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Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

Aims/Introduction The aim of this study was to elucidate whether sodium–glucose cotransporter 2 inhibitors (SGLT2is) treatment has any renoprotective effect for type 2 diabetes mellitus patients with an estimated glomerular filtration rate (eGFR) of, Administration of sodium–glucose cotransporter 2 inhibitors slowed the annual estimated glomerular filtration rate decline in type 2 diabetes patients with an estimated glomerular filtration rate of

Although Rathke's cleft cysts (RCCs) are common sellar/parasellar lesions, studies examining pituitary function in patients with nonsurgical RCC are limited. This study aimed to clarify the importance of RCCs, including small nonsurgical ones, as a cause of hypopituitarism by determining the prevalence of pituitary hormone secretion impairment and its relationship to cyst/tumor size in patients with RCC and in those with nonfunctioning pituitary adenoma (NFA). We retrospectively investigated the basal levels of each anterior pituitary hormone, its responses in the stimulation test(s), and cyst/tumor size in patients with RCC (n = 67) and NFA (n = 111) who were consecutively admitted to our hospital for endocrinological evaluation. RCCs were much smaller than NFAs (median height, 12 vs. 26 mm). The prevalence of gonadotropin, PRL, and GH secretion impairment in RCC was lower in comparison to NFA (19% vs. 44%, 34% vs. 61%, and 24% vs. 46%, respectively), whereas the prevalence of TSH and ACTH secretion impairment was comparable (21-27% and 17-24%, respectively). A significant positive relationship between cyst/tumor size and number of impaired hormones was observed in both groups, but smaller cysts could cause hormone secretion impairment in RCC. Stimulation tests suggested that most hormone secretion impairment was attributable to the interrupted hypothalamic-pituitary axis in both groups. Therefore, RCC, even small ones, can cause pituitary dysfunction. Different mechanisms may underlie hypothalamic-pituitary interruption in RCC and NFA.

Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis. We have reported that N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP) restored levels of diabetes mellitus-suppressed FGFR1 (fibroblast growth factor receptor 1), the endothelial receptor essential for combating EndMT. However, the molecular regulation and biological/pathological significance of the AcSDKP-FGFR1 relationship has not been elucidated yet. Here, we demonstrated that endothelial FGFR1 deficiency led to AcSDKP-resistant EndMT and severe fibrosis associated with EndMT-stimulated fibrogenic programming in neighboring cells. Diabetes mellitus induced severe kidney fibrosis in endothelial FGFR1-deficient mice ( FGFR1 fl/fl ; VE-cadherin-Cre: FGFR1 EKO ) but not in control mice (FGFR1 fl/fl ); AcSDKP completely or partially suppressed kidney fibrosis in control or FGFR1 EKO mice. Severe fibrosis was also induced in hearts of diabetic FGFR1 EKO mice; however, AcSDKP had no effect on heart fibrosis in FGFR1 EKO mice. AcSDKP also had no effect on EndMT in either kidney or heart but partially suppressed epithelial-to-mesenchymal transition in kidneys of diabetic FGFR1 EKO mice. The medium from FGFR1-deficient endothelial cells stimulated TGFβ (transforming growth factor β)/Smad-dependent epithelial-to-mesenchymal transition in cultured human proximal tubule epithelial cell line, AcSDKP inhibited such epithelial-to-mesenchymal transition. These data demonstrated that endothelial FGFR1 is essential as an antifibrotic core molecule as the target of AcSDKP.

Aims/introduction To establish novel therapies to combat diabetic kidney disease, a human disease-relevant animal model is essential. However, a type 2 diabetic mouse model presenting progressive kidney fibrosis has not yet been established. Kidneys of streptozotocin-induced diabetic CD-1 mice showed severe fibrosis compared with other backgrounds of mice associated with the suppression of antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline. The BKS background (BKSdb / db ) is often utilized for diabetic kidney disease research; the kidney fibrosis in the BKSdb / db phenotype is minimal. Materials and methods We generated CD-1db / db mice by backcrossing the db gene into the CD-1 background, and analyzed phenotypic differences compared with BKSdb / db and CD-1db / m mice. Results Male CD-1db / db mice appeared to have elevated blood glucose levels compared with those of BKSdb / db mice. Fasting insulin levels declined in CD-1db / db mice. Plasma cystatin C levels tended to be elevated in CD-1db / db mice from 16 to 24 weeks-of-age. Male CD-1db / db mice showed significantly progressive kidney and heart fibrosis from 16 to 24 weeks-of-age when compared with that of age-matched BKSdb / db mice. The gene expression profile showed fibrogenic program-associated genes in male CD-1db / db mice. Male CD-1db / db mice displayed significantly lower urine antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline when compared to that of BKSdb / db at 24 weeks-of-age. The gene expression of prolyl oligopeptidase, the enzyme essential for antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline production from thymosin β4, was significantly lower in the CD-1 mice. Thymosin β4 levels were also lower in CD-1 mice. Conclusions These results suggest that CD-1db / db mice are a novel type 2 diabetic mouse model with progressive kidney and heart fibrosis.

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P, The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.

