Trk-fused gene plays a critical role in diet-induced adipose tissue expansion and is also involved in thyroid hormone action.

Mutations in the Trk-fused gene (TFG) cause hereditary motor and sensory neuropathy with proximal dominant involvement, which reportedly has high co-incidences with diabetes and dyslipidemia, suggesting critical roles of the TFG in metabolism as well. We found that TFG expression levels in white adipose tissues (WATs) were elevated in both genetically and diet-induced obese mice and that TFG deletion in preadipocytes from the stromal vascular fraction (SVF) markedly inhibited adipogenesis. To investigate its role in vivo, we generated tamoxifen-inducible adipocyte-specific TFG knockout (AiTFG KO) mice. While a marked down-regulation of the peroxisome proliferator-activated receptor gamma target, de novo lipogenesis (DNL), and mitochondria-related gene expressions were observed in subcutaneous WAT (scWAT) from AiTFG KO mice, these effects were blunted in SVF-derived adipocytes when the TFG was deleted after differentiation into adipocytes, implying cell nonautonomous effects. Intriguingly, expressions of thyroid hormone receptors, as well as carbohydrate responsive element-binding protein ß, which mediates the metabolic actions of thyroid hormone, were drastically down-regulated in scWAT from AiTFG KO mice. Reduced DNL and thermogenic gene expressions in AiTFG KO mice might be attributable to impaired thyroid hormone action in vivo. Finally, when adipocyte TFG was deleted in either the early or the late phase of high-fat diet feeding, the former brought about an impaired expansion of epididymal WAT, whereas the latter caused prominent adipocyte cell death. TFG deletion in adipocytes markedly exacerbated hepatic steatosis in both experimental settings. Collectively, these observations indicate that the TFG plays essential roles in maintaining normal adipocyte functions, including an enlargement of adipose tissue, thyroid hormone function, and thermogenic gene expressions, and in preserving hypertrophic adipocytes.

Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer Cells.

Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation.

Hepatic Pin1 Expression, Particularly in Nuclei, Is Increased in NASH Patients in Accordance with Evidence of the Role of Pin1 in Lipid Accumulation Shown in Hepatoma Cell Lines.

Our previous studies using rodent models have suggested an essential role for Pin1 in the pathogenesis of non-alcoholic steatohepatitis (NASH). In addition, interestingly, serum Pin1 elevation has been reported in NASH patients. However, no studies have as yet examined the Pin1 expression level in human NASH livers. To clarify this issue, we investigated the expression level and subcellular distribution of Pin1 in liver specimens obtained using needle-biopsy samples from patients with NASH and healthy liver donors. Immunostaining using anti-Pin1 antibody revealed the Pin1 expression level to be significantly higher, particularly in nuclei, in the livers of NASH patients than those of healthy donors. In the samples from patients with NASH, the amount of nuclear Pin1 was revealed to be negatively related to serum alanine aminotransferase (ALT), while tendencies to be associated with other serum parameters such as aspartate aminotransferase (AST) and platelet number were noted but did not reach statistical significance. Such unclear results and the lack of a significant relationship might well be attributable to our small number of NASH liver samples (n = 8). Moreover, in vitro, it was shown that addition of free fatty acids to medium induced lipid accumulation in human hepatoma HepG2 and Huh7 cells, accompanied with marked increases in nuclear Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), in accordance with the aforementioned observations in human NASH livers. In contrast, suppression of Pin1 gene expression using siRNAs attenuated the free fatty acid-induced lipid accumulation in Huh7 cells. Taken together, these observations strongly suggest that increased expression of Pin1, particularly in hepatic nuclei, contributes to the pathogenesis of NASH with lipid accumulation.

Association of Glycated Hemoglobin Level with Self-Reported Chewing Problems in Elderly Community-Dwelling Individuals in Japan.

