Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target.

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota-host cross-talk. We developed an enzyme activity-screening platform to investigate how gut microbiota-derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.

Associations between myeloperoxidase and paraoxonase-1 and type 2 diabetes in patients with ischemic heart disease.

BACKGROUND: The phrase "dysfunctional high-density lipoprotein" has been developed in the literature to describe the particle which loses its basic role- anti-oxidative and anti-inflammatory activity. In this porcess, the significance of enzymes- pro-oxidant myeloperoxidase (MPO) and antioxidant paraoxonase-1 (PON-1) from the perspective of HDL-C function has been noted. AIMS: The objective of this study was to analyze the associations between two enzymes -MPO and PON-1 and type 2 diabetes (T2DM) in patients with ischemic heart disease (IHD). METHODS: An observational cross-sectional study including 70 patients with IHD of whom 35 had also T2DM, and 35 had no T2DM. Laboratory tests (MPO, PON-1, fasting glucose, glycated hemoglobin, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and high-sensitivity C-reactive protein) were performed. RESULTS: The study revealed a significant difference in the serum concentration of the enzymes between patients with IHD with and without T2DM. Our results showed increased MPO concentration levels in diabetic patients. The analysis also revealed that T2DM is independently associated with an increase in MPO levels. Simultaneously, a decrease in PON-1 levels was observed in patients with T2DM. The study also revealed that T2DM is independently associated with a decrease in PON-1 levels. CONCLUSIONS: In patients with type 2 diabetes the profile of enzymes involved in high-density lipoprotein metabolism in patients with IHD is worse than in patients without T2DM. The increase in the levels of MPO, an enzyme with oxidative and atherogenic properties and on a decrease in PON-1 levels, an enzyme with antioxidant and atheroprotective properties is observed.

DPP4 inhibitors as a potential therapeutic option for sarcopenia: A 6-month follow-up study in diabetic older patients.

OBJECTIVES: Sarcopenia is associated with increased morbidity and mortality in older adults with type 2 diabetes mellitus (T2DM). This study investigates the effects of dipeptidyl peptidase-4 inhibitors (DPP4i) as an add-on therapy for sarcopenia in older adults with T2DM over a six-month follow-up period. METHODS: This is a retrospective and six-month follow-up study. The study was performed on 90 participants who are followed in a geriatric clinic hospital. Sarcopenia was diagnosed as per the EGWSOP-2 criteria. The patients were divided into two groups regarding DPP4i use. Each patient was evaluated for sarcopenia and sarcopenia-related parameters at baseline and at the end of 6 months. RESULTS: The mean age of the patients was 72.57 ± 7.089, and 60% of them were female. DPP4i users had worse glycemic control and decreased rate of low muscle strength at the end of 6 months (39.6% vs. 25.0%, P = .039). Forty-two patients without DPP4i therapy had reduced muscle strength (22.71 ± 6.95 kg vs. 20.88 ± 6.32 kg, P = .046) and stable Hba1c levels (6.45 ± 0.56% vs. 6.40 ± 0.52, P = .380) at their six-month follow-up control. CONCLUSIONS: Adding DPP4i to treatment for T2DM yields a positive effect on muscle strength and glycemic control. These agents may offer higher prospects in managing T2DM while counteracting sarcopenia. BRIEF SUMMARY: T2DM and Sarcopenia are common in older adults. Considering the increased prevalence of T2DM and the risk of coexistent sarcopenia in older adults, the additional positive effects of DPP4i may be crucial in the choice of treatment for these patients.

Time series RNA-seq analysis identifies MAPK10 as a critical gene in diabetes mellitus-induced atrial fibrillation in mice.

