Diabetes-related Diseases Research Articles

229-OR: Physical Fitness and Cardiovascular Risk Factors in Diabetes Subgroups

Physical inactivity promotes insulin resistance and increases the risk of diabetes and cardiovascular disease. Clustering based on simple clinical measures has been introduced for identifying diabetes subgroups with different risk of complications. However, little is known about physical fitness and cardiovascular risk factors in these clusters. We hypothesized that the insulin resistant diabetes (SIRD) cluster would associate with lower physical fitness and increased cardiovascular risk factors. Cycling spiroerogometry, physical activity questionnaire (Baecke index) and cardiovascular risk scores (Framingham Risk Scores (FRS) and triglycerides to high-density lipoproteins (TG:HDL) ratio) were analyzed in 746 participants with newly diagnosed diabetes of the German Diabetes Study (GDS). SIRD showed lower VO2max compared to the severe autoimmune diabetes (SAID), moderate age-related (MARD) and moderate obesity-related (MOD) clusters (all p<0.01) but was not different to the severe insulin deficient (SIDD) cluster (p= 0.87). Further, Baecke index was lower in SIRD [7.3 (6.8-8.4)] than SAID [8.5 (7.6-9.5)] and MARD [8.4 (7.3-9.4)] and SIRD had the highest TG:HDL ratio compared to all other groups (p<0.05) after adjustments for age, sex and BMI. This was underlined by a strong association between estimates of insulin resistance (HOMA-IR) and TG:HDL ratio (r= 0.59 p= <.0001) across all groups. Finally, SIRD showed higher FRS [33.1 (25.3-54.9)%] compared to MOD [16.2 (7.4-24.4)%], SAID [3.9 (1.6-9.4)%] and SIDD [12.4 (4.7-34.9)%]. In conclusion, SIRD and MARD showed lowest physical fitness and SIRD was least physically active and has the highest risk scores for diabetes-related cardiovascular diseases. Disclosure N. Saatmann: None. O. P. Zaharia: None. K. Strassburger: None. D. Pesta: None. V. Burkart: None. J. Szendroedi: None. M. Roden: Advisory Panel; Self; Allergan plc, Bristol-Myers Squibb Company, Novo Nordisk A/S, Research Support; Self; Boehringer Ingelheim International GmbH, Danone Nutricia, Sanofi-Aventis Deutschland GmbH.

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications.

Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, whose prevalence is increasing dramatically worldwide and can lead to a range of serious complications. Wnt ligands (Wnts) and their activating Wnt signalling pathways are closely involved in the regulation of various processes that are important for the occurrence and progression of T2DM and related complications. However, our understanding of their roles in these diseases is quite rudimentary due to the numerous family members of Wnts and conflicting effects via activating the canonical and/or non‐canonical Wnt signalling pathways. In this review, we summarize the current findings on the expression pattern and exact role of each human Wnt in T2DM and related complications, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11 and Wnt16. Moreover, the role of main antagonists (sFRPs and WIF‐1) and coreceptor (LRP6) of Wnts in T2DM and related complications and main challenges in designing Wnt‐based therapeutic approaches for these diseases are discussed. We hope a deep understanding of the mechanistic links between Wnt signalling pathways and diabetic‐related diseases will ultimately result in a better management of these diseases.

Study of Omentin-1 and Chemerin as Predictors of Coronary Artery Disease in Elderly Patients, with Retrospective Studying of their Relation to Diabetes Mellitus Type 2