Purpose: Chewing problems are associated with increased mortality, geriatric syndromes and poor activities of daily living. Starting in 2018, in Japan, a self-reported questionnaire investigating chewing status was implemented in the annual health checkup program. Considering the bidirectional association between hyperglycemia and poor oral health, it is hypothesized that people with self-reported chewing problems will have relatively poor glycemic profiles. We investigated the metabolic characteristics of elderly community dwellers with self-reported chewing problems, as well as the association between the problems and HbA1c levels. Patients and Methods: This was a retrospective, cross-sectional study. We reviewed the data of 1018 adults ≥ 65 years of age who had undergone an annual health checkup at Nihon University Hospital during the period from January 2019 through December 2019. The presence of chewing problems was investigated using a self-reported questionnaire constructed based on guidance provided by the Japanese government. Results: In the 1018 participants, the overall prevalence of chewing problems was 10.4%. Participants with chewing problems showed significantly higher levels and worse categories of HbA1c than those without such problems (HbA1c < 6.0%, 42.5% vs 54.8%; HbA1c 6.0-6.9%, 41.5% vs 37.0%; HbA1c ≥ 7.0%, 16.0% vs 8.2%, p = 0.008). Participants with HbA1c ≥ 7.0% have a significantly increased risk of chewing problems as compared to those with HbA1c < 6.0% (odds ratio 2.76, p = 0.002), even after adjusting for the effects of age, sex, body mass index, eating behaviors, and history of diabetes mellitus. Conclusion: HbA1c ≥ 7.0% is associated with self-reported chewing problems in elderly Japanese community-dwellers. We thus recommend a proactive assessment of oral conditions for this population.

A large-scale functional analysis of genes expressed differentially in insulin secreting MIN6 sublines with high versus mildly reduced glucose-responsiveness.

Molecular mechanisms of glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells are not fully understood. GSIS deteriorations are believed to underlie the pathogenesis of type 2 diabetes mellitus. By comparing transcript levels of 3 insulin secreting MIN6 cell sublines with strong glucose-responsiveness and 3 with mildly reduced responsiveness, we identified 630 differentially expressed genes. Using our recently developed system based on recombinase-mediated cassette exchange, we conducted large-scale generation of stable clones overexpressing such genes in the doxycycline-regulated manner. We found that overexpressions of 18, out of 83, genes altered GSIS. Sox11 ((sex determining region Y)-box 11) was selected to confirm its roles in regulating insulin secretion, and the gene was subjected to shRNA-mediated suppression. While Sox11 overexpression decreased GSIS, its suppression increased GSIS, confirming the role of Sox11 as a negative regulator of insulin secretion. Furthermore, metabolic experiments using radiolabelled glucose showed Sox11 to participate in regulating glucose metabolism. Our data suggested that overexpression screening is a feasible option for systemic functional testing to identify important genes in GSIS.

Two Patients with Spontaneous Spinal Epidural Hematoma Carrying a Good Prognosis without Surgical Operations.

(1) Introduction: Spontaneous spinal epidural hematoma (SSEH) points to hematoma within the epidural space of the spinal cord without traumatic or iatrogenic causes. (2) Case Reports: One patient showed paraplegia, numbness of both legs with acute onset, acute myelopathic signs, subsequent to back pain. Magnetic resonance imaging (MRI) showed hematoma in the posterior part of the thoracic spinal cord. Another patient showed acute numbness in the shoulder, upper part of the back, and the upper extremity on the right side after pain in the back, shoulder, and neck on the right side. Sagittal computed tomography (CT) images of the cervical bone showed a high-density area behind the spinal cord between C4 and C7. MRI analysis showed hematoma in the right diagonally posterior part of the cervical spinal cord. These 2 patients lacked traumatic or iatrogenic events, and their symptoms abated without surgical operation. (3) Conclusions: The location of hematoma correlated with symptoms in each patient. SSEH is rare but should be taken into account in patients with myelopathy or radiculopathy with acute onset subsequent to back pain. The usefulness of emergent CT scans of the spinal cord prior to MRI analysis was shown in the diagnosis of SSEH.

