 2 diabetes (T2D) in combination with heart failure with preserved (HFpEF) and mid-range ejection fraction (HFmrEF) and compare the data obtained with clinical characteristics of myocardial remodeling.Material and methods. The study included 42 patients with T2D (men — 53%, mean age — 60 years) with clinical manifestations of class II HF: 29 patients with HFpEF (group 1) and 13 patients with HFmrEF (group 2). The control group consisted of 13 healthy people, which were comparable in sex and age and had a normal body mass index (BMI). Patients received stable glucose-lowering and optimal drug therapy for HF for 3 months prior to enrollment in the study. Patients with HFpEF and HFmrEF were comparable in clinical and demographic parameters, had glycated hemoglobin (HbA ) of 8,5% and 8,8%, respectively (p&gt;0,05), increased BMI or grade I-II obesity.We studied following biomarkers: NT-proBNP, highly sensitive C-reactive protein (hsCRP), sST2, galectin-3, procollagen type I C-terminal propeptide (PICP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1).Results. Volumetric parameters of the left ventricle (LV),LV mass indexed to growth and NT-proBNP were higher in the group of HFpEF patients (p&lt;0,05 for all). The concentrations of galectin-3, PICP were higher, and the MMP-9/TIMP-1 ratio decreased in patients with T2D compared with the control group (p&lt;0,05 for all). PICP values were higher in patients with HFmrEF compared with patients with HFpEF (106,4 (85,4; 140,4) ng/ml vs 46,8 (12,6; 98,6 ng/ml), respectively, p=0,043). In patients with T2D and HF, a relationship was found between TIMP-1 andLV end-diastolic volume (r=-0,68; p=0,042).Conclusion. Patients with HFmrEF and T2D have higherLV volume and mass, higher concentrations of NT-proBNP and PICP in comparison with patients with HFpEF. The direction of MMP-9/TIMP-1 changes may reflect a decrease in antifibrotic processes. Further prospective studies on large samples using a multiple biomarker model are required in T2D and various HF phenotypes.

Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?

Type 2 diabetes (T2D) is a metabolic disease with impact on brain function through mechanisms that include glucose toxicity, vascular damage and blood–brain barrier (BBB) impairments, mitochondrial dysfunction, oxidative stress, brain insulin resistance, synaptic failure, neuroinflammation, and gliosis. Rodent models have been developed for investigating T2D, and have contributed to our understanding of mechanisms involved in T2D-induced brain dysfunction. Namely, mice or rats exposed to diabetogenic diets that are rich in fat and/or sugar have been widely used since they develop memory impairment, especially in tasks that depend on hippocampal processing. Here we summarize main findings on brain energy metabolism alterations underlying dysfunction of neuronal and glial cells promoted by diet-induced metabolic syndrome that progresses to a T2D phenotype.

Transcriptomic responses of hypothalamus to acute exercise in type 2 diabetic Goto-Kakizaki rats.

The hypothalamus has an integral role in energy homeostasis regulation, and its dysfunctions lead to the development of type 2 diabetes (T2D). Physical activity positively affects the prevention and treatment of T2D. However, there is not much information on the adaptive mechanisms of the hypothalamus. In this study, RNA sequencing was used to determine how acute exercise affects hypothalamic transcriptome from both type 2 diabetic Goto-Kakizaki (GK) and control Wistar rats with or without a single session of running (15 m/min for 60 min). Through pairwise comparisons, we identified 957 differentially expressed genes (DEGs), of which 726, 197, and 98 genes were found between GK and Wistar, exercised GK and GK, and exercised Wistar and Wistar, respectively. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment revealed that lipid metabolism-related terms and pathways were enriched in GK and exercised GK rats, and nervous system related terms and pathways were enriched in exercised GK and Wistar rats. Furthermore, 45 DEGs were associated with T2D and related phenotypes according to the annotations in the Rat Genome Database. Among these 45 DEGs, several genes (Plin2, Cd36, Lpl, Wfs1, Cck) related to lipid metabolism or the nervous system are associated with the exercise-induced benefits in the hypothalamus of GK rats. Our findings might assist in identifying potential therapeutic targets for T2D prevention and treatment.