Monocyte chemoattractant protein-1 (MCP-1) is the first discovered and most extensively studied chemotactic cytokines (CC = chemokine). Many studies on its role in the etiologies of obesity- and diabetes-related diseases have been increased exponentially during the past two decades. MCP-1, a chemokine involved in monocyte chemotaxis can be consistently found at high levels in the patients with type 2 diabetes mellitus. MCP1 may be an early predictor of complications of diabetes. Objective: Assessment of the levels of MCP-1 and other biochemical markers in diabetic subjects compared to a healthy group, which in turn can be beneficial to clarify the correlations of MCP-1 levels in diabetes mellitus with other clinical and biochemical parameters. Patients and methods: Eighty-one participants including both male and female, of cross-matched ages ranging between 30 – 60 years old were included in this study. They were divided into three equal groups: group I (control group), group II (recently diagnosed T2DM) and group III (old diagnosed T2DM more than 10 years). Results: The highest level of MCP-1 was found in the old diagnosed diabetic group while the lowest level was found in the non-diabetic control group. The LSD statistical analysis showed there was significant difference between all groups of the study. Our results showed that serum MCP-1 was elevated in cases of the group 3 (old diagnosed diabetic patients) who were suffering from diabetic nephropathy (9/27), diabetic retinopathy (9/27) and the last 9/27 were suffering of neuropathy. Conclusion: The MCP-1 level is increased in type 2 Diabetic patients and significantly increased with the progression of diabetes complications as diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

Evaluation of Monocyte Chemoattractant Protein 1(MCP-1) as a Predictor of Complications in Type 2 Diabetes Mellitus in Zagazig University Hospital

ABSTRACT Background: Monocyte chemoattractant protein-1 (MCP-1) is the first discovered and most extensively studied chemotactic cytokines (CC = chemokine). Many studies on its role in the etiologies of obesity- and diabetes-related diseases have been increased exponentially during the past two decades. MCP-1, a chemokine involved in monocyte chemotaxis can be consistently found at high levels in the patients with type 2 diabetes mellitus. MCP1 may be an early predictor of complications of diabetes. Objective: Assessment of the levels of MCP-1 and other biochemical markers in diabetic subjects compared to a healthy group, which in turn can be beneficial to clarify the correlations of MCP-1 levels in diabetes mellitus with other clinical and biochemical parameters. Patients and methods: Eighty-one participants including both male and female, of cross-matched ages ranging between 30 – 60 years old were included in this study. They were divided into three equal groups: group I (control group), group II (recently diagnosed T2DM) and group III (old diagnosed T2DM more than 10 years). Results: The highest level of MCP-1 was found in the old diagnosed diabetic group while the lowest level was found in the non-diabetic control group. The LSD statistical analysis showed there was significant difference between all groups of the study. Our results showed that serum MCP-1 was elevated in cases of the group 3 (old diagnosed diabetic patients) who were suffering from diabetic nephropathy (9/27), diabetic retinopathy (9/27) and the last 9/27 were suffering of neuropathy. Conclusion: The MCP-1 level is increased in type 2 Diabetic patients and significantly increased with the progression of diabetes complications as diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

Organelle stress and glycation in kidney disease.

Glycation of proteins is a non-enzymatic posttranslational modification. Such random modification often deranges the structure and function of a wide range of proteins, and in turn leads to cellular dysfunction and organ damage. Protein glycation is thus an important topic in understanding the molecular mechanisms of the development or progression of various kinds of diabetes-related diseases. Meanwhile, organelle stress, such as mitochondrial or endoplasmic reticulum (ER) damage, is a causal factor for cellular dysfunction. Under pathogenic conditions, mitochondrial stress and ER stress are induced by glycated proteins. Intensive research has revealed the molecular mechanism of how glycation contributes to cell fate via organelle stress. This article will summarize the most recent evidence on organelle stress and glycation in kidney disease, especially diabetic kidney disease (DKD) associated with high glycation status.

O-linked N-acetylglucosaminyltransferase OGT inhibits diabetic nephropathy by stabilizing histone methyltransferases EZH2 via the HES1/PTEN axis