Involvement of neuronal and muscular Trk-fused gene (TFG) defects in the development of neurodegenerative diseases.

Trk-fused gene (TFG) mutations have been identified in patients with several neurodegenerative diseases. In this study, we attempted to clarify the effects of TFG deletions in motor neurons and in muscle fibers, using tissue-specific TFG knockout (vMNTFG KO and MUSTFG KO) mice. vMNTFG KO, generated by crossing TFG floxed with VAChT-Cre, showed deterioration of motor function and muscle atrophy especially in slow-twitch soleus muscle, in line with the predominant Cre expression in slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons. Consistently, denervation of the neuromuscular junction (NMJ) was apparent in the soleus, but not in the extensor digitorum longus, muscle. Muscle TFG expressions were significantly downregulated in vMNTFG KO, presumably due to decreased muscle IGF-1 concentrations. However, interestingly, MUSTFG KO mice showed no apparent impairment of muscle movements, though a denervation marker, AChRγ, was elevated and Agrin-induced AChR clustering in C2C12 myotubes was inhibited. Our results clarify that loss of motor neuron TFG is sufficient for the occurrence of NMJ degeneration and muscle atrophy, though lack of muscle TFG may exert an additional effect. Reduced muscle TFG, also observed in aged mice, might be involved in age-related NMJ degeneration, and this issue merits further study.

Impact of Female Sex on the Susceptibility to Hypernatremia Among Older Community-Dwelling Individuals in Japan.

PURPOSE: Older individuals are at high risk for hypernatremia. However, actual data on serum sodium levels and differences between the sexes remain unclear in the older Japanese population. This study aimed to describe the data regarding serum sodium level and hypernatremia prevalence and to investigate whether female sex is associated with an increased risk of hypernatremia. PATIENTS AND METHODS: We retrospectively analyzed the data of adults aged ≥65 years without severely reduced kidney function who underwent an annual health checkup in 2019. Serum sodium levels were investigated as the outcome and corrected for glucose, if necessary. Clinical characteristics were compared between women and men. RESULTS: In the 903 participants consisting of 273 women and 630 men who were enrolled in this study, the overall prevalence of hypernatremia, defined as a serum sodium level ≥145 mmol/L, was 12.5%. Female participants showed significantly more frequent hypernatremia than male participants (17.6% vs 10.3%, p = 0.003) and higher serum sodium levels (median [interquartile range]; 143.0 [142.0, 144.0] vs 142.4 [141.5, 144.0], p <0.001). Serum creatinine (sCr), but not estimated glomerular filtration rate (eGFR), was correlated with serum sodium levels (rs = -0.108, p = 0.001). In the binary logistic regression analysis, female sex was significantly associated with hypernatremia (odds ratio, 1.89; 95% confidence interval, 1.23-2.89; p = 0.004) even after adjusting for age, alcohol use, antihypertensive agent use, body mass index, and winter season. The association between female sex was reduced and no longer significant after adjusting for sCr, although the association remained unchanged after adjustment for eGFR. CONCLUSION: One-eighth of the older community dwellers in Japan exhibits hypernatremia after an overnight fast, and female sex is a significant risk factor. Since sCr is a surrogate of muscle mass, smaller muscle mass possibly mediates the association between female sex and hypernatremia.

Clinical Study of Cerebral Ischemia in Moyamoya Disease from the View of Development of the Anterior Choroidal Artery.

