Nutritional and metabolic control of germ cell fate through O-GlcNAc regulation.

Fate determination of primordial germ cells (PGCs) is regulated in a multi-layered manner, involving signaling pathways, epigenetic mechanisms, and transcriptional control. Chemical modification of macromolecules, including epigenetics, is expected to be closely related with metabolic mechanisms but the detailed molecular machinery linking these two layers remains poorly understood. Here, we show that the hexosamine biosynthetic pathway controls PGC fate determination via O-linked ß-N-acetylglucosamine (O-GlcNAc) modification. Consistent with this model, reduction of carbohydrate metabolism via a maternal ketogenic diet that decreases O-GlcNAcylation levels causes repression of PGC formation in vivo. Moreover, maternal ketogenic diet intake until mid-gestation affects the number of ovarian germ cells in newborn pups. Taken together, we show that nutritional and metabolic mechanisms play a previously unappreciated role in PGC fate determination.

O-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding.

Adipose tissues accumulate excess energy as fat and heavily influence metabolic homeostasis. O-linked N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), which involves the addition of N-acetylglucosamine to proteins by O-GlcNAc transferase (Ogt), modulates multiple cellular processes. However, little is known about the role of O-GlcNAcylation in adipose tissues during body weight gain due to overnutrition. Here, we report on O-GlcNAcylation in mice with high-fat diet (HFD)-induced obesity. Mice with knockout of Ogt in adipose tissue achieved using adiponectin promoter-driven Cre recombinase (Ogt-FKO) gained less body weight than control mice under HFD. Surprisingly, Ogt-FKO mice exhibited glucose intolerance and insulin resistance, despite their reduced body weight gain, as well as decreased expression of de novo lipogenesis genes and increased expression of inflammatory genes, resulting in fibrosis at 24 weeks of age. Primary cultured adipocytes derived from Ogt-FKO mice showed decreased lipid accumulation. Both primary cultured adipocytes and 3T3-L1 adipocytes treated with OGT inhibitor showed increased secretion of free fatty acids. Medium derived from these adipocytes stimulated inflammatory genes in RAW 264.7 macrophages, suggesting that cell-to-cell communication via free fatty acids might be a cause of adipose inflammation in Ogt-FKO mice. In conclusion, O-GlcNAcylation is important for healthy adipose expansion in mice. Glucose flux into adipose tissues may be a signal to store excess energy as fat.NEW & NOTEWORTHY We evaluated the role of O-GlcNAcylation in adipose tissue in diet-induced obesity using adipose tissue-specific Ogt knockout mice. We found that O-GlcNAcylation in adipose tissue is essential for healthy fat expansion and that Ogt-FKO mice exhibit severe fibrosis upon long-term overnutrition. O-GlcNAcylation in adipose tissue may regulate de novo lipogenesis and free fatty acid efflux to the degree of overnutrition. We believe that these results provide new insights into adipose tissue physiology and obesity research.

Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes.

Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P < 1.0 × 10-4) in an independent case-control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stages 1 and 2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, P = 1.62 × 10-9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11-1.23, and rs140508424 within PALM2 on chromosome 9, P = 4.19 × 10-8, OR = 1.61, 95% CI 1.36-1.91. However, the association of these two loci was not replicated in Korean, European or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (P = 2.17 × 10-6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

Relationship between the magnitude of body mass index reductions and remission in patients with type 2 diabetes in real world settings: Analysis of nationwide patient registry in Japan (JDDM74).