Atrial fibrillation (AF) is a major complication of type 2 diabetes mellitus (T2DM) and plays critical roles in the pathogenesis of atrial remodeling. However, the differentially expressed genes in atria during the development of AF induced by hyperglycemia have rarely been reported. Here, we showed time-dependent increased AF incidence and duration, atrial enlargement, inflammation, fibrosis, conduction time and action potential duration in db/db mice, a model of T2DM. RNA sequencing analysis showed that 2256 genes were differentially expressed in the atria at 12, 14 and 16 weeks. Gene Ontology analysis showed that these genes participate primarily in cell adhesion, cellular response to interferon-beta, immune system process, positive regulation of cell migration, ion transport and cellular response to interferon-gamma. Analysis of significant pathways revealed the IL-17 signaling pathway, TNF signaling pathway, MAPK signaling pathway, chemokine signaling pathway, and cAMP receptor signaling. Additionally, these differentially expressed genes were classified into 50 profiles by hierarchical clustering analysis. Twelve of these profiles were significant and comprised 1115 genes. Gene coexpression network analysis identified that mitogen-activated protein kinase 10 (MAPK10) was localized in the core of the gene network and was the most highly expressed gene at different time points. Knockdown of MAPK10 markedly attenuated DM-induced AF incidence, atrial inflammation, fibrosis, electrical disorder and apoptosis in db/db mice. In summary, the present findings revealed that many genes are involved in DM-induced AF and that MAPK10 plays a central role in this disease, indicating that strategies targeting MAPK10 may represent a potential therapeutic approach to treat DM-induced AF.

Angiotensin-(1-7) improves diabetes mellitus-induced erectile dysfunction in rats by regulating nitric oxide synthase levels.

This study explores the role of inducible nitric oxide synthase (iNOS) in the pathogenesis of diabetes mellitus-induced erectile dysfunction (DMED) and the effect of angiotensin 1-7 (Ang- [1-7]) on NOS levels. A type 2 diabetes mellitus (DM) rat model was established. Erectile function was assessed by measuring intracavernous pressure and mean arterial pressure after electrical stimulation. The expression of iNOS, endothelial NOS (eNOS), eNOS phosphorylated at Ser 1177 (p-eNOS [Ser 1177]), and AKT/p-AKT in corpus cavernosum smooth muscle cells (CCSMCs) was measured by Western blotting and immunofluorescence. The plasma levels of NO, SOD, malondialdehyde, and peroxynitrite were calculated. Intracellular calcium content was determined by flow cytometry. DMED rats exhibited decreased erectile function and severe oxidative stress. Ang-(1-7) treatment improved erectile response and suppressed oxidative stress by upregulating p-eNOS/eNOS and downregulating iNOS levels. Silencing iNOS in CCSMCs decreased oxidative stress and intracellular calcium levels induced by high glucose. In turn, iNOS overexpression increased oxidative stress and intracellular calcium level. Treatment with the MAS receptor antagonist A779 and the Akt antagonist LY294002 reversed the effects of Ang-(1-7) on iNOS. Ang-(1-7) improved DMED through the MAS/AKT signaling pathway.

Machine Learning and In Vitro Chemical Screening of Potential α-Amylase and α-Glucosidase Inhibitors from Thai Indigenous Plants.

Diabetes mellitus is a major predisposing factor for cardiovascular disease and mortality. α-Amylase and α-glucosidase enzymes are the rate-limiting steps for carbohydrate digestion. The inhibition of these two enzymes is clinically used for the treatment of diabetes mellitus. Here, in vitro study and machine learning models were employed for the chemical screening of inhibiting the activity of 31 plant samples on α-amylase and α-glucosidase enzymes. The results showed that the ethanolic twig extract of Pinus kesiya had the highest inhibitory activity against the α-amylase enzyme. The respective ethanolic extract of Croton oblongifolius stem, Parinari anamense twig, and Polyalthia evecta leaf showed high inhibitory activity against the α-glucosidase enzyme. The classification analysis revealed that the α-glucosidase inhibitory activity of Thai indigenous plants was more predictive based on phytochemical constituents, compared with the α-amylase inhibitory activity (1.00 versus 0.97 accuracy score). The correlation loading plot revealed that flavonoids and alkaloids contributed to the α-amylase inhibitory activity, while flavonoids, tannins, and reducing sugars contributed to the α-glucosidase inhibitory activity. In conclusion, the ethanolic extracts of P. kesiya, C. oblongifolius, P. anamense, and P. evecta have the potential for further chemical characterization and the development of anti-diabetic recipes.

An In Silico and an In Vitro Inhibition Analysis of Glycogen Phosphorylase by Flavonoids, Styrylchromones, and Pyrazoles.

Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway. GP inhibitors are currently under investigation as a new liver-targeted approach to managing type 2 diabetes mellitus (DM). The aim of the present study was to evaluate the inhibitory activity of a panel of 52 structurally related chromone derivatives; namely, flavonoids, 2-styrylchromones, 2-styrylchromone-related derivatives [2-(4-arylbuta-1,3-dien-1-yl)chromones], and 4- and 5-styrylpyrazoles against GP, using in silico and in vitro microanalysis screening systems. Several of the tested compounds showed a potent inhibitory effect. The structure-activity relationship study indicated that for 2-styrylchromones and 2-styrylchromone-related derivatives, the hydroxylations at the A and B rings, and in the flavonoid family, as well as the hydroxylation of the A ring, were determinants for the inhibitory activity. To support the in vitro experimental findings, molecular docking studies were performed, revealing clear hydrogen bonding patterns that favored the inhibitory effects of flavonoids, 2-styrylchromones, and 2-styrylchromone-related derivatives. Interestingly, the potency of the most active compounds increased almost four-fold when the concentration of glucose increased, presenting an IC50 < 10 µM. This effect may reduce the risk of hypoglycemia, a commonly reported side effect of antidiabetic agents. This work contributes with important considerations and provides a better understanding of potential scaffolds for the study of novel GP inhibitors.

Trimethylguanosine synthase 1 is a novel regulator of pancreatic beta-cell mass and function.

Type 2 diabetes is a metabolic disorder associated with abnormal glucose homeostasis and is characterized by intrinsic defects in ß-cell function and mass. Trimethylguanosine synthase 1 (TGS1) is an evolutionarily conserved enzyme that methylates small nuclear and nucleolar RNAs and that is involved in pre-mRNA splicing, transcription, and ribosome production. However, the role of TGS1 in ß-cells and glucose homeostasis had not been explored. Here, we show that TGS1 is upregulated by insulin and upregulated in islets of Langerhans from mice exposed to a high-fat diet and in human ß-cells from type 2 diabetes donors. Using mice with conditional (ßTGS1KO) and inducible (MIP-CreERT-TGS1KO) TGS1 deletion, we determined that TGS1 regulates ß-cell mass and function. Using unbiased approaches, we identified a link between TGS1 and endoplasmic reticulum stress and cell cycle arrest, as well as and how TGS1 regulates ß-cell apoptosis. We also found that deletion of TGS1 results in an increase in the unfolded protein response by increasing XBP-1, ATF-4, and the phosphorylation of eIF2α, in addition to promoting several changes in cell cycle inhibitors and activators such as p27 and Cyclin D2. This study establishes TGS1 as a key player regulating ß-cell mass and function. We propose that these observations can be used as a stepping-stone for the design of novel strategies focused on TGS1 as a therapeutic target for the treatment of diabetes.

Hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea and Chlorella sorokiniana possess synergistic hypoglycemic activity through inhibiting α-glucosidase and dipeptidyl peptidase-4 activity.

BACKGROUND: The prevalence of diabetes mellitus worldwide has increased in recent decades. Maintaining the level of blood glucose is the most basic and important issue for diabetics. This study aimed to investigate the hypoglycemic activity of a combination of hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea (ACH) and Chlorella sorokiniana (PCH). RESULTS: Combined supplementation of ACH and PCH synergistically inhibited α-glucosidase and DPP4 activities in vitro. After 4 weeks of treatment with ACH and/or PCH, the plasma glucose concentration and insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), total cholesterol (TC) and triglyceride (TG) levels significantly decreased. The hypoglycemic peptides in ACH and PCH were purified and assayed for α-glucosidase and DPP4 activity. The hypoglycemic peptides in ACH and PCH effectively decreased α-glucosidase and DPP4 activities. In silico assays showed that these two peptide types have different docking poses, which determined their inhibitory effect against α-glucosidase and DPP4 activity. CONCLUSION: Combined treatment with hypoglycemic peptide-enriched ACH and PCH could modulate blood glucose by synergistically inhibiting α-glucosidase and DPP4 activities. © 2021 Society of Chemical Industry.

Comparison of amylase and lipase levels of patients with Type 2 diabetes under different treatment modalities.