BackgroundO-linked N-acetylglucosaminyltransferase (OGT) is involved in diabetes-related diseases including diabetic nephropathy (DN), and responsible for O-GlcNAcylation. Moreover, O-GlcNAcylation and OGT could be induced by high glucose. Thus, we sought to explore the molecular mechanism of OGT in DN. MethodsLoss- and gain-functions were conducted to determine the roles of OGT, enhancer of zeste homolog 2 (EZH2), hairy and enhancer of split 1 (HES1) and phosphatase and tensin homolog (PTEN) in the viability, cell cycle and fibrosis of mesangial cells (MCs), followed by the assessment using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blot assay (fibrosis-related proteins). The interaction between OGT and EZH2 and the effect on EZH2 glycosylation were verified by chromatin immunoprecipitation (ChIP) and glutathione S-transferase (GST) pull-down assays. EZH2 stability was checked by treatment with cycloheximide. ResultsExpression of OGT was repressed in the DN mice and high glucose-treated MCs. Elevated OGT suppressed viability of high glucose-treated MCs, blocked proliferation characterized by repressed cyclin D1, but enhanced p21 levels, and inhibited fibrosis evidenced by reduced levels of fibronectin (FN) and collagen-4 (col-4). OGT interacted with EZH2 and promoted its glycosylation thus stabilizing the EZH2. EZH2 overexpression enhanced the enrichment of EZH2 and histone H3 Lys27 trimethylation (H3K27me3) in the HES1 promoter. HES1 was upregulated and PTEN was downregulated in DN mice. Transduction of lentivirus vector containing overexpression (oe)-OGT alleviated renal injury in DN mice. ConclusionsCollectively, OGT stabilizes histone methyltransferases EZH2 to regulate HES1/PTEN thus inhibiting DN.

Prevalence of Diabetes and Diabetes-Related Cardiovascular Risk Factors in a Rural Population in Burkina Faso

RésuméObjectifsLe milieu rural est confronté de nos jours à des changements du mode de vie qui jouent un rôle important dans l'augmentation de la prévalence du diabète sucré et des autres facteurs de risque cardio-vasculaire. Le but de cette enquête était de déterminer la prévalence et les facteurs de risque associés au diabète sucré dans une population rurale du Burkina Faso.MéthodologieNous avons récolté au cours d'une campagne de dépistage volontaire du diabète des variables épidémio-cliniques et mesuré la glycémie capillaire de tous les sujets à jeun de 16 ans et plus dans les communes de la province du Zondoma.RésultatsNeuf-cent-soixante-dix personnes d'un âge moyen de 49,06 ± 16,97 ans se sont soumises volontairement au test de dépistage. La majorité des personnes avait un âge compris entre 40 ans et 65 ans (48,5%) et 57,5% étaient des femmes. La prévalence du diabète sucré était de 5,7% et 9% des sujets avaient une glycémie entre 1,10 g/l et 1,26 g/l (hyperglycémie modérée à jeun). Un antécédent familial de diabète a été retrouvé dans 4,3% des cas. Pour les autres facteurs de risques cardio-vasculaires, 24,3% de la population était en surcharge pondérale et 23,6% avait une hypertension artérielle. L'âge (p = 0,001), la profession (p = 0,015) et l'IMC (p = 0,036) étaient significativement associés au diabète.ConclusionLe diabète sucré est présent en milieu rural au Burkina Faso avec une proportion non négligeable de pré-diabète. L'âge, la profession et l'IMC sont les principaux facteurs associés.

From diabetes to renal aging: the therapeutic potential of adiponectin.

Nowadays, the complications related to diabetes, such as nephropathy, cardiovascular problems, and aging, are highly being considered. Renal cell aging is affected by various mechanisms of inflammation, oxidative stress, and basement membrane thickening, which are significant causes of renal dysfunction in diabetes. Due to recent studies, adiponectin plays a key role in diabetes-related kidney diseases as a fat-derived hormone. In diabetes, reduced adiponectin levels are associated to renal cell aging. Oxidative stress and related signaling pathways are the main routes in which adiponectin may be effective to decline diabetes-associated aging. Therefore, adiponectin signaling in target tissues becomes one of the research areas of interest in metabolism and clinical medicine. Studies on adiponectin signaling will increase our understanding of adiponectin role in diabetes-linked diseases as well as shortening life span conditions which may guide the design of antidiabetic and anti-aging drugs.

Diabetic eye disease: A review of screening and management recommendations.