Diabetic kidney disease (DKD), a microvascular complication of diabetes, has been the leading cause of end-stage kidney disease (ESKD). Accordingly, patients with type 2 diabetes mellitus (T2DM) develop renal damage due to multiple metabolic and cardiorenal disease-related risk factors, including hyperglycemia, hypertension, dyslipidemia, hyperuricemia, and overnutrition/obesity. Despite multifactorial management including the administration of renin–angiotensin system inhibitors, patients often do not experience sufficient suppression of DKD progression and, thus, remain at risk for ESKD. Recent studies on cardiovascular outcomes among patients with T2DM have clearly shown that sodium–glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin, canagliflozin, and dapagliflozin, have cardiorenal protective effects apart from their glucose-lowering effects. In particular, SGLT2 inhibitors have been found to improve renal outcomes, including ESKD, by slowing renal function decline and reducing urinary albumin excretion through their class effect. The proposed mechanisms for the renoprotective effects of SGLT2 inhibitors include the action of tubulo-glomerular feedback system and attenuation of hypoxia and metabolic stress in proximal tubular cells mediated through the inhibition of excessive glucose and sodium reabsorption, increased erythropoiesis, or increased ketone body production.

Mitochondrial oxidative stress is a significant contributor to the pathogenesis of diabetic kidney disease (DKD). We previously showed that mitochondrial oxidative stress in the kidneys of Zucker diabetic fatty rats is associated with a decreased intracellular NAD+/NADH ratio and NAD+-dependent deacetylase Sirt3 activity, and increased expression of the NAD+-degrading enzyme CD38. In this study, we used a CD38 inhibitor, apigenin, to investigate the role of CD38 in DKD. Apigenin significantly reduced renal injuries, including tubulointerstitial fibrosis, tubular cell damage, and pro-inflammatory gene expression in diabetic rats. In addition, apigenin down-regulated CD38 expression, and increased the intracellular NAD+/NADH ratio and Sirt3-mediated mitochondrial antioxidative enzyme activity in the kidneys of diabetic rats. In vitro, inhibition of CD38 activity by apigenin or CD38 knockdown increased the NAD+/NADH ratio and Sirt3 activity in renal proximal tubular HK-2 cells cultured under high-glucose conditions. Together, these results demonstrate that by inhibiting the Sirt3 activity and increasing mitochondrial oxidative stress in renal tubular cells, CD38 plays a crucial role in the pathogenesis of DKD.

Macroautophagy/autophagy plays a vital role in the homeostasis of diverse cell types. Vascular endothelial cells contribute to vascular health and play a unique role in vascular biology. Here, we demonstrated that autophagy defects in endothelial cells induced IL6 (interleukin 6)-dependent endothelial-to-mesenchymal transition (EndMT) and organ fibrosis with metabolic defects in mice. Inhibition of autophagy, either by a specific inhibitor or small interfering RNA (siRNA) for ATG5 (autophagy related 5), in human microvascular endothelial cells (HMVECs) induced EndMT. The IL6 level was significantly higher in ATG5 siRNA-transfected HMVECs culture medium compared with the control HMVECs culture medium, and neutralization of IL6 by a specific antibody completely inhibited EndMT in ATG5 siRNA-transfected HMVECs. Similar to the in vitro data, endothelial-specific atg5 knockout mice (Atg5 Endo; Cdh5-Cre Atg5 flox/flox mice) displayed both EndMT-associated kidney and heart fibrosis when compared to littermate controls. The plasma level of IL6 was higher in Atg5 Endo compared to that of control mice, and fibrosis was accelerated in Atg5 Endo treated with a HFD; neutralization of IL6 by a specific antibody inhibited EndMT and fibrosis in HFD-fed Atg5 Endo associated with the amelioration of metabolic defects. These results revealed the essential role of autophagy in endothelial cell integrity and revealed that the disruption of endothelial autophagy could lead to significant pathological IL6-dependent EndMT and organ fibrosis. Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; EndMT: endothelial-to-mesenchymal transition; HES: hematoxylin and eosin stain; HFD: high-fat diet; HMVECs: human microvascular endothelial cells; IFNG: interferon gamma; IL6: interleukin 6; MTS: Masson’s trichrome staining; NFD: normal-fat diet; siRNA: small interfering RNA; SMAD3: SMAD family member 3; TGFB: transforming growth factor β; TNF: tumor necrosis factor; VEGFA: vascular endothelial growth factor A

Lifestyle improvement, including through exercise, has been recognized as an important mode of therapy for the suppression of diabetic kidney disease (DKD). However, the detailed molecular mechanisms by which exercise exerts beneficial effects in the suppression of DKD have not yet been fully elucidated. In this study, we investigate the effects of treadmill exercise training (TET) for 8 weeks (13 m/min, 30 min/day, 5 days/week) on kidney injuries of type 2 diabetic male rats with obesity (Wistar fatty (fa/fa) rats: WFRs) at 36 weeks of age. TET significantly suppressed the levels of albuminuria and urinary liver-type fatty-acid-binding protein (L-FABP), tubulointerstitial fibrosis, inflammation, and oxidative stress in the kidneys of WFRs. In addition, TET mitigated excessive apoptosis and restored autophagy in the renal cortex, as well as suppressed the development of morphological abnormalities in the mitochondria of proximal tubular cells, which were also accompanied by the restoration of AMP-activated kinase (AMPK) activity and suppression of the mechanistic target of rapamycin complex 1 (mTORC1). In conclusion, TET ameliorates diabetes-induced kidney injury in type 2 diabetic fatty rats.