AIMS: To determine the association between the magnitude of weight loss and incidence of remission according to baseline characteristics in patients with diabetes in clinical settings. METHODS: In total, 39 676 Japanese patients with type 2 diabetes aged ≥18 years with glycated haemoglobin (HbA1c) ≥6.5% and/or glucose-lowering drug prescription were identified from databases of specialists' clinics from 1989 and followed until September 2022. Remission was diagnosed as maintaining HbA1c <6.5% at least 3 months after cessation of a glucose-lowering drug. Factors associated with remission were evaluated by logistic regression analysis according to weight change in 1 year (i.e. ≥10%, 7.0-9.9%, 3.0-6.9% reduction, <3% change and ≥3.0% increase). RESULTS: During the study period, 3454 remissions occurred. The rates of remission were higher in the group with the greatest reduction of body mass index (BMI) in any category examined (i.e. baseline BMI, HbA1c, duration of diabetes and treatment). The incidences of remission per 1000 person-years were about 25 and 50, respectively, for those with BMI ≥22.5 and reductions in BMI of 7.0-9.9% and ≥10% in 1 year. Remissions per 1000 person-years were 99.2 and 91.8, respectively, for those with baseline HbA1c of 6.5-6.9 and a 10% BMI reduction and those not taking glucose-lowering drugs accompanied by a 10% BMI reduction. CONCLUSIONS: Modest weight losses of 3.0-7.9% were significantly associated with remission, but a minimum of 10% weight loss would be required in addition to an early diagnosis to achieve a 10% remission rate in clinical settings. Our results implied that remission may be expected with a relatively lower BMI in an Asian population compared with that was reported in Western populations if accompanied by weight loss.

Incidence and predictors of remission and relapse of type 2 diabetes mellitus in Japan: Analysis of a nationwide patient registry (JDDM73).

AIMS: To determine the incidence of remission and 1-year relapse from remission and associated factors in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 48 320 Japanese patients with type 2 diabetes aged ≥18 years, with glycated haemoglobin (HbA1c) levels ≥48 mmol/mol (6.5%) and/or glucose-lowering drug prescription, were identified from databases of specialist clinics from 1989 and followed until September 2022. Remission was defined as HbA1c <48 mmol/mol at least 3 months after cessation of a glucose-lowering drug. Relapse was defined as failure to maintain remission for 1 year. Factors associated with remission and relapse were evaluated by logistic regression analysis. RESULTS: The overall incidence of remissions per 1000 person-years was 10.5, and for those with HbA1c levels of 48 to 53 mmol/mol (6.5% to 6.9%), those taking no glucose-lowering drugs at baseline, and those with a ≥10% body mass index (BMI) reduction in 1 year, it was 27.8, 21.7 and 48.2, respectively. Shorter duration, lower baseline HbA1c, higher baseline BMI, higher BMI reduction at 1 year, and no glucose-lowering drugs at baseline were significantly associated with remission. Among 3677 persons with remission, approximately two-thirds (2490) relapsed within 1 year. Longer duration, lower BMI at baseline, and lower BMI reduction at 1 year were significantly associated with relapse. CONCLUSIONS: The results showed that the incidence of remission and predictors of relapse, especially baseline BMI, might differ greatly between East Asian and Western populations. Furthermore, the relationships of BMI reduction with remission and relapse may be greater in East Asian than in Western populations, implying ethnic differences in returning from overt hyperglycaemia to nearly normal glucose levels.

Cardio- and reno-protective effects of dipeptidyl peptidase III in diabetic mice.

Diabetes mellitus (DM) causes injury to tissues and organs, including to the heart and kidney, resulting in increased morbidity and mortality. Thus, novel potential therapeutics are continuously required to minimize DM-related organ damage. We have previously shown that dipeptidyl peptidase III (DPPIII) has beneficial roles in a hypertensive mouse model, but it is unknown whether DPPIII has any effects on DM. In this study, we found that intravenous administration of recombinant DPPIII in diabetic db/db mice for 8 weeks suppressed the DM-induced cardiac diastolic dysfunctions and renal injury without alteration of the blood glucose level. This treatment inhibited inflammatory cell infiltration and fibrosis in the heart and blocked the increase in albuminuria by attenuating the disruption of the glomerular microvasculature and inhibiting the effacement of podocyte foot processes in the kidney. The beneficial role of DPPIII was, at least in part, mediated by the cleavage of a cytotoxic peptide, named Peptide 2, which was increased in db/db mice compared with normal mice. This peptide consisted of nine amino acids, was a digested fragment of complement component 3 (C3), and had an anaphylatoxin-like effect determined by the Miles assay and chemoattractant analysis. The effect was dependent on its interaction with the C3a receptor and protein kinase C-mediated RhoA activation downstream of the receptor in endothelial cells. In conclusion, DPPIII plays a protective role in the heart and kidney in a DM animal model through cleavage of a peptide that is a part of C3.