The prevalence of diabetes is rapidly increasing, and it is now the leading cause of blindness worldwide. Although early detection of diabetic retinopathy is key to preventing vision loss, many patients do not receive appropriate examinations. Using a multidisciplinary approach, primary care physicians and eye care providers should follow evidence-based recommendations for screening and monitoring diabetic patients while working to improve patients' glycaemic index, blood pressure, and metabolic risk factors. Anti-vascular endothelial growth factor intravitreal injections in combination with panretinal photocoagulation and focal laser treatment remain the cornerstones of modern therapy. The many landmark studies for diabetic eye disease management should guide counselling and decision making for treating diabetic macular oedema, proliferative retinopathy and other diabetes-related eye diseases.

Association between birthweight, cardiovascular risk factors, and depression in young Mexican adults.

Background: the aim of this study was to investigate the association between birthweight, cardiovascular disease (CVD) risk factors, and depression in young Mexican adults. Methods: birthweight reports, family history of CVD and diabetes-related diseases, anthropometrics, serum lipid profile (total cholesterol [TC], triglycerides [TG], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], and very-low density lipoprotein-cholesterol [VLDL-C]), and depressive symptoms were measured in 778 subjects of the UP-AMIGOS cohort study. To investigate the association between birthweight categories and CVD risk factors and depression, a one-way analysis of variance with post-hoc test was performed of quantitative variables, and 2 test for qualitative variables. Results: mean age was 17.8 years and 469 (60.3 %) of patients were female (n = 469, 60.3 %). The percentage of patients with low birthweight (LBW) was 8.1 % (n = 63), and 3.3 % (n = 26) reported high birthweight (HBW). Young adults with HBW were associated with elevated diastolic blood pressure (DBP), and high weight and body mass index (BMI) when compared to LBW subjects, the difference being statically significant (p < 0.05). Birthweight had no significant association with depression (p > 0.67). Conclusion: the findings from this population-based study revealed a positive relation between birthweight categories and some CVD risk factors. Depression was not related to birthweight.

Revealing the Interactions Between Diabetes, Diabetes-Related Diseases, and Cancers Based on the Network Connectivity of Their Related Genes.

Diabetes-related diseases (DRDs), especially cancers pose a big threat to public health. Although people have explored pathological pathways of a few common DRDs, there is a lack of systematic studies on important biological processes (BPs) connecting diabetes and its related diseases/cancers. We have proposed and compared 10 protein–protein interaction (PPI)-based computational methods to study the connections between diabetes and 254 diseases, among which a method called DIconnectivity_eDMN performs the best in the sense that it infers a disease rank (according to its relation with diabetes) most consistent with that by literature mining. DIconnectivity_eDMN takes diabetes-related genes, other disease-related genes, a PPI network, and genes in BPs as input. It first maps genes in a BP into the PPI network to construct a BP-related subnetwork, which is expanded (in the whole PPI network) by a random walk with restart (RWR) process to generate a so-called expanded modularized network (eMN). Since the numbers of known disease genes are not high, an RWR process is also performed to generate an expanded disease-related gene list. For each eMN and disease, the expanded diabetes-related genes and disease-related genes are mapped onto the eMN. The association between diabetes and the disease is measured by the reachability of their genes on all eMNs, in which the reachability is estimated by a method similar to the Kolmogorov–Smirnov (KS) test. DIconnectivity_eDMN achieves an area under receiver operating characteristic curve (AUC) of 0.71 for predicting both Type 1 DRDs and Type 2 DRDs. In addition, DIconnectivity_eDMN reveals important BPs connecting diabetes and DRDs. For example, “respiratory system development” and “regulation of mRNA metabolic process” are critical in associating Type 1 diabetes (T1D) and many Type 1 DRDs. It is also found that the average proportion of diabetes-related genes interacting with DRDs is higher than that of non-DRDs.