OBJECTIVES: The anterior choroidal artery (AchA) is one of the collateral vessels in moyamoya disease (MMD). The incidence of cerebral ischemia in MMD was analyzed through the association between development of the AchA and advancement of MMD stage. MATERIALS AND METHODS: Twelve patients of MMD with cerebral ischemia (infarction; 9 patients, transient ischemic attack; 3 patients) were enrolled. Advancement of MMD was evaluated using Suzuki's stage. The grades in Suzuki's stage were subclassified into a non-progressive stage for grades 1 and 2, and a progressive stage for grades 4 and 5. Dilatation of the AchA was judged as the presence of development of this artery. Development of the AchA was grouped into proximal type and proximal and distal type. RESULTS: Most frequent locations of infarcts were the anterior and parietal lobes in 6 patients each. Development of the AchA was confirmed on the ischemic side in all patients and on the non-ischemic side in 9 patients. Development of the AchA in the progressive stage was limited in the proximal and distal type on both sides. Development of the AchA in the non-progressive stage was the proximal type on the ischemic side. CONCLUSIONS: The cause of cerebral ischemia was possibly associated with inadequate blood supply of the AchA in the non-progressive stage, and the lower blood flow from the internal carotid artery (ICA) in the progressive stage. Disparity between collateral blood flow from the AchA and the blood flow from the ICA was considered to relate to incidence of cerebral ischemia in MMD.

Impact of Plasma Xanthine Oxidoreductase Activity on the Mechanisms of Distal Symmetric Polyneuropathy Development in Patients with Type 2 Diabetes.

To unravel associations between plasma xanthine oxidoreductase (XOR) and diabetic vascular complications, especially distal symmetric polyneuropathy (DSP), we investigated plasma XOR activities using a novel assay. Patients with type 2 diabetes mellitus (T2DM) with available nerve conduction study (NCS) data were analyzed. None were currently taking XOR inhibitors. XOR activity of fasting blood samples was assayed using a stable isotope-labeled substrate and LC-TQMS. JMP Clinical version 5.0. was used for analysis. We analyzed 54 patients. Mean age was 64.7 years, mean body mass index was 26.0 kg/m2, and mean glycated hemoglobin was 9.4%. The logarithmically transformed plasma XOR activity (ln-XOR) correlated positively with hypoxanthine, xanthine, visceral fatty area, and liver dysfunction but negatively with HDL cholesterol. ln-XOR correlated negatively with diabetes duration and maximum intima-media thickness. Stepwise multiple regression analysis revealed ln-XOR to be among selected explanatory factors for various NCS parameters. Receiver operating characteristic curves showed the discriminatory power of ln-XOR. Principal component analysis revealed a negative relationship of ln-XOR with F-waves as well as positive relationships of ln-XOR with hepatic steatosis and obesity-related disorders. Taken together, our results show plasma XOR activity to be among potential disease status predictors in T2DM patients. Plasma XOR activity measurements might reliably detect pre-symptomatic DSP.

Pathological Role of Pin1 in the Development of DSS-Induced Colitis.

Inflammatory bowel diseases (IBDs) are serious disorders of which the etiologies are not, as yet, fully understood. In this study, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) protein was shown to be dramatically upregulated in the colons of dextran sodium sulfate (DSS)-induced ulcerative colitis model mice. Interestingly, Pin1 knockout (KO) mice exhibited significant attenuation of DSS-induced colitis compared to wild-type (WT) mice, based on various parameters, including body weight, colon length, microscopic observation of the intestinal mucosa, inflammatory cytokine expression, and cleaved caspase-3. In addition, a role of Pin1 in inflammation was suggested because the percentage of M1-type macrophages in the colon was decreased in the Pin1 KO mice while that of M2-type macrophages was increased. Moreover, Pin1 KO mice showed downregulation of both Il17 and Il23a expression in the colon, both of which have been implicated in the development of colitis. Finally, oral administration of Pin1 inhibitor partially but significantly prevented DSS-induced colitis in mice, raising the possibility of Pin1 inhibitors serving as therapeutic agents for IBD.

Tuberculosis Relapse in the Epididymis After the Completion of Nine Months of Anti-Tuberculosis Chemotherapy in a Patient with Poorly Controlled Diabetes Mellitus.