Limited effects of systemic or renal lipoprotein lipase deficiency on renal physiology and diseases.

Lipoprotein lipase (LPL) is an enzyme that catalyzes the hydrolysis of circulating triglyceride and the transport of fatty acids into cells. Its activity is positively regulated by insulin, and insulin resistance is associated with low LPL activity and subsequent hypertriglyceridemia. The involvement of hypertriglyceridemia in chronic kidney disease (CKD) is still under the debate in a clinical setting. Therefore, we aimed to study the role of hypertriglyceridemia in the disease using mice with systemic or renal-specific LPL deficiency. Systemic LPL deficiency was characterized by hypertriglyceridemia, but not renal injury or dyslipidemia-related conditions, such as fatty liver. Furthermore, the LPL deficiency-induced hypertriglyceridemia was not associated with a worsening of the CKD phenotype or atherosclerosis, even when CKD was induced by 5/6 nephrectomy. Next, because LPL-mediated fatty acid uptake may be important for energy metabolism in proximal tubular epithelial cells (PTECs), the role of renal LPL in renal physiology was studied by generating mice lacking LPL specifically in PTECs. These mice showed no abnormalities in their histology or renal reabsorption of micro molecules. These findings suggest that systemic and renal lipid abnormalities caused by LPL deficiency do not cause or worsen the development of renal injury, and provide novel insight regarding the potential role of lipotoxicity in the pathogenesis of obesity-related kidney injury.

Interconnection between cardiovascular, renal and metabolic disorders: A narrative review with a focus on Japan.

Insights from epidemiological, clinical and basic research are illuminating the interplay between metabolic disorders, cardiovascular disease (CVD) and kidney dysfunction, termed cardio-renal-metabolic (CRM) disease. Broadly defined, CRM disease involves multidirectional interactions between metabolic diseases such as type 2 diabetes (T2D), various types of CVD and chronic kidney disease (CKD). T2D confers increased risk for heart failure, which-although well known-has only recently come into focus for treatment, and may differ by ethnicity, whereas atherosclerotic heart disease is a well-established complication of T2D. Many people with T2D also have CKD, with a higher risk in Asians than their Western counterparts. Furthermore, CVD increases the risk of CKD and vice versa, with heart failure, notably, present in approximately half of CKD patients. Molecular mechanisms involved in CRM disease include hyperglycaemia, insulin resistance, hyperactivity of the renin-angiotensin-aldosterone system, production of advanced glycation end-products, oxidative stress, lipotoxicity, endoplasmic reticulum stress, calcium-handling abnormalities, mitochondrial malfunction and deficient energy production, and chronic inflammation. Pathophysiological manifestations of these processes include diabetic cardiomyopathy, vascular endothelial dysfunction, cardiac and renal fibrosis, glomerular hyperfiltration, renal hypoperfusion and venous congestion, reduced exercise tolerance leading to metabolic dysfunction, and calcification of atherosclerotic plaque. Importantly, recognition of the interaction between CRM diseases would enable a more holistic approach to CRM care, rather than isolated treatment of individual conditions, which may improve patient outcomes. Finally, aspects of CRM diseases may differ between Western and East Asian countries such as Japan, a super-ageing country, with potential differences in epidemiology, complications and prognosis that represent an important avenue for future research.

Differential Association of Serum n-3 Polyunsaturated Fatty Acids with Various Cerebrovascular Lesions in Japanese Men.

BACKGROUND: An association between a high intake of marine-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) with a lower risk of coronary heart disease was previously reported. However, the association between n-3 PUFAs and cerebrovascular lesions remains unclear. We evaluated this association in a general-population-based sample of Japanese men. METHODS: Participants were community-dwelling men (40-79 years old) living in Kusatsu City, Shiga, Japan. Serum concentrations of n-3 PUFAs, defined as the sum of eicosapentaenoic and docosahexaenoic acids, were measured via gas-liquid chromatography between 2006 and 2008. Magnetic resonance imaging was used to assess cerebrovascular lesions (including intracerebral large-artery stenosis, lacunar infarction, and microbleeds) and white matter lesions between 2012 and 2015. Logistic regression adjusting for conventional cardiovascular risk factors was used to estimate the odds ratio of prevalent cerebrovascular lesions per 1 standard deviation higher serum concentration of n-3 PUFAs. RESULTS: Of a total of 739 men, the numbers (crude prevalence in %) of prevalent cerebral large-artery stenoses, lacunar infarctions, microbleeds, and white matter lesions were 222 (30.0), 162 (21.9), 103 (13.9), and 164 (22.2), respectively. A 1 standard deviation higher concentration of n-3 PUFAs (30.5 µmol/L) was independently associated with lower odds of cerebral large-artery stenosis (multivariable-adjusted odds ratio, 0.80; 95% confidential interval, 0.67-0.97). There were no significant associations of n-3 PUFAs with the other types of lesions. CONCLUSIONS: n-3 PUFAs may have protective effects against large-artery stenosis, but not small vessel lesions, in the brain.

A case of central diabetes insipidus due to neurophysin II gene abnormality diagnosed based on a family history of nocturnal enuresis.

The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

Clinical course of different long-acting insulin therapies-glargine U100, U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes: a multicenter retrospective observational study (JDDM65 study).

This study aimed to retrospectively compare the clinical efficacy of different types of long-acting insulin therapies-glargine U100, glargine U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes after insulin use was initiated in an outpatient setting. The study consisted of 822 insulin-naïve patients in Japan who started using long-acting insulin for treatment of type 2 diabetes and continued for over 12 months. In addition, the impact of insulin type on insulin withdrawal was investigated by dividing the participants into two groups: those who achieved insulin withdrawal and those who did not, during the 12-month observation period based on a Cox proportional hazards model. As a result, HbA1c was decreased, and BMI was increased in all participants regardless of the insulin type used. A total of 185 participants succeeded in insulin withdrawal. After adjustment was made for several confounders, the positive determinant factors for withdrawal were short duration of diabetes and the choice of IDegAsp when compared with Gla100; the negative determinant factor was use of insulin secretagogues at the start of the study. In conclusion, all long-acting insulins were a powerful tool for treatment of type 2 diabetes, and patients with short duration of diabetes and/or no usage of insulin secretagogues resulted in favorable outcomes in terms of insulin withdrawal within a year in an outpatient setting. In addition, insulin degludec/insulin aspart was found to possibly be a better choice for treatment when it was compared with glargine U100 among the four types of insulin.

New classification and diagnostic criteria for insulin resistance syndrome.

This report of a working group established by the Japan Diabetes Society proposes a new classification and diagnostic criteria for insulin resistance syndrome. Insulin resistance syndrome is defined as a condition characterized by severe attenuation of insulin action due to functional impairment of the insulin receptor or its downstream signaling molecules. This syndrome is classified into two types: genetic insulin resistance syndrome, caused by gene abnormalities, and type B insulin resistance syndrome, caused by autoantibodies to the insulin receptor. Genetic insulin resistance syndrome includes type A insulin resistance as well as Donohue and Rabson-Mendenhall syndromes, all of which are caused by abnormalities of the insulin receptor gene; conditions such as SHORT syndrome caused by abnormalities of PIK3R1, which encodes a regulatory subunit of phosphatidylinositol 3-kinase; conditions caused by abnormalities of AKT2, TBC1D4, or PRKCE; and conditions in which a causative gene has not yet been identified. Type B insulin resistance syndrome is characterized by severe impairment of insulin action due to the presence of insulin receptor autoantibodies. Cases in which hypoglycemia alone is induced by autoantibodies that stimulate insulin receptor were not included in Type B insulin resistance syndrome.

Geometry of Sleeve Gastrectomy Measured by 3D CT Versus Weight Loss: Preliminary Analysis.

BACKGROUND: The size of the remnant stomach with respect to weight loss failure after laparoscopic sleeve gastrectomy (LSG) remains controversial. This study aimed to evaluate the impact of the actual size and volume of the remnant stomach, as measured by three-dimensional computed tomography (3D-CT) volumetry, on weight loss after LSG. METHODS: The clinical outcomes of 52 patients who underwent LSG between October 2008 and February 2019 were assessed. Weight metrics were recorded at 1, 3, and 6 months and 1 year postoperatively. 3D-CT volumetry was performed 1 year postoperatively, and the total remnant stomach volume (TSV), proximal stomach volume (PSV), antral stomach volume (ASV), and the distance between the pylorus and the distal edge of staple line (DPS) were measured. The relationship between the weight metrics and aforementioned factors was analyzed. RESULTS: Of the 52 patients who underwent LSG, 40 patients participated in this study. The average body mass index preoperatively was 38.3 ± 5.1 kg/m2, and the average percentage of total weight loss (%TWL) 1 year after LSG was 26.6 ± 9.3%. The average TSV, PSV, ASV, and DPS were 123.2 ± 60.3 ml, 73.4 ± 37.2 ml, 49.8 ± 30.3 ml, and 59.9 ± 18.5 mm, respectively. The DPS (r = - 0.394, p = 0.012) and ASV (r = - 0.356, p = 0.024) were correlated with %TWL 1 year postoperatively. CONCLUSIONS: The actual DPS and ASV measured by 3D-CT affected weight loss after LSG. 3D-CT may be useful for the immediate identification of factors affecting insufficient weight loss in patients; this may, in turn, aid in the implementation of early intervention treatments.

Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM).

The STELLA-LONG TERM prospective post-marketing surveillance study assessed ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis of patients with liver impairment used the final 3-year results. Data on patients, adverse drug reactions (ADRs), and changes in glycemic parameters and liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [γ-GTP] and alkaline phosphatase [ALP]) were collected, and the fatty liver index (FLI) was calculated. In the effectiveness analysis (n = 8,763), baseline liver function was normal in 2,605 patients (ALT <31/<21 U/L [men/women]) and abnormal in 3,277 (ALT ≥31/≥21 U/L). The abnormal liver function group had higher mean body weight and BMI than the normal liver function group (p < 0.001). In the safety analysis (n = 11,051), urinary tract infections, genital infections and hepatic disorders were more common in the abnormal than normal liver function group (2.25% vs. 1.07%; 1.78% vs. 1.14% and 1.85% vs. 1.01%). In the abnormal liver function group, there were significant (p < 0.001) decreases from baseline at 36 months in AST and ALT (from 38.8 and 53.7 U/L to 29.3 and 37.7 U/L, respectively), γ-GTP (from 75.4 to 51.7 U/L) and ALP (from 254.8 to 234.5 U/L), which were greater than in the normal liver function group. FLI reductions at 36 months were significant (p < 0.001) in subgroups with baseline FLI of ≥30 or ≥60. In conclusion, ipragliflozin improved liver function over 3 years in patients with impaired liver function, although ADRs occurred more frequently than in the normal liver function group.

Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis.

Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, Atg5, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific Atg5 gene deficient mice (Atg5 ΔIEC mice) were generated by cross of Atg5-floxed mice (Atg5 fl/fl ) with transgenic mice expressing Cre-recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60-day period. The dysfunction of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non-inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS-colitis was exacerbated in Atg5 ΔIEC mice compared to control Atg5 fl/fl mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1α (IRE1α), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1α, were significantly enhanced in IECs in DSS-treated Atg5 ΔIEC mice. Accumulation of phosphorylated IRE1α was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5 ΔIEC mice. These findings suggest that Atg5 suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1α.

Protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes.

To examine the cell-protective role of podocyte autophagy against glomerular endothelial dysfunction in diabetes, we analyzed the renal phenotype of tamoxifen (TM)-inducible podocyte-specific Atg5-deficient (iPodo-Atg5-/-) mice with experimental endothelial dysfunction. In both control and iPodo-Atg5-/- mice, high fat diet (HFD) feeding induced glomerular endothelial damage characterized by decreased urinary nitric oxide (NO) excretion, collapsed endothelial fenestrae, and reduced endothelial glycocalyx. HFD-fed control mice showed slight albuminuria and nearly normal podocyte morphology. In contrast, HFD-fed iPodo-Atg5-/- mice developed massive albuminuria accompanied by severe podocyte injury that was observed predominantly in podocytes adjacent to damaged endothelial cells by scanning electron microscopy. Although podocyte-specific autophagy deficiency did not affect endothelial NO synthase deficiency-associated albuminuria, it markedly exacerbated albuminuria and severe podocyte morphological damage when the damage was induced by intravenous neuraminidase injection to remove glycocalyx from the endothelial surface. Furthermore, endoplasmic reticulum stress was accelerated in podocytes of iPodo-Atg5-/- mice stimulated with neuraminidase, and treatment with molecular chaperone tauroursodeoxycholic acid improved neuraminidase-induced severe albuminuria and podocyte injury. In conclusion, podocyte autophagy plays a renoprotective role against diabetes-related structural endothelial damage, providing an additional insight into the pathogenesis of massive proteinuria in diabetic nephropathy.

A role for bone marrow-derived cells in diabetic nephropathy.

Diabetes mellitus causes systemic disorders. We previously demonstrated that diabetic condition forced bone marrow-derived cells (BMDCs) to express TNF-α, leading to the development of diabetic neuropathy in mice. Here, we hypothesized that these abnormal BMDCs are also involved in diabetic nephropathy. To test our hypothesis, mice were irradiated to receive total bone marrow (BM) from the transgenic mice expressing green fluorescent protein before diabetes was induced by streptozotocin. Confocal microscopy showed that the diabetic glomerulus had more BMDCs compared with the nondiabetic glomerulus. Most of these cells exhibited endothelial phenotypes, being negative for several markers, including podocin (a maker of podocyte), α8 integrin (mesangial cell), CD68, and F4/80 (macrophage). Next, the total BM of diabetic mice was transplanted into nondiabetic mice to examine if diabetic BM per se could cause glomerular injury. The recipient mice exhibiting normal glycemia developed albuminuria and mesangial expansion with an increase in capillary area. The number of BMDCs increased in the glomerulus of the recipient mice. These cells were found to exhibit the endothelial phenotype and to express TNF-α. These data suggest that diabetic BMDCs per se could initiate glomerular disease. Finally, eNOS knockout mice were used to examine if residential endothelial injury could attract BMDCs into the glomerulus. However, endothelial dysfunction due to eNOS deficiency failed to attract BMDCs into the glomerulus. In summary, BMDCs may be involved in the development of diabetic nephropathy.-Nobuta, H., Katagi, M., Kume, S., Terashima, T., Araki, S., Maegawa, H., Kojima, H., Nakagawa, T. A role for bone marrow-derived cells in diabetic nephropathy.

Validity of the Use of a Triaxial Accelerometer and a Physical Activity Questionnaire for Estimating Total Energy Expenditure and Physical Activity Level among Elderly Patients with Type 2 Diabetes Mellitus: CLEVER-DM Study.

INTRODUCTION: Evaluation of total energy expenditure (TEE) and physical activity level (PAL) is important for treatment of patients with type 2 diabetes mellitus (T2DM). However, the validity of accelerometers (ACC) and physical activity questionnaires (PAQ) for estimating TEE and PAL remains unknown in elderly populations with T2DM. We evaluated the accuracy of TEE and PAL results estimated by an ACC (TEEACC and PALACC) and a PAQ (TEEPAQ and PALPAQ) in elderly patients with T2DM. METHODS: Fifty-one elderly patients with T2DM (aged 61-79 years) participated in this study. TEEACC was calculated with PALACC using a triaxial ACC (Active style Pro HJA-750c) over 2 weeks and predicted basal metabolic rate (BMR) by Ganpule's equation. TEEPAQ was estimated using predicted BMR and the PALPAQ from the -Japan Public Health Center Study-Long questionnaire. We compared the results to TEEDLW measured with the doubly labeled water (DLW) method and PALDLW calculated with BMR using indirect calorimetry. RESULTS: TEEDLW was 2,165 ± 365 kcal/day, and TEEACC was 2,014 ± 339 kcal/day; TEEACC was strongly correlated with TEEDLW (r = 0.87, p < 0.01) but significantly underestimated (-150 ± 183 kcal/day, p < 0.05). There was no significant difference in TEEPAQ and TEEDLW (-49 ± 284 kcal/day), while the range of difference seemed to be larger than TEEACC. PALDLW, PALACC, and PALPAQ were calculated to be 1.71 ± 0.17, 1.69 ± 0.16, and 1.78 ± 0.24, respectively. -PALACC was strongly correlated with PALDLW (r = 0.71, p < 0.01), and there was no significant difference between the 2 values. PALPAQ was moderately correlated with PALDLW (r = 0.43, p < 0.01) but significantly overestimated. Predicted BMR was significantly lower than the BMR -measured by indirect calorimetry (1,193 ± 186 vs. 1,262 ± 155 kcal/day, p < 0.01). CONCLUSIONS: The present ACC and questionnaire showed acceptable correlation of TEE and PAL compared with DLW method in elderly patients with T2DM. Systematic errors in estimating TEE may be improved by the better equation for predicting BMR.

Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes.

BACKGROUND: Energy metabolism in proximal tubular epithelial cells (PTECs) is unique, because ATP production largely depends on lipolysis in both the fed and fasting states. Furthermore, disruption of renal lipolysis is involved in the pathogenesis of diabetic tubulopathy. Emerging evidence suggests that protein O-GlcNAcylation, an intracellular nutrient-sensing system, may regulate a number of metabolic pathways according to changes in nutritional status. Although O-GlcNAcylation in PTECs has been demonstrated experimentally, its precise role in lipolysis in PTECs is unclear. METHODS: To investigate the mechanism of renal lipolysis in PTECs-specifically, the role played by protein O-GlcNAcylation-we generated mice with PTECs deficient in O-GlcNAc transferase (Ogt). We analyzed their renal phenotypes during ad libitum feeding, after prolonged fasting, and after mice were fed a high-fat diet for 16 weeks to induce obesity and diabetes. RESULTS: Although PTEC-specific Ogt-deficient mice lacked a marked renal phenotype during ad libitum feeding, after fasting 48 hours, they developed Fanconi syndrome-like abnormalities, PTEC apoptosis, and lower rates of renal lipolysis and ATP production. Proteomic analysis suggested that farnesoid X receptor-dependent upregulation of carboxylesterase-1 is involved in O-GlcNAcylation's regulation of lipolysis in fasted PTECs. PTEC-specific Ogt-deficient mice with diabetes induced by a high-fat diet developed severe tubular cell damage and enhanced lipotoxicity. CONCLUSIONS: Protein O-GlcNAcylation is essential for renal lipolysis during prolonged fasting and offers PTECs significant protection against lipotoxicity in diabetes.

Microbiome potentiates endurance exercise through intestinal acetate production.

The intestinal microbiome produces short-chain fatty acids (SCFAs) from dietary fiber and has specific effects on other organs. During endurance exercise, fatty acids, glucose, and amino acids are major energy substrates. However, little is known about the role of SCFAs during exercise. To investigate this, mice were administered either multiple antibiotics or a low microbiome-accessible carbohydrate (LMC) diet, before endurance testing on a treadmill. Two-week antibiotic treatment significantly reduced endurance capacity versus the untreated group. In the cecum acetate, propionate, and butyrate became almost undetectable in the antibiotic-treated group, plasma SCFA concentrations were lower, and the microbiome was disrupted. Similarly, 6-wk LMC treatment significantly reduced exercise capacity, and fecal and plasma SCFA concentrations. Continuous acetate but not saline infusion in antibiotic-treated mice restored their exercise capacity (P < 0.05), suggesting that plasma acetate may be an important energy substrate during endurance exercise. In addition, running time was significantly improved in LMC-fed mice by fecal microbiome transplantation from others fed a high microbiome-accessible carbohydrate diet and administered a single portion of fermentable fiber (P < 0.05). In conclusion, the microbiome can contribute to endurance exercise by producing SCFAs. Our findings provide new insight into the effects of the microbiome on systemic metabolism.