Novel enzymatically crosslinked chitosan hydrogels with free-radical-scavenging property and promoted cellular behaviors under hyperglycemia

The impairment of regenerative processes induced by high blood-glucose level (hyperglycemia) and excessive reactive oxygen species (ROS) contributes to the diabetic complication progression and development. In this study, an injectable, in situ crosslinkable chitosan hydrogel with ROS-scavenging capability was developed by conjugating gallic acid onto the chitosan backbone (CGA). We hypothesized that gallic acid serves as both antioxidant and crosslinking moieties to form hydrogel in situ by means of enzymatic crosslinking with horseradish peroxidase (HRP). The rapid gelation (from 30 s) was observed by vial tilting. The mechanical properties and microstructures of CGA hydrogels can be well controlled by varying the concentrations of H2O2. The ROS-scavenging ability of these CGA hydrogels was demonstrated against DPPH radical, hydroxyl radical, and total reducing power. Notably, in an in vitro hyperglycemia environment, CGA hydrogels significantly improved the proliferation and migration of human dermal fibroblast cells, which are closely related to diabetic wound healing. These results suggest that CGA hydrogels have potential as advanced materials for the treatment of diabetes-related diseases via attenuating the excessive ROS production and improving cellular behaviors.

Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025

Diabetes mellitus is a leading cause of mortality and reduced life expectancy. We aim to estimate the burden of diabetes by type, year, regions, and socioeconomic status in 195 countries and territories over the past 28 years, which provide information to achieve the goal of World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases in 2025. Data were obtained from the Global Burden of Disease Study 2017. Overall, the global burden of diabetes had increased significantly since 1990. Both the trend and magnitude of diabetes related diseases burden varied substantially across regions and countries. In 2017, global incidence, prevalence, death, and disability-adjusted life-years (DALYs) associated with diabetes were 22.9 million, 476.0 million, 1.37 million, and 67.9 million, with a projection to 26.6 million, 570.9 million, 1.59 million, and 79.3 million in 2025, respectively. The trend of global type 2 diabetes burden was similar to that of total diabetes (including type 1 diabetes and type 2 diabetes), while global age-standardized rate of mortality and DALYs for type 1 diabetes declined. Globally, metabolic risks (high BMI) and behavioral factors (inappropriate diet, smoking, and low physical activity) contributed the most attributable death and DALYs of diabetes. These estimations could be useful in policy-making, priority setting, and resource allocation in diabetes prevention and treatment.

Cellular and Functional Effects of Insulin Based Therapies and Exercise on Endothelium

Endothelial dysfunction is a hallmark of type 2 diabetes that can have severe consequences on vascular function, including hypertension and changes in blood flow, as well as exercise performance. Because endothelium is also the barrier for insulin movement into tissues, it acts as a gatekeeper for transport and glucose uptake. For this reason, endothelial dysfunction is a tempting area for pharmacological and/or exercise intervention with insulin-based therapies. In this review, we describe the current state of drugs that can be used to treat endothelial dysfunction in type 2 diabetes and diabetes-related diseases (e.g., obesity) at the molecular levels, and also discuss their role in exercise.

Protective Effect of Benzoquinone Isolated from the Roots of Averrhoa carambola L. on Streptozotocin-Induced Diabetic Mice by Inhibiting the TLR4/NF-κB Signaling Pathway.

BackgroundStudies have demonstrated that the roots of Averrhoa carambola L. (Oxalidaceae), a traditional Chinese medicine, can be used to treat diabetes and diabetes-related diseases. Nevertheless, the potential beneficial effects and mechanism of benzoquinone isolated from the roots of Averrhoa carambola L. (BACR) on diabetes remain unclear.MethodsDiabetic Kunming mice were injected with STZ (120 mgkg−1) in the tail vein. Fasting blood glucose (FBG) and the change of body weight were measured after oral administration of BACR (120, 60, 30 mg/kg/d) every week. The levels of the total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), glucosylated hemoglobin (GHb), fasting insulin (FINS), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured. The histological examination of pancreatic tissues and the TLR4/NF-κB pathway was analyzed by RT-PCR, immunohistochemistry and Western blot.ResultsThe study found that clearly the BACR obviously reduced the blood glucose, serum lipids, GHb and FINS. In addition, BACR treatment markedly reduced the release of inflammatory factors, including IL-6 and TNF-α, and down-regulated the expression of the TLR4/NF-κB pathway.ConclusionBACR has potential benefits for the treatment of diabetes by ameliorating metabolic functions and attenuating the inflammatory response via inhibition of the activation of theTLR4/NF-κB pathway.