The standard six-month tuberculosis (TB) treatment comprises an intensive phase lasting two months, followed by a continuation phase lasting four months. Meanwhile, the nine-month regimen, which has a prolonged continuation phase, is indicated for patients with complicated diabetes mellitus (DM) because of their poor response to treatment. A 61-year-old Japanese man with poorly controlled DM for five years presented with bilateral scrotal swelling noticed two weeks ago. He had a history of pleuritis, pericarditis, and peritonitis two years ago. These symptoms led to the diagnosis of culture-negative extrapulmonary TB. He received the nine-month chemotherapy regimen (isoniazid, rifampin, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for seven months), and his symptoms significantly improved. The swollen scrotum was accompanied by mild tenderness and pus discharge from a fistula. Imaging study revealed bilaterally diffusely enlarged epididymis. However, the acid-fast bacilli smear and culture and polymerase chain reaction using urine and pus discharge tested negative. Bilateral epididymectomy was performed. Although the acid-fast bacilli smear was negative, the pathology demonstrated granuloma formation and acid-fast bacilli tissue culture confirmed multi-drug resistant Mycobacterium tuberculosis. The optimal treatment regimen and duration for extrapulmonary TB with unknown drug susceptibility are debatable. The nine-month regimen can be insufficient in some cases. Thus, detailed follow-up is essential, and TB relapse should be thoroughly monitored.

Carnosic Acid and Carnosol Activate AMPK, Suppress Expressions of Gluconeogenic and Lipogenic Genes, and Inhibit Proliferation of HepG2 Cells.

Carnosic acid (CA), carnosol (CL) and rosmarinic acid (RA), components of the herb rosemary, reportedly exert favorable metabolic actions. This study showed that both CA and CL, but not RA, induce significant phosphorylation of AMP-dependent kinase (AMPK) and its downstream acetyl-CoA carboxylase 1 (ACC1) in HepG2 hepatoma cells. Glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1), rate-limiting enzymes of hepatic gluconeogenesis, are upregulated by forskolin stimulation, and this upregulation was suppressed when incubated with CA or CL. Similarly, a forskolin-induced increase in CRE transcriptional activity involved in G6PC and PCK1 regulations was also stymied when incubated with CA or CL. In addition, mRNA levels of ACC1, fatty acid synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP-1c) were significantly reduced when incubated with CA or CL. Finally, it was shown that CA and CL suppressed cell proliferation and reduced cell viability, possibly as a result of AMPK activation. These findings raise the possibility that CA and CL exert a protective effect against diabetes and fatty liver disease, as well as subsequent cases of hepatoma.

Prolyl isomerase Pin1 interacts with adipose triglyceride lipase and negatively controls both its expression and lipolysis.

BACKGROUND: Lipolysis is essential for the supply of nutrients during fasting, the control of body weight, and remodeling of white adipose tissues and thermogenesis. In the obese state, lipolysis activity and the expression of adipose triglyceride lipase (ATGL), a rate-limiting enzyme, is suppressed. However, the mechanism underlying the regulation of ATGL remains largely unknown. We previously reported that a high-fat diet obviously increases protein levels of the prolyl isomerase, Pin1, in epididymal white adipose tissue (epiWAT) of mice and that Pin1 KO mice are resistant to developing obesity. RESULTS: The present study found that deletion of the Pin1 gene in epiWAT upregulated lipolysis and increased ATGL protein expression by ~2-fold. In addition, it was demonstrated that Pin1 directly associated with ATGL and enhanced its degradation through the ubiquitin proteasome system. Indeed, Pin1 overexpression decreased ATGL expression levels, whereas Pin1 knockdown by siRNA treatment upregulated ATGL protein levels without altering mRNA levels. Moreover, under a high fat diet (HFD)-fed condition, adipocyte-specific Pin1 KO (adipoPin1 KO) mice had 2-fold increase lipolytic activity and upregulated ß-oxidation-related gene expressions. These mice also gained less body weight, and had better glucose metabolism according to the results of glucose and insulin tolerance tests. CONCLUSION: Taken together, these results showed that Pin1 directly interacted with and degraded ATGL via a ubiquitin-proteasome system, consequently causing the downregulation of lipolysis. Therefore, Pin1 could be considered a target for the treatment of dyslipidemia and related disorders.