Autophagy is an evolutionarily conserved, lysosome-dependent catabolic process whereby cytoplasmic components, including damaged organelles, protein aggregates and lipid droplets, are degraded and their components recycled. Autophagy has an essential role in maintaining cellular homeostasis in response to intracellular stress; however, the efficiency of autophagy declines with age and overnutrition can interfere with the autophagic process. Therefore, conditions such as sarcopenic obesity, insulin resistance and type 2 diabetes mellitus (T2DM) that are characterized by metabolic derangement and intracellular stresses (including oxidative stress, inflammation and endoplasmic reticulum stress) also involve the accumulation of damaged cellular components. These conditions are prevalent in ageing populations. For example, sarcopenia is an age-related loss of skeletal muscle mass and strength that is involved in the pathogenesis of both insulin resistance and T2DM, particularly in elderly people. Impairment of autophagy results in further aggravation of diabetes-related metabolic derangements in insulin target tissues, including the liver, skeletal muscle and adipose tissue, as well as in pancreatic β-cells. This Review summarizes the role of autophagy in the pathogenesis of metabolic diseases associated with or occurring in the context of ageing, including insulin resistance, T2DM and sarcopenic obesity, and describes its potential as a therapeutic target. The cellular consequences of dysfunctional autophagy contribute to numerous diseases. In this Review, Kitada and Koya consider the relationship between impaired autophagy and age-related metabolic derangements, including insulin resistance, type 2 diabetes mellitus and sarcopenic obesity, and discuss candidate autophagy-based therapies.

The redox reaction and energy metabolism status in mitochondria is involved in the pathogenesis of metabolic related disorder in kidney including diabetic kidney disease (DKD). Nicotinamide adenine dinucleotide (NAD+) is a cofactor for redox reactions and energy metabolism in mitochondria. NAD+ can be synthesized from four precursors through three pathways. The accumulation of NAD+ may ameliorate oxidative stress, inflammation and improve mitochondrial biosynthesis via supplementation of precursors and intermediates of NAD+ and activation of sirtuins activity. Conversely, the depletion of NAD+ via NAD+ consuming enzymes including Poly (ADP-ribose) polymerases (PARPs), cADPR synthases may contribute to oxidative stress, inflammation, impaired mitochondrial biosynthesis, which leads to the pathogenesis of DKD. Therefore, homeostasis of NAD+ may be a potential target for the prevention and treatment of kidney diseases including DKD. In this review, we focus on the regulation of the metabolic balance of NAD+ on the pathogenesis of kidney diseases, especially DKD, highlight benefits of the potential interventions targeting NAD+-boosting in the treatment of these diseases.

Sodium-glucose cotransporter2 (SGLT2) inhibitors have a reno-protective effect in diabetic kidney disease. However, the detailed mechanism remains unclear. In this study, human proximal tubular cells (HK-2) were cultured in 5 mM glucose and 25 mM mannitol (control), 30 mM glucose (high glucose: HG), or HG and SGLT2 inhibitor, dapagliflozin-containing medium for 48 h. The autophagic flux was decreased, accompanied by the increased phosphorylation of S6 kinase ribosomal protein (p-S6RP) and the reduced phosphorylation of AMP-activated kinase (p-AMPK) expression in a HG condition. Compared to those of the control, dapagliflozin and SGLT2 knockdown ameliorated the HG-induced alterations of p-S6RP, p-AMPK, and autophagic flux. In addition, HG increased the nuclear translocation of nuclear factor-κB p65 (NF-κB) p65 and the cytoplasmic nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), mature interleukin-1β (IL-1β), IL-6, and tumor necrosis factorα (TNFα) expression. Dapagliflozin, SGLT2 knockdown, and NF-κB p65 knockdown reduced the extent of these HG-induced inflammatory alterations. The inhibitory effect of dapagliflozin on the increase in the HG-induced nuclear translocation of NF-κB p65 was abrogated by knocking down AMPK. These data indicated that in diabetic renal proximal tubular cells, dapagliflozin ameliorates: (1) HG-induced autophagic flux reduction, via increased AMPK activity and mTOR suppression, and (2) inflammatory alterations due to NF-κB pathway suppression.

Simple Summary Dipeptidyl peptidase (DPP)-4 inhibitor is widely used for type 2 diabetes. Although DPP-4/CD26 has been recognized as both a suppressor and inducer in tumor biology due to its various functions, how DPP-4 inhibitor affects cancer progression in diabetic patients is still unknown. The aim of this review is to summarize one unfavorable aspect of DPP-4 inhibitor in cancer-bearing diabetic patients. Abstract DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field.

The redox reaction and energy metabolism status in mitochondria is involved in the pathogenesis of metabolic related disorder in kidney including diabetic kidney disease (DKD). Nicotinamide adenine dinucleotide (NAD+) is a cofactor for redox reactions and energy metabolism in mitochondria. NAD+ can be synthesized from four precursors through three pathways. The accumulation of NAD+ may ameliorate oxidative stress, inflammation and improve mitochondrial biosynthesis via supplementation of precursors and intermediates of NAD+ and activation of sirtuins activity. Conversely, the depletion of NAD+ via NAD+ consuming enzymes including Poly (ADP-ribose) polymerases (PARPs), cADPR synthases may contribute to oxidative stress, inflammation, impaired mitochondrial biosynthesis, which leads to the pathogenesis of DKD. Therefore, homeostasis of NAD+ may be a potential target for the prevention and treatment of kidney diseases including DKD. In this review, we focus on the regulation of the metabolic balance of NAD+ on the pathogenesis of kidney diseases, especially DKD, highlight benefits of the potential interventions targeting NAD+-boosting in the treatment of these diseases.

Large-scale RNA sequencing and genome-wide profiling data revealed the identification of a heterogeneous group of noncoding RNAs, known as long noncoding RNAs (lncRNAs). These lncRNAs play central roles in health and disease processes in diabetes and cancer. The critical association between aberrant expression of lncRNAs in diabetes and diabetic kidney disease have been reported. LncRNAs regulate diverse targets and can function as sponges for regulatory microRNAs, which influence disease phenotype in the kidneys. Importantly, lncRNAs and microRNAs may regulate bidirectional or crosstalk mechanisms, which need to be further investigated. These studies offer the novel possibility that lncRNAs may be used as potential therapeutic targets for diabetes and diabetic kidney diseases. Here, we discuss the functions and mechanisms of actions of lncRNAs, and their crosstalk interactions with microRNAs, which provide insight and promise as therapeutic targets, emphasizing their role in the pathogenesis of diabetes and diabetic kidney disease

Atherosclerosis is the main cause of mortality in metabolic-related diseases, including cardiovascular disease and type 2 diabetes (T2DM). Atherosclerosis is characterized by lipid accumulation and increased inflammatory cytokines in the vascular wall, endothelial cell and vascular smooth muscle cell dysfunction and foam cell formation initiated by monocytes/macrophages. The characteristics of metabolic syndrome (MetS), including obesity, glucose intolerance, dyslipidemia and hypertension, may activate multiple mechanisms, such as insulin resistance, oxidative stress and inflammatory pathways, thereby contributing to increased risks of developing atherosclerosis and T2DM. Autophagy is a lysosomal degradation process that plays an important role in maintaining cellular metabolic homeostasis. Increasing evidence indicates that impaired autophagy induced by MetS is related to oxidative stress, inflammation, and foam cell formation, further promoting atherosclerosis. Basal and mild adaptive autophagy protect against the progression of atherosclerotic plaques, while excessive autophagy activation leads to cell death, plaque instability or even plaque rupture. Therefore, autophagic homeostasis is essential for the development and outcome of atherosclerosis. Here, we discuss the potential role of autophagy and metabolic syndrome in the pathophysiologic mechanisms of atherosclerosis and potential therapeutic drugs that target these molecular mechanisms.

COMT (Catechol-O-methyl transferase), an enzyme that metabolizes catechol, requires magnesium (Mg 2+ ) to maintain its activity. Low COMT activity causes insufficient 2-methoxyestradiol (2-ME), a biologically active metabolite from hydroxyestradiol, which leads to hypertensive disorders, including preeclampsia. Hypoestrogenism increases the risk of salt-sensitive hypertension (SSH). SSH and preeclampsia are risk factors for each other; however, the molecular mechanism of this interaction is unclear. We focused on the interactive effect of Mg 2+ insufficiency and genetic COMT deficiency on SSH using 2 strains of mice with genetically distinct COMT activity. In male mice, BL6 (C57BL/6J), a high-activity COMT strain, displayed unaltered blood pressure regardless of the Mg 2+ and salt levels in food; DBA (DBA/2J), a low-activity COMT strain, developed SSH under low Mg 2+ and high-salt conditions. COMT inhibition in C57BL/6J strain also induced SSH. Treatment with 2-ME ameliorated SSH in both models. The ATR1 (angiotensin II type 1 receptor)–STE20-SPAK (serine-proline alanine-rich kinase)–NCC (sodium chloride cotransporter) axis, molecules associated with sodium reabsorption in distal convoluted tubules, was activated in mice that developed SSH. In female DBA mice, ovariectomized mice displayed SSH under low Mg 2+ associated with activation of ATR1-SPAK-NCC axis; 2-ME inhibited all, whereas the blood pressure of sham mice was unaltered regardless of any intervention. Our findings revealed that Mg 2+ insufficiency exaggerated the low COMT activity and induced SSH via the ATR1-SPAK-NCC axis due to 2-ME insufficiency, suggesting a new pathophysiological role that links COMT/2-ME deficiency with hypertensive syndrome.

Aims To investigate the effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors vs. dipeptidyl peptidase‐4 (DPP‐4) inhibitors on renal function preservation (RFP) using real‐world data of patients with type 2 diabetes in Japan, and to identify which subgroups of patients obtained greater RFP benefits with SGLT2 inhibitors vs. DPP‐4 inhibitors. Methods We retrospectively analysed claims data recorded in the Medical Data Vision database in Japan of patients with type 2 diabetes (aged ≥18 years) prescribed any SGLT2 inhibitor or any DPP‐4 inhibitor between May 2014 and September 2016 (identification period), in whom estimated glomerular filtration rate (eGFR) was measured at least twice (baseline, up to 6 months before the index date; follow‐up, 9 to 15 months after the index date) with continuous treatment until the follow‐up eGFR. The endpoint was the percentage of patients with RFP, defined as no change or an increase in eGFR from baseline to follow‐up. A proprietary supervised learning algorithm (Q‐Finder; Quinten, Paris, France) was used to identify the profiles of patients with an additional RFP benefit of SGLT2 inhibitors vs. DPP‐4 inhibitors. Results Data were available for 990 patients prescribed SGLT2 inhibitors and 4257 prescribed DPP‐4 inhibitors. The proportion of patients with RFP was significantly greater in the SGLT2 inhibitor group (odds ratio 1.27; P = 0.01). The Q‐Finder algorithm identified four clinically relevant subgroups showing superior RFP with SGLT2 inhibitors (P

Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (

Lifespan and metabolic health are influenced by dietary nutrients. Recent studies show that a reduced protein intake or low-protein/high-carbohydrate diet plays a critical role in longevity/metabolic health. Additionally, specific amino acids (AAs), including methionine or branched-chain AAs (BCAAs), are associated with the regulation of lifespan/ageing and metabolism through multiple mechanisms. Therefore, methionine or BCAAs restriction may lead to the benefits on longevity/metabolic health. Moreover, epidemiological studies show that a high intake of animal protein, particularly red meat, which contains high levels of methionine and BCAAs, may be related to the promotion of age-related diseases. Therefore, a low animal protein diet, particularly a diet low in red meat, may provide health benefits. However, malnutrition, including sarcopenia/frailty due to inadequate protein intake, is harmful to longevity/metabolic health. Therefore, further study is necessary to elucidate the specific restriction levels of individual AAs that are most effective for longevity/metabolic health in humans. Keywords: Low protein intake, Low-protein/high-carbohydrate diet, Methionine, Branched-chain amino acids, Red meat, Longevity, Metabolic health

Diabetic kidney disease (DKD) is appeared to be higher risk of declining kidney function compared to non-diabetic kidney disease with same magnitude of albuminuria. Epithelial-mesenchymal transition (EMT) program of tubular epithelial cells (TECs) could be important for the production of the extracellular matrix in the kidney. Caveolin-1 (CAV1), dipeptidyl peptidase-4 (DPP-4) and integrin β1 have shown to be involved in EMT program. Here, we found diabetic kidney is prone for albuminuria-induced TECs damage and DPP-4 plays a vital role in such parenchymal damages in diabetic mice. The bovine serum albumin (BSA) injection induced severe TECs damage and altered expression levels of DPP-4, integrin β1, CAV1, and EMT programs including relevant microRNAs in type 1 diabetic CD-1 mice when compared to non-diabetic mice; teneligliptin (TENE) ameliorated these alterations. TENE suppressed the close proximity among DPP-4, integrin β1 and CAV1 in a culture of HK-2 cells. These findings suggest that DPP-4 inhibition can be relevant for combating proteinuric DKD by targeting the EMT program induced by the crosstalk among DPP-4, integrin β1 and CAV1.

A biomarker, by which we can predict alterations of renal function in normoalbuminuric diabetic patients, is not available. Here, we report that endogenous anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) represents a potential biomarker to predict alterations in eGFR in normoalbuminuric diabetic patients. We analyzed 21 normoalbuminuric diabetic patients with eGFR ≥ 30 ml/min/1.73 m2 and measured AcSDKP levels in first morning void urine. We divided patients into two groups based on the median values: low or high urinary AcSDKP groups (uAcSDKP/Crlow or uAcSDKP/Crhigh). At baseline, no significant differences in sex, age, HbA1c, BMI, serum creatinine levels, etc., were observed between the two groups. During ~ 4 years, the alteration in eGFR [ΔeGFRop (ΔeGFR observational periods)] was significantly stable in uAcSDKP/Crhigh group compared with uAcSDKP/Crlow group over time (P = 0.003, χ2 = 8.58). We also evaluated urine kidney injury molecule-1 (uKim-1) levels and found that ΔeGFRop was also stable in low uKim-1 group compared with high uKim-1 group over time (P = 0.004, χ2 = 8.38). Patients who fulfilled the criteria for both uAcSDKP/Crhigh and uKim-1low exhibited stable ΔeGFRop (P

Aims/Introduction The objective of the present study was to elucidate the effect of switching to teneligliptin from other dipeptidyl peptidase‐4 (DPP‐4) inhibitors on glucose control and renoprotection in type 2 diabetes mellitus patients with diabetic kidney disease. Materials and Methods The present study was a single‐arm, open‐label, observational study. A total of 23 patients, who had urinary albumin/creatinine ratios (UACR) ≥30 mg/gCr in their first urine in the early morning, and received other DPP‐4 inhibitors and renin‐angiotensin system inhibitors, switched to teneligliptin 20 mg/day. After switching to teneligliptin for 24 weeks, we evaluated changes in glycated hemoglobin (HbA1c), fasting plasma glucose levels, plasma DPP‐4 activity and UACR. Results HbA1c, fasting plasma glucose and UACR values showed no significant change after 24 weeks compared with baseline. However, plasma DPP‐4 activity was significantly reduced after 24 weeks (0.57 ± 0.26 nmol/min/mL, P = 0.012, vs baseline), compared with baseline (1.49 ± 1.73 nmol/min/mL), and there was a positive relationship between the change rate of plasma DPP‐4 activity (Δ%DPP‐4) for 24 weeks and the levels of plasma DPP‐4 activity (r = −0.5997, P = 0.0025) and fasting plasma glucose (r = −0.4235, P = 0.0440) at baseline. Additionally, the Δ%DPP‐4 for 24 weeks was significantly correlated to the change rate of UACR (r = 0.556, P = 0.0059). However, there was no relationship between Δ%DPP‐4 and ΔHbA1c (amount of HbA1c change). Conclusions Switching to teneligliptin from other DPP‐4 inhibitors for 24 weeks reduces plasma DPP‐4 activity, which is associated with a reduction in albuminuria, independent of the change in glucose levels, in type 2 diabetes mellitus patients with diabetic kidney disease.

Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect of MetR on lifespan extension and metabolic health is mediated partially through a reduction in oxidative stress. Methionine metabolism is involved in the supply of methyl donors such as S-adenosyl-methionine (SAM), glutathione synthesis and polyamine metabolism. SAM, a methionine metabolite, activates mechanistic target of rapamycin complex 1 and suppresses autophagy; therefore, MetR can induce autophagy. In the process of glutathione synthesis in methionine metabolism, hydrogen sulfide (H2S) is produced through cystathionine-β-synthase and cystathionine-γ-lyase; however, MetR can induce increased H2S production through this pathway. Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy. In addition, MetR decreases oxidative stress by inhibiting reactive oxygen species production in mitochondria. Thus, MetR can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health. In this review, we summarize the current understanding of the effects of MetR on lifespan extension and metabolic health, focusing on the reduction in oxidative stress.

Summary Defects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain of function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis, whereas its loss of function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGFβ/Smad3-dependent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial SIRT3 is a fundamental regulator of defective metabolism regulating health and disease processes in the kidney., Graphical abstract, Highlights • Endothelial SIRT3 protects against renal fibrosis in diabetes • Endothelial SIRT3 regulates mesenchymal metabolic shifts • Amelioration of endothelial SIRT3 could be a potential therapeutic approach • Targeting defective metabolism offers new therapeutics against kidney diseases, Biological Sciences ; Cell Biology ; Functional Aspects of Cell Biology

Aims/Introduction Tubulointerstitial fibrosis is a hallmark of diabetic nephropathy and is associated with an epithelial‐to‐mesenchymal transition (EMT) program and aberrant glycolysis. Dimeric pyruvate kinase (PK) M2 (PKM2) acts as a key protein kinase in aberrant glycolysis by promoting the accumulation of hypoxia‐inducible factor (HIF)‐1α, while tetrameric PKM2 functions as a pyruvate kinase in oxidative phosphorylation. The aim of the research is to study the effect of PKM2 tetramer activation on preventing kidney fibrosis via suppression of aberrant glycolysis and the EMT program. Materials and methods In vivo: Streptozotocin (STZ) was utilized to induce diabetes in 8‐week‐old CD‐1 mice; 4 weeks after diabetes induction, proteinuria‐induced kidney fibrosis was developed by intraperitoneal injection of bovine serum albumin (BSA: 0.3 g/30 g BW) for 14 days; The PKM2 activator TEPP‐46 was also administered orally simultaneously. In vitro: HK2 cells were co‐treated with high‐glucose media or/and TGF‐β1 and TEPP46 for 48 h, cellular protein was extracted for evaluation. Results Diabetic mice developed kidney fibrosis associated with aberrant glycolysis and EMT; BSA injection accelerated kidney fibrosis in both the control and diabetic mice; TEPP‐46 rescued the kidney fibrosis. In HK2 cells, TEPP‐46 suppressed the EMT program induced by TGF‐β1 and/or high‐glucose incubation. TEPP‐46‐induced PKM2 tetramer formation and PK activity resulted in suppression of HIF‐1α and lactate accumulation. Specific siRNA‐mediated knockdown of HIF‐1α expression diminished high glucose‐induced mesenchymal protein levels. Conclusion PKM2 activation could restore the tubular phenotype via suppression of the EMT program and aberrant glycolysis, providing an alternative target to mitigate fibrosis in diabetic kidneys., Diabetic kidney disease displayed kidney fibrosis associated with aberrant glycolysis and EMT program, these alterations were related to the increased level of dimeric‐PKM2 formation, PKM2 activation by TEPP46 rescued the kidney fibrosis by promoting PKM2 tetramer formation, and inhibiting dimeric‐PKM2 which directly interacted with HIF‐1α and promoted its transcription.

The aim of this study was to investigate the effects of dietary supplementation with a nonalcoholic red wine extract (RWE), including resveratrol and polyphenols, on insulin sensitivity and Sirt1 expression in nondiabetic humans. The present study was a single-arm, open-label and prospective study. Twelve subjects received supplementation with RWE, including 19.2 mg resveratrol and 136 mg polyphenols, daily for 8 weeks. After 8 weeks, metabolic parameters, including glucose/lipid metabolism and inflammatory markers, were evaluated. mRNA expression of Sirt1 was evaluated in isolated peripheral blood mononuclear cells (PBMNCs). Additionally, Sirt1 and phosphorylated AMP-activated kinase (p-AMPK) expression were evaluated in cultured human monocytes (THP-1 cells). Supplementation with RWE for 8 weeks decreased the homeostasis model assessment for insulin resistance (HOMA-IR), which indicates an increase in insulin sensitivity. Serum low-density lipoprotein-cholesterol (LDL-C), triglyceride (TG) and interleukin-6 (IL-6) were significantly decreased by RWE supplementation for 8 weeks. Additionally, Sirt1 mRNA expression in isolated PBMNCs was significantly increased after 8 weeks of RWE supplementation. Moreover, the rate of increase in Sirt1 expression was positively correlated with the rate of change in HOMA-IR. The administration of RWE increased Sirt1 and p-AMPK expression in cultured THP-1 cells. Supplementation with RWE improved metabolism, such as insulin sensitivity, lipid profile and inflammation, in humans. Additionally, RWE supplementation induced an increase in Sirt1 expression in PBMNCs, which may be associated with an improvement in insulin sensitivity.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

The mitochondria are a major source of reactive oxygen species (ROS). Superoxide anion (O2 •-) is produced by the process of oxidative phosphorylation associated with glucose, amino acid, and fatty acid metabolism, resulting in the production of adenosine triphosphate (ATP) in the mitochondria. Excess production of reactive oxidants in the mitochondria, including O2 •-, and its by-product, peroxynitrite (ONOO-), which is generated by a reaction between O2 •- with nitric oxide (NO•), alters cellular function via oxidative modification of proteins, lipids, and nucleic acids. Mitochondria maintain an antioxidant enzyme system that eliminates excess ROS; manganese superoxide dismutase (Mn-SOD) is one of the major components of this system, as it catalyzes the first step involved in scavenging ROS. Reduced expression and/or the activity of Mn-SOD results in diminished mitochondrial antioxidant capacity; this can impair the overall health of the cell by altering mitochondrial function and may lead to the development and progression of kidney disease. Targeted therapeutic agents may protect mitochondrial proteins, including Mn-SOD against oxidative stress-induced dysfunction, and this may consequently lead to the protection of renal function. Here, we describe the biological function and regulation of Mn-SOD and review the significance of mitochondrial oxidative stress concerning the pathogenesis of kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), with a focus on Mn-SOD dysfunction.

Platelet-derived growth factor-B (PDGF-B) is a main factor to promote adipose tissue angiogenesis, which is responsible for the tissue expansion in obesity. In this process, PDGF-B induces the dissociation of pericytes from blood vessels; however, its regulatory mechanism remains unclear. In the present study, we found that stromal cell-derived factor 1 (SDF1) plays an essential role in this regulatory mechanism. SDF1 mRNA was increased in epididymal white adipose tissue (eWAT) of obese mice. Ex vivo pharmacological analyses using cultured adipose tissue demonstrated that physiological concentrations (1–100 pg/mL) of SDF1 inhibited the PDGF-B-induced pericyte dissociation from vessels via two cognate SDF1 receptors, CXCR4 and CXCR7. In contrast, higher concentrations (> 1 ng/mL) of SDF1 alone caused the dissociation of pericytes via CXCR4, and this effect disappeared in the cultured tissues from PDGF receptor β (PDGFRβ) knockout mice. To investigate the role of SDF1 in angiogenesis in vivo, the effects of anagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP4) that degrades SDF1, were examined in mice fed a high-fat diet. Anagliptin increased the SDF1 levels in the serum and eWAT. These changes were associated with a reduction of pericyte dissociation and fat accumulation in eWAT. AMD3100, a CXCR4 antagonist, cancelled these anagliptin effects. In flow-cytometry analysis, anagliptin increased and decreased the PDGF-B expression in endothelial cells and macrophages, respectively, whereas anagliptin reduced the PDGFRβ expression in pericytes of eWAT. These results suggest that SDF1 negatively regulates the adipose tissue angiogenesis in obesity by altering the reactivity of pericytes to PDGF-B.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are beneficial in halting diabetic kidney disease; however, the complete mechanisms have not yet been elucidated. The epithelial-mesenchymal transition (EMT) is associated with the suppression of sirtuin 3 (Sirt3) and aberrant glycolysis. Here, we hypothesized that the SGLT2 inhibitor empagliflozin restores normal kidney histology and function in association with the inhibition of aberrant glycolysis in diabetic kidneys. CD-1 mice with streptozotocin-induced diabetes displayed kidney fibrosis that was associated with the EMT at 4 months after diabetes induction. Empagliflozin intervention for 1 month restored all pathological changes; however, adjustment of blood glucose by insulin did not. Empagliflozin normalized the suppressed Sirt3 levels and aberrant glycolysis that was characterized by HIF-1α accumulation, hexokinase 2 induction, and pyruvate kinase isozyme M2 dimer formation in diabetic kidneys. Empagliflozin also suppressed the accumulation of glycolysis byproducts in diabetic kidneys. Another SGLT2 inhibitor, canagliflozin, demonstrated similar in vivo effects. High-glucose media induced the EMT, which was associated with Sirt3 suppression and aberrant glycolysis induction, in the HK2 proximal tubule cell line; SGLT2 knockdown suppressed the EMT, with restoration of all aberrant functions. SGLT2 suppression in tubular cells also inhibited the mesenchymal transition of neighboring endothelial cells. Taken together, SGLT2 inhibitors exhibit renoprotective potential that is partially dependent on the inhibition of glucose reabsorption and subsequent aberrant glycolysis in kidney tubules.

Sterol regulatory-element binding proteins (SREBPs) are classical regulators of cellular lipid metabolism in the kidney and other tissues. SREBPs are currently recognized as versatile transcription factors involved in a myriad of cellular processes. Meanwhile, SREBPs have been recognized to mediate lipotoxicity, contributing to the progression of kidney diseases. SREBP1 has been shown to bind to the promoter region of TGFβ, a major pro-fibrotic signaling mechanism in the kidney. Conversely, TGFβ activates SREBP1 transcriptional activity suggesting a positive feedback loop of SREBP1 in TGFβ signaling. Public ChIP-seq data revealed numerous non-lipid transcriptional targets of SREBPs that plausibly play roles in progressive kidney disease and fibrosis. This review provides new insights into SREBP as a mediator of kidney fibrosis via lipid-independent pathways.

Two class of drugs 1) angiotensin-converting enzyme inhibitors (ACEis) and 2) angiotensin II receptor blockers (ARBs) are well-known conventional drugs that can retard the progression of chronic nephropathies to end-stage renal disease. However, there is a lack of comparative studies on the effects of ACEi versus ARB on renal fibrosis. Here, we observed that ACEi ameliorated renal fibrosis by mitigating DPP-4 and TGF&beta, signaling, whereas, ARB did not show. Moreover, the combination of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), one of the substrates of ACE, with ACEi slightly enhanced the inhibitory effects of ACEi on DPP-4 and associated-TGF&beta, signaling. Further, the comprehensive miRome analysis in kidneys of ACEi+AcSDKP (combination) treatment revealed the emergence of miR-29s and miR-let-7s as key antifibrotic players. Treatment of cultured cells with ACEi alone or in combination with AcSDKP prevented the downregulated expression of miR-29s and miR-let-7s induced by TGF&beta, stimulation. Interestingly, ACEi also restored miR-29 and miR-let-7 family cross-talk in endothelial cells, an effect that is shared by AcSDKP suggesting that AcSDKP may be partially involved in the anti-mesenchymal action of ACEi. The results of the present study promise to advance our understanding of how ACEi regulates antifibrotic microRNAs crosstalk and DPP-4 associated-fibrogenic processes which is a critical event in the development of diabetic kidney disease.

Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes., The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.

The biological influence of antidiabetic drugs on cancer cells and diabetic cancer patients has not yet been completely elucidated. We reported that a dipeptidyl peptidase (DPP)-4 inhibitor accelerates mammary cancer metastasis by inducing epithelial–mesenchymal transition (EMT) through the CXCL12/CXCR4/mTOR axis. Metformin has been shown to inhibit the mTOR signaling pathway. In this study, we investigated whether metformin mitigates breast cancer metastasis induced by a DPP-4 inhibitor via suppression of mTOR signaling. In cultured mouse mammary and human breast cancer cells, metformin suppressed DPP-4 inhibitor KR62436 (KR)-induced EMT and cell migration via suppression of the mTOR pathway associated with AMPK activation. For the in vivo study, metformin intervention was performed in an allograft 4T1 breast cancer model mouse with or without KR. We also analyzed mice transplanted with shRNA-mediated DPP-4 knockdown 4T1 cells. Treatment with metformin inhibited the lung metastasis of DPP-4–deficient 4T1 mammary tumor cells generated by either KR administration or DPP-4 knockdown. Immunostaining of primary tumors indicated that DPP-4 suppression promoted the expression of EMT-inducing transcription factor Snail through activation of the CXCR4-mediated mTOR/p70S6K pathway in an allograft breast cancer model; metformin abolished this alteration. Metformin treatment did not alter DPP-4–deficiency-induced expression of CXCL12 in either plasma or primary tumors. Our findings suggest that metformin may serve as an antimetastatic agent by mitigating the undesirable effects of DPP-4 inhibitors in patients with certain cancers. Implications: Metformin could combat the detrimental effects of DPP-4 inhibitor on breast cancer metastasis via mTOR suppression, suggesting the potential clinical relevance. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/1/61/F1.large.jpg.

Adipose tissue macrophages (ATMs) play a central role in tissue remodeling and homeostasis. However, whether ATMs promote adipose angiogenesis in obesity remains unclear. We examined the impact of ATMs deletion on adipose angiogenesis and tissue expansion in the epididymal white adipose tissue (eWAT) of high-fat diet (HFD)-fed mice by using liposome-encapsulated clodronate. We further elucidated the induction mechanisms of platelet-derived growth factor (PDGF)-B in macrophages in response to obesity-associated metabolic stresses, since it plays a significant role in the regulation of pericyte behavior for the initiation of neoangiogenesis during tissue expansion. ATM depletion prevented adipose tissue expansion in HFD-fed mice by inhibiting pericyte detachment from vessels, resulting in less vasculature in eWAT. The lipopolysaccharide (LPS) stimulation and high glucose concentration augmented glucose incorporation and glycolytic capacity with the induction of Pdgfb mRNA. This effect was mediated through extracellular signal-regulated kinase (ERK) among mitogen-activated protein kinases coupled with glycolysis in RAW264.7 macrophages. The Pdgfb induction system was distinct from that of inflammatory cytokines mediated by mechanistic target of rapamycin complex 1 (mTORC1) and NFκB signaling. Thus, obesity-associated hyperglycemia and chronic inflammation fuels ERK signaling coupled with glycolysis in pro-inflammatory macrophages, which contribute to the expansion of eWAT through PDGF-B-dependent vascular remodeling.

Dipeptidyl peptidase (DPP)-4, a molecular target of DPP-4 inhibitors, which are type 2 diabetes drugs, is expressed in a variety of cell types, tissues and organs. DPP-4 has been shown to be involved in cancer biology, and we have recently shown that a DPP-4 inhibitor promoted the epithelial mesenchymal transition (EMT) in breast cancer cells. The EMT is known to associate with chemotherapy resistance via the induction of ATP-binding cassette (ABC) transporters in cancer cells. Here, we demonstrated that deficiency in DPP-4 promoted chemotherapy resistance via the CXCL12/CXCR4/mTOR axis, activating the TGF&beta, signaling pathway via the expression of ABC transporters. DPP-4 inhibition enhanced ABC transporters in vivo and in vitro. Doxorubicin (DOX) further induced ABC transporters in DPP-4-deficient 4T1 cells, and the induction of ABC transporters was suppressed by either the CXCR4 inhibitor AMD3100, the mTOR inhibitor rapamycin or a neutralizing TGF&beta, (1, 2 and 3) antibody(N-TGF&beta, ). Knockdown of snail, an EMT-inducible transcription factor, suppressed ABC transporter levels in DOX-treated DPP-4-deficient 4T1 cells. In an allograft mouse model, however, the effects of DOX in either primary tumor or metastasis were not statistically different between control and DPP-4-kd 4T1. Taken together, our findings suggest that DPP-4 inhibitors potentiate chemotherapy resistance via the induction of ABC transporters by the CXCL12/CXCR4/mTOR/TGF&beta, signaling pathway in breast cancer cells.

Muscle biology is important topic in diabetes research. We have reported that a diet with ketogenic amino acids rich replacement (KAAR) ameliorated high-fat diet (HFD)-induced hepatosteatosis via activation of the autophagy system. Here, we found that a KAAR ameliorated the mitochondrial morphological alterations and associated mitochondrial dysfunction induced by an HFD through induction of the AKT/4EBP1 and autophagy signaling pathways in both fast and slow muscles. The mice were fed with a standard HFD (30% fat in food) or an HFD with KAAR (HFDKAAR). In both the gastrocnemius and the soleus, HFDKAAR ameliorated HFD-impaired mitochondrial morphology and mitochondrial function, characterized by decreased mitofusin 2, optic atrophy 1, peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α and PPARα levels and increased dynamin-related protein 1 levels. The decreased levels of phosphorylated AKT and 4EBP1 in the gastrocnemius and soleus of HFD-fed mice were remediated by HFDKAAR. Furthermore, the HFDKAAR ameliorated the HFD-induced autophagy defects in the gastrocnemius and soleus. These findings suggest that KAAR may be a novel strategy to combat obesity-induced mitochondrial dysfunction, likely through induction of the AKT/4EBP1 and autophagy pathways in skeletal muscle.