332-OR: Medicare Part B Fee-for-Service Claims for Diabetes-Related Eye Diseases

Background: Diabetic retinopathy is the leading cause of incident blindness among working age U.S. adults. Only slightly more than half of Medicare beneficiaries with diabetes receive an annual eye exam, and this rate is lower among Hispanic and black beneficiaries compared to white beneficiaries. Objective: We examine racial/ethnic differences in diabetes-related eye disease and treatment claims, among Medicare beneficiaries with diabetes. Methods: We analyzed 2017 Medicare claims for 8,341,000 beneficiaries (both ≥65 years and &amp;lt;65 years with disabilities) with diagnosed diabetes who were continuously enrolled during 2017 in Part B fee-for-service (FFS) insurance. Diagnoses for diabetes and diabetes-related eye diseases were defined using ICD-10-CM diagnosis codes and treatments were classified using procedure codes in the claims. We present crude national percentages. Results: In 2017, 28% of FFS beneficiaries had diabetes. Of these, 9.6% had a claim for any diabetes-related eye disease; this annual rate was higher among Hispanic (13.1%), non-Hispanic black (11.2%), and Asian/Pacific Islander (11.4%) beneficiaries than among white beneficiaries (8.7%). Early/mild diabetic retinopathy was the most prevalent form (6.3%) and diabetic macular edema was the least prevalent (0.6%). Of beneficiaries with diabetes-related eye disease, 15.2% had at least one type of treatment; treatment types received were anti-vascular endothelial growth factor injections (11.8%), laser photocoagulation (4.7%), vitrectomy (1.3%), and retinal detachment repair (0.7%). Annual prevalence of any treatment was higher among Hispanic (19.0%) and non-Hispanic black (15.5%) beneficiaries compared to white beneficiaries (14.7%); it was lowest among Asian/Pacific Islander beneficiaries (12.9%). Conclusions: Annually, around one-in-ten Medicare Part B FFS beneficiaries with diabetes has a claim for diabetes-related eye disease, and this rate is higher among Hispanic and black beneficiaries. Disclosure E.A. Lundeen: None. D.B. Rein: None. J. Wittenborn: None. J.B. Saaddine: None.

Proteomic profiling of MIN6 cell-derived exosomes

Exosomes have been widely used in research on the early clinical diagnosis, prognosis and treatment of various cancers due to their features of small size (30–120 nm), non-immunogenicity and ability to cross biological barriers. However, few studies have investigated exosomes involved in metabolic diseases. Early studies have found that adipose tissue can be a source of exosomes regulating metabolism, but the related functions of exosomes secreted by other tissues in the regulation of metabolic diseases have not been determined. In addition, islets were found to be able to secrete miRNA via exosomes, suggesting that islet exosomes may be among the sources of exosomes involved in the regulation of metabolic diseases and that the relevant protein profiles have not been characterized to date. Therefore, identifying the protein contents of pancreatic β cell-derived exosomes would benefit further research investigating the protein functions and mechanisms associated with diabetes-related metabolic diseases. SignificanceExosomes are emerging tools for investigating metabolic diseases in recent years, but little research has been done. In our work, functional identification of MIN6 cell-derived exosomal proteins and comparative analysis of islet β cell exosomal protein data from different cell lines or from different species revealed that exosomes secreted by islet β cells may be involved in the regulation of glucose metabolism. These results may suggest that intercellular communication induced by exosome transfer among tissues may account for the major reason of diabetic metabolic disorder. In addition, these results may provide a theoretical basis for the study of the physiological and pathological functions of islet β cell exosomes for the future studies.

Effect of Aerobic and Resistance Training on Endothelial Progenitor Cells in Mice with Type 2 Diabetes.