Aim: Study aims to assess amylase, lipase of patients with Type 2 diabetes under different types of treatments. Materials & methods: Patients' treatment modalities including insulin, metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors, insulin secretagogues, dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists were compared. Results: There was no difference in amylase and lipase levels between dipeptidyl peptidase-4 inhibitor users and non-users (p = 0.2, p = 0.3, respectively) and glucagon like peptide-1 analog users and non-users (p = 0.1, p = 0.7, respectively). Patients who use insulin secretagogues had significantly higher amylase, lipase (77.2 ± 39.8 vs 69.5 ± 33.0, p = 0.038 and 47.2 ± 33.2 vs 39.6 ± 26.8, p = 0.01, respectively) and patients on basal insulin had lower amylase levels (69.9 ± 37.7 vs 77.2 ± 33.7, p = 0.014). Conclusion: Incretin-based therapies showed no difference in amylase and lipase levels whereas there was increase with secretagogues and decrease with basal insulin.

In Silico Approaches to Identify Polyphenol Compounds as α-Glucosidase and α-Amylase Inhibitors against Type-II Diabetes.

Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., Bignoniaceae, Ericaceae, Dryopteridaceae, Campanulaceae, Geraniaceae, Euphorbiaceae, Rubiaceae, Acanthaceae, Rutaceae, and Moraceae as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through Monte Carto molecular modeling. Autodock, MOE-Dock, Biovia Discovery Studio, PyMOL, and Accelrys have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.

Functional Characterization of a Novel Heterozygous Mutation in the Glucokinase Gene That Causes MODY2 in Chinese Pedigrees.

Background: Glucokinase (GCK) plays a central role in glucose regulation. The heterozygous mutations of GCK can cause a monogenic form of diabetes, maturity-onset diabetes of the young (MODY) directly. In our study, we aimed to explore the mechanism of the novel mutation GCK p.Ala259Thr leading to glucokinase deficiency and hyperglycemia. Methods: Thirty early-onset diabetes pedigrees were referred to whole exome sequencing for novel mutations identification. Purified wild-type and mutant GCK proteins were obtained from E.coli systems and then subjected to the kinetic and thermal stability analysis to test the effects on GCK activity. Results: One novel missense mutation GCK p.Ala259Thr was identified and co-segregated with diabetes in a Chinese MODY2 pedigree. The kinetic analysis showed that this mutation result in a decreased affinity and catalytic capability for glucose. The thermal stability analysis also indicated that the mutant protein presented dramatically decreased activity at the same temperature. Conclusion: Our study firstly identified a novel MODY2 mutation p.Ala259Thr in Chinese diabetes pedigrees. The kinetic and thermal stability analysis confirmed that this mutation caused hyperglycemia through severely damaging the enzyme activities and protein stability.

ALDH2/SIRT1 Contributes to Type 1 and Type 2 Diabetes-Induced Retinopathy through Depressing Oxidative Stress.

Clinical observations found vision-threatening diabetic retinopathy (DR) occurs in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients, but T1DM may perform more progressive retinal abnormalities at the same diabetic duration with or without clinical retinopathy. In the present study, T1DM and T2DM patients without manifestations of DR were included in our preliminary clinical retrospective observation study to investigate the differentiated retinal function at the preclinical stage. Then, T1DM and T2DM rat models with 12-week diabetic duration were constructed to explore the potential mechanism of the discrepancy in retinal disorders. Our data demonstrated T1DM patients presented a poor retinal function, a higher allele frequency for ALDH2GA/AA, and a depressed aldehyde dehydrogenase 2 (ALDH2) activity and silent information regulator 1 (SIRT1) level, compared to T2DM individuals. In line with this, higher amplitudes of neurovascular function-related waves of electroretinograms were found in T2DM rats. Furthermore, the retinal outer nuclear layers were reduced in T1DM rats. The levels of retinal oxidative stress biomarkers including total reactive oxygen species, NADPH oxidase 4 and mitochondrial DNA damage, and inflammatory indicators covering inducible/endothelial nitric acid synthase ratio, interleukin-1, and interleukin-6 were obviously elevated. Notably, the level of retinal ALDH2 and SIRT1 in T1DM rats was significantly diminished, while the expression of neovascularization factors was dramatically enhanced compared to T2DM. Together, our data indicated that the ALDH2/SIRT1 deficiency resulted in prominent oxidative stress and was in association with DR progression. Moreover, a differentiating ALDH2/SIRT1 expression may be responsible for the dissimilar severity of DR pathological processes in chronic inflammatory-related T1DM and T2DM.

Adiponectin ameliorates lung ischemia-reperfusion injury through SIRT1-PINK1 signaling-mediated mitophagy in type 2 diabetic rats.

BACKGROUND: Diabetes mellitus (DM) is a key contributing factor to poor survival in lung transplantation recipients. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of diabetic lung ischemia-reperfusion (IR) injury. The protective effects of adiponectin have been demonstrated in our previous study, but the underlying mechanism remains unclear. Here we demonstrated an important role of mitophagy in the protective effect of adiponectin during diabetic lung IR injury. METHODS: High-fat diet-fed streptozotocin-induced type 2 diabetic rats were exposed to adiponectin with or without administration of the SIRT1 inhibitor EX527 following lung transplantation. To determine the mechanisms underlying the action of adiponectin, rat pulmonary microvascular endothelial cells were transfected with SIRT1 small-interfering RNA or PINK1 small-interfering RNA and then subjected to in vitro diabetic lung IR injury. RESULTS: Mitophagy was impaired in diabetic lungs subjected to IR injury, which was accompanied by increased oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Adiponectin induced mitophagy and attenuated subsequent diabetic lung IR injury by improving lung functional recovery, suppressing oxidative damage, diminishing inflammation, decreasing cell apoptosis, and preserving mitochondrial function. However, either administration of 3-methyladenine (3-MA), an autophagy antagonist or knockdown of PINK1 reduced the protective action of adiponectin. Furthermore, we demonstrated that APN affected PINK1 stabilization via the SIRT1 signaling pathway, and knockdown of SIRT1 suppressed PINK1 expression and compromised the protective effect of adiponectin. CONCLUSION: These data demonstrated that adiponectin attenuated reperfusion-induced oxidative stress, inflammation, apoptosis and mitochondrial dysfunction via activation of SIRT1- PINK1 signaling-mediated mitophagy in diabetic lung IR injury.

Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Glucose Homeostasis and Diabetes-Related Endothelial Cell Dysfunction.

Oxidative stress within the vascular endothelium, due to excess generation of reactive oxygen species (ROS), is thought to be fundamental to the initiation and progression of the cardiovascular complications of type 2 diabetes mellitus. The term ROS encompasses a variety of chemical species including superoxide anion (O2•-), hydroxyl radical (OH-) and hydrogen peroxide (H2O2). While constitutive generation of low concentrations of ROS are indispensable for normal cellular function, excess O2•- can result in irreversible tissue damage. Excess ROS generation is catalysed by xanthine oxidase, uncoupled nitric oxide synthases, the mitochondrial electron transport chain and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Amongst enzymatic sources of O2•- the Nox2 isoform of NADPH oxidase is thought to be critical to the oxidative stress found in type 2 diabetes mellitus. In contrast, the transcriptionally regulated Nox4 isoform, which generates H2O2, may fulfil a protective role and contribute to normal glucose homeostasis. This review describes the key roles of Nox2 and Nox4, as well as Nox1 and Nox5, in glucose homeostasis, endothelial function and oxidative stress, with a key focus on how they are regulated in health, and dysregulated in type 2 diabetes mellitus.

Characteristics of Food Protein-Derived Antidiabetic Bioactive Peptides: A Literature Update.

Diabetes, a glucose metabolic disorder, is considered one of the biggest challenges associated with a complex complication of health crises in the modern lifestyle. Inhibition or reduction of the dipeptidyl peptidase IV (DPP-IV), alpha-glucosidase, and protein-tyrosine phosphatase 1B (PTP-1B) enzyme activities or expressions are notably considered as the promising therapeutic strategies for the management of type 2 diabetes (T2D). Various food protein-derived antidiabetic bioactive peptides have been isolated and verified. This review provides an overview of the DPP-IV, PTP-1B, and α-glucosidase inhibitors, and updates on the methods for the discovery of DPP-IV inhibitory peptides released from food-protein hydrolysate. The finding of novel bioactive peptides involves studies about the strategy of separation fractionation, the identification of peptide sequences, and the evaluation of peptide characteristics in vitro, in silico, in situ, and in vivo. The potential of bioactive peptides suggests useful applications in the prevention and management of diabetes. Furthermore, evidence of clinical studies is necessary for the validation of these peptides' efficiencies before commercial applications.

Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.

Mof acetyltransferase inhibition ameliorates glucose intolerance and islet dysfunction of type 2 diabetes via targeting pancreatic α-cells.

BACKGROUND: Previously, we reported that Mof was highly expressed in α-cells, and its knockdown led to ameliorated fasting blood glucose (FBG) and glucose tolerance in non-diabetic mice, attributed by reduced total α-cell but enhanced prohormone convertase (PC)1/3-positive α-cell mass. However, how Mof and histone 4 lysine 16 acetylation (H4K16ac) control α-cell and whether Mof inhibition improves glucose handling in type 2 diabetes (T2DM) mice remain unknown. METHODS: Mof overexpression and chromatin immunoprecipitation sequence (ChIP-seq) based on H4K16ac were applied to determine the effect of Mof on α-cell transcriptional factors and underlying mechanism. Then we administrated mg149 to α-TC1-6 cell line, wild type, db/db and diet-induced obesity (DIO) mice to observe the impact of Mof inhibition in vitro and in vivo. In vitro, western blotting and TUNEL staining were used to examine α-cell apoptosis and function. In vivo, glucose tolerance, hormone levels, islet population, α-cell ratio and the co-staining of glucagon and PC1/3 or PC2 were examined. RESULTS: Mof activated α-cell-specific transcriptional network. ChIP-seq results indicated that H4K16ac targeted essential genes regulating α-cell differentiation and function. Mof activity inhibition in vitro caused impaired α-cell function and enhanced apoptosis. In vivo, it contributed to ameliorated glucose intolerance and islet dysfunction, characterized by decreased fasting glucagon and elevated post-challenge insulin levels in T2DM mice. CONCLUSION: Mof regulates α-cell differentiation and function via acetylating H4K16ac and H4K16ac binding to Pax6 and Foxa2 promoters. Mof inhibition may be a potential interventional target for T2DM, which led to decreased α-cell ratio but increased PC1/3-positive α-cells.

Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes.

Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.

Biliverdin reductase-A protein levels are reduced in type 2 diabetes and are associated with poor glycometabolic control.

AIM: Biliverdin reductase-A (BVR-A) other than its canonical role in the degradation pathway of heme as partner of heme oxygenase-1 (HO1), has recently drawn attention as a protein with pleiotropic functions involved in insulin-glucose homeostasis. However, whether BVR-A expression is altered in type 2 diabetes (T2D) has never been evaluated. MAIN METHODS: BVR-A protein levels were evaluated in T2D (n = 44) and non-T2D (n = 29) subjects, who underwent complete clinical workup and routine biochemistry. In parallel, levels HO1, whose expression is regulated by BVR-A as well as levels of tumor necrosis factor α (TNFα), which is a known repressor for BVR-A with pro-inflammatory properties, were also assessed. KEY FINDINGS: BVR-A levels were significantly lower in T2D subjects than in non-T2D subjects. Reduced BVR-A levels were associated with greater body mass, systolic blood pressure, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), triglycerides, transaminases and TNFα, and with lower high-density lipoprotein (HDL) levels. Lower BVR-A levels are associated with reduced HO1 protein levels and the multivariate analysis showed that BVR-A represented the main determinant of HO1 levels in T2D after adjustment. In addition, reduced BVR-A levels were able to predict the presence of T2D with AUROC = 0.69. for potential confounders. SIGNIFICANCE: Our results demonstrate for the first time that BVR-A protein levels are reduced in T2D individuals, and that this alteration strictly correlates with poor glycometabolic control and a pro-inflammatory state. Hence, these observations reinforce the hypothesis that reduced BVR-A protein levels may represent a key event in the dysregulation of intracellular pathways finally leading to metabolic disorders.