Effect of Adult Weight Gain on Non-Alcoholic Fatty Liver Disease and Its Association with Anthropometric Parameters in the Lean Japanese Population.

Limited data are available on the prevalence of non-alcoholic fatty liver disease (NAFLD) and its association with adult weight gain (AWG) in the lean population. This study aimed to determine the prevalence of NAFLD and to investigate whether AWG is associated with NAFLD in the lean Japanese population. We retrospectively analyzed patients who underwent abdominal ultrasonography as part of the annual health checkup between January 2019 and December 2019. Participants were classified into two groups: those with AWG ≥ 10 kg (AWG group, n = 497), and those without gain (non-AWG group, n = 3006). To adjust for the confounding effects, we generated 482 pairs using 1:1 propensity score matching. The associations between AWG and NAFLD, anthropometric parameters and NAFLD were investigated using univariate logistic regression analysis. We identified NAFLD in 197 (5.6%) participants. AWG was significantly associated with NAFLD (odds ratio (OR), 1.81; p = 0.003). Waist circumference was significantly associated with NAFLD in both the AWG (OR, 1.24; p < 0.001) and non-AWG groups (OR, 1.17; p < 0.001). The association between body mass index and NAFLD existed in the former group (OR, 1.76; p < 0.001), but was not significant in the latter group. AWG is a risk factor for NAFLD even in the lean Japanese population, and associations between anthropometric parameters and NAFLD become stronger if AWG coexists.

Seasonal variation in hydration status among community-dwelling elderly in Japan.

AIM: While the heat during the summer season may dehydrate the elderly, little is known about the seasonal variation in dehydration. This study aimed to investigate the seasonal variation in hydration status among the community-dwelling elderly in Japan. METHODS: We retrospectively analyzed the data collected after an overnight fast of adults aged ≥65 years who had no advanced kidney disease and underwent an annual health checkup at Nihon University Hospital between January and December 2019. Participants were classified according to their checkup date, whether summer (n = 265) or not summer (n = 638). The not summer group was subdivided into spring (n = 235), autumn (n = 213) and winter (n = 190). RESULTS: Among the four seasons, the spring group showed the highest levels of plasma osmolality (306.1 ± 3.9 mOsm/L), urine specific gravity (1.0172 ± 0.0058) and prevalence rates of urine specific gravity ≥1.020 (34.0%). However, seasonal differences were clinically mild, and >90% of participants showed plasma osmolality ≥300 mOsm/L, indicating dehydration, in all four seasons. The summer group showed lower urine specific gravity levels (1.0150 ± 0.0062 vs. 1.0165 ± 0.0064, P < 0.001) and prevalence rates of urine specific gravity ≥1.020 (22.6% vs. 30.4%, P = 0.023) than did the not summer group. The summer season was associated with low urine specific gravity levels even after adjusting for the multiple linear regression model. CONCLUSION: Japanese elderly after overnight fast are more dehydrated during the spring rather than the summer. Geriatr Gerontol Int 2020; 20: 904-910.

A case of prosopometamorphopsia caused by infarction of the splenium of the corpus callosum and major forceps.

An adult female complained of enlargement of right eyes in other people. Diffusion-weighted imaging detected an abnormal high-intensity area in the region from the splenium of the corpus callosum to the major forceps on the right side. The patient reported that right eyes appeared larger in size, which suggested prosopometamorphopsia. Adichotic listening test identified left-ear deficit. Acombination of prosopometamorphopsia and left-ear deficit was not identified in the reported patients. Prosopometamorphopsia in most of the reported patients included the eye as did that in our patient. This result suggested the importance of information on the eye in recognizing faces.

Inverse Correlation Between Grip Strength and Serum Phosphorus: A Retrospective Observational Study in Japanese Elderly with Poorly Controlled Type 2 Diabetes.

The aim of this study was to investigate factors associated with sarcopenia among elderly patients with poorly controlled diabetes mellitus (DM). We retrospectively analyzed 41 patients with type 2 DM, aged ≥65 years who required diabetes education hospitalization. Patients were classified into two groups according to the presence or absence of a weakened hand grip, and clinical characteristics were compared. Patients with a weakened hand grip (n = 21) scored worse on a mini-mental state examination (24.3 vs. 26.5, p = 0.04), showed a higher prevalence of diabetic peripheral neuropathy (76% vs. 40%, p = 0.03), and had a higher serum phosphorus concentration (3.8 vs. 3.3 mg/dL, p < 0.01) compared to those without a weakened hand grip (n = 20). The serum phosphorus concentration was inversely correlated to hand grip strength (r = -0.501, p < 0.001) among the total of 41 patients. This inverse association was also confirmed after adjusting the effects of estimated glomerular filtration rate, age, and glycated hemoglobin. Thus, cognitive impairment, diabetic peripheral neuropathy, and high serum phosphorus concentrations are associated with hand grip weakness in elderly patients with type 2 DM.

Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB).

Metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i) is the most common therapy for Japanese patients with type 2 diabetes. This 24-week, multicentre, open-label, parallel-group trial randomized patients on dual therapy to add-on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31). The primary outcome was change in body fat percentage. The secondary outcomes included changes in HbA1c, fat mass, fat-free mass, liver function variables and uric acid. Tofogliflozin and glimepiride reduced HbA1c to a similar extent. Body fat percentage did not change from baseline in either group. Fat mass was reduced by tofogliflozin but was increased by glimepiride (by -2.0 ± 1.7 kg and +1.6 ± 1.6 kg, P = .002). Fat-free mass was also reduced by tofogliflozin and increased by glimepiride (by -1.3 ± 1.3 kg and +0.9 ± 2.0 kg, P < .001). Alanine aminotransferase and uric acid levels were reduced by tofogliflozin (P = .006 and P < .001, respectively). These data provide novel information useful for selecting the third oral agent for patients whose diabetes is inadequately controlled with metformin plus DPP-4i dual therapy.

Hyponatremia Associated with Prophylactic Low-Dose Trimethoprim during Systemic Corticosteroid Therapy for AQP4-Positive Optic Neuritis in a Diabetic Patient.

Hyponatremia associated with low-dose trimethoprim in patients on concomitant systemic corticosteroid therapy has rarely been reported. Here, we describe a 57-year-old woman with a history of diabetes mellitus and hypertension treated with telmisartan, who presented with progressive visual impairment of the left eye due to anti-aquaporin-4 antibody-positive optic neuritis. The patient received pulsed intravenous methylprednisolone followed by oral prednisolone at 30 mg/day and trimethoprim-sulfamethoxazole prophylaxis (160 mg and 800 mg daily). Her serum sodium level steadily decreased, and the potassium level was slightly elevated despite well-preserved renal function. This state persisted even after telmisartan discontinuation. In addition to hypotonic hyponatremia (125 mEq/L) with natriuresis, hyperkalemic renal tubular acidosis was diagnosed based on normal anion gap metabolic acidosis and hyperkalemia with low urinary potassium excretion. After trimethoprim-sulfamethoxazole cessation, electrolytes and acid-base imbalances swiftly recovered. We can conclude that caution must be exercised when treating such patients, because even low-dose trimethoprim may cause hyponatremia concomitant with hyperkalemic renal tubular acidosis, despite the mineralocorticoid effects of systemic corticosteroids.