Since no study has explored whether exercise could improve impaired proliferation, migration, and angiogenesis of endothelial progenitor cells (EPCs) in animal models or humans with type 2 diabetes, we aimed to explore the effect of different models of exercise on EPC function and expression of caveolin-1, PI3K, and AKT in mice with type 2 diabetes. Male db/db mice (age: 8 weeks) with type 2 diabetes were subjected to aerobic training (AT), resistance training (RT), or combined aerobic and resistance training (AT+RT) 3 or 4 days/week. Mice in the control group remained sedentary with no specific training requirement. Bone marrow-derived EPCs were isolated, and the protein concentrations of caveolin-1, Pi3k, and AKT, and EPC function, were identified in the 1st, 4th, 8th, and 12th weeks of the intervention. Greater increases in proliferation, migration, and angiogenesis were observed in the AT, RT, and AT+RT groups than in the control group. AT+RT was more effective than AT or RT in improving the migratory and angiogenesis function of EPCs in mice with type 2 diabetes and achieved maximum improvement after 8 weeks of intervention. Western blot analysis showed that caveolin-1, p-PI3k, and p-Akt levels were obviously increased in the AT, RT, and AT+RT groups compared with the control group. The expression level of these proteins in the AT+RT group was higher than that in the AT and RT groups. AT+RT may be a helpful reference when choosing exercise methods for the prevention of diabetes-related cardiovascular diseases.

Transient receptor potential vanilloid4 channels as therapeutic targets in diabetes and diabetes-related complications.

With an estimated 425 million diabetes patients worldwide in 2019, type 2 diabetes has reached a pandemic proportion and represents a major unmet medical need. A key determinant of the development and progression of type 2 diabetes is pancreatic ‐cell dysfunction, including the loss of cell mass, the impairment of insulin biosynthesis and inadequate exocytosis. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), a Ca2+‐permeable non‐selective cation channel, is involved in ‐cell replication, insulin production and secretion. TRPV4 agonists have insulinotropic activity in pancreatic ‐cell lines, but the prolonged activation of TRPV4 leads to ‐cell dysfunction and death. In addition, TRPV4 is involved in a wide variety of pathophysiological activities, and has been reported to play an important role in diabetes‐related complications, such as obesity, cardiovascular diseases, diabetic retinopathy, nephropathy and neuropathy. In a rodent type 2 diabetes model, Trpv4 agonists promote vasodilation and improve cardiovascular function, whereas Trpv4 antagonists reduce high‐fat diet‐induced obesity, insulin resistance, diabetic nephropathy, retinopathy and neuropathy. These findings raise interest in using TRPV4 as a therapeutic target for type 2 diabetes. In this review, we intend to summarize the latest findings regarding the role of TRPV4 in diabetes as well as diabetes‐related conditions, and to evaluate its potential as a therapeutic target for diabetes and diabetes‐related diseases.

Mitochondrial ion channels in pancreatic β-cells: Novel pharmacological targets for the treatment of Type 2 diabetes.

Pancreatic beta‐cells are central regulators of glucose homeostasis. By tightly coupling nutrient sensing and granule exocytosis, beta‐cells adjust the secretion of insulin to the circulating blood glucose levels. Failure of beta‐cells to augment insulin secretion in insulin‐resistant individuals leads progressively to impaired glucose tolerance, Type 2 diabetes, and diabetes‐related diseases. Mitochondria play a crucial role in β‐cells during nutrient stimulation, linking the metabolism of glucose and other secretagogues to the generation of signals that promote insulin secretion. Mitochondria are double‐membrane organelles containing numerous channels allowing the transport of ions across both membranes. These channels regulate mitochondrial energy production, signalling, and cell death. The mitochondria of β‐cells express ion channels whose physio/pathological role is underappreciated. Here, we describe the mitochondrial ion channels identified in pancreatic β‐cells, we further discuss the possibility of targeting specific β‐cell mitochondrial channels for the treatment of Type 2 diabetes, and we finally highlight the evidence from clinical studies.LINKED ARTICLESThis article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc