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.

Therapy Combining Glucagon-Like Peptide-1 Receptor Agonist with Sodium-Glucose Cotransporter 2 Inhibitor Suppresses Atherosclerosis in Diabetic ApoE-Deficient Mice.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have beneficial effects on cardiovascular disease in addition to their glucose-lowering effects. In this study, the effects of these drugs, when used individually or in combination, on cardiovascular atherosclerotic lesion development were compared in diabetic ApoE-deficient (ApoE KO) hyperlipidemic mice. METHODS: ApoE-KO mice were treated with streptozotocin and nicotinamide, generating a type 2 diabetes model. The mice were randomly divided into four groups: vehicle-treated (untreated), liraglutide (LIRA), ipragliflozin (IPRA), and combination therapy (combo). These mice, as well as non-diabetic controls, were fed a high-fat diet. After 8 weeks of drug administration, the heart and aorta were removed and analyzed. RESULTS: Atherosclerotic lesions evaluated by oil red O (ORO) staining were significantly larger in the untreated group (13.4±0.8% of the total aortic area) than in the non-diabetic controls (4.4±0.5%, p<0.01), while being reduced in the combo group (6.0±1.0%, p<0.01) as compared with the untreated group. The ORO stain-positive area in the LIRA and IPRA groups tended to be reduced but their differences were not statistically significant. Transcript levels of Mcp1 and Sirt1 were significantly reduced and increased, respectively, in the combo compared with the untreated group, while no significant changes were observed in the monotherapy groups. CONCLUSIONS: The data suggest that combination therapy with liraglutide and ipragliflozin may be an efficient regimen for preventing the development of atherosclerosis in diabetic mice deficient in ApoE.

Efficacy and Safety of Switching from Sitagliptin to Ipragliflozin in Obese Japanese Patients with Type 2 Diabetes Mellitus: A Single-Arm Multicenter Interventional Study.

BACKGROUND: Dipeptidyl peptidase-4 inhibitors have limited efficacy in improving glycemic control for obese Japanese patients with type 2 diabetes mellitus. Sodium-glucose co-transporter 2 inhibitors are recommended for use in patients with type 2 diabetes with obesity. Nevertheless, there has been no previously published study on the effect of switching from dipeptidyl peptidase-4 inhibitors to sodium-glucose co-transporter 2 inhibitors on the systemic and organic effects in obese Japanese patients with type 2 diabetes. OBJECTIVES: We evaluated the efficacy and safety of switching from sitagliptin to ipragliflozin for 24 weeks in obese Japanese patients with inadequately controlled type 2 diabetes. METHODS: Fifty-one obese patients with type 2 diabetes (body mass index > 25 kg/m2) treated with sitagliptin (50 mg) and metformin but with inadequate glycemic control (glycosylated hemoglobin [HbA1c] > 7.5% and < 9.0%) were enrolled. After a 4-week observation period, sitagliptin was switched to ipragliflozin (50 mg) for 24 weeks. The primary outcome was the change in HbA1c from baseline to the end of treatment. The secondary outcomes were changes in clinical characteristics and other biochemical variables. RESULTS: Fifty-one patients with an average HbA1c of 8.37 ± 0.48% and body mass index of 28.8 ± 3.8 kg/m2 were enrolled. Fifty patients completed the study, one patient stopped ipragliflozin at 4 weeks because of the development of hyperosmolar hyperglycemic syndrome. No significant change in HbA1c from baseline to the end of treatment was observed (- 0.02 ± 0.75%). However, fasting plasma glucose was reduced (- 16.2 ± 28.4 mg/dL, p < 0.001), and biochemical variables associated with insulin resistance, oxidative stress, and hepatic and renal functions showed significant improvements. No severe adverse effects were observed, except in the one aforementioned case. CONCLUSIONS: Switching from sitagliptin to ipragliflozin did not alter HbA1c in obese patients with type 2 diabetes, while improving parameters related to organ homeostasis. These data provide novel information useful for selecting oral anti-diabetic agents for patients with type 2 diabetes with obesity, a risk factor for developing various complications of diabetes. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT#031190022.

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.

Identification of serum metabolome signatures associated with retinal and renal complications of type 2 diabetes.

BACKGROUND: Type 2 diabetes is a common disease around the world and its major complications are diabetic retinopathy (DR) and diabetic kidney disease (DKD). Persons with type 2 diabetes with complications, especially who have both DR and DKD, have poorer prognoses than those without complications. Therefore, prevention and early identification of the complications of type 2 diabetes are necessary to improve the prognosis of persons with type 2 diabetes. The aim of this study is to identify factors associated with the development of multiple complications of type 2 diabetes. METHODS: We profiled serum metabolites of persons with type 2 diabetes with both DR and DKD (N = 141) and without complications (N = 159) using a comprehensive non-targeted metabolomics approach with mass spectrometry. Based on the serum metabolite profiles, case-control comparisons and metabolite set enrichment analysis (MSEA) were performed. RESULTS: Here we show that five metabolites (cyclohexylamine, P = 4.5 × 10-6; 1,2-distearoyl-glycero-3-phosphocholine, P = 7.3 × 10-6; piperidine, P = 4.8 × 10-4; N-acetylneuraminic acid, P = 5.1 × 10-4; stearoyl ethanolamide, P = 6.8 × 10-4) are significantly increased in those with the complications. MSEA identifies fatty acid biosynthesis as the type 2 diabetes complications-associated biological pathway (P = 0.0020). CONCLUSIONS: Our metabolome analysis identifies the serum metabolite features of the persons with type 2 diabetes with multiple complications, which could potentially be used as biomarkers.

In the management of type 2 diabetes, prevention and early identification of diabetes complications are important. In particular, people with type 2 diabetes with diabetic retinopathy (DR), affecting the eye, and diabetic kidney disease (DKD), have poorer outcomes than those without complications and need early intervention. Here, we comprehensively profiled blood metabolites, or breakdown products of the biological processes occurring in the body, of people with type 2 diabetes with both DR and DKD and those without complications. We found that five metabolites were significantly increased in those with complications, and we identified a specific metabolic pathway associated with having complications. Our analysis identified the blood metabolite features of people with type 2 diabetes with multiple complications, which could potentially be used as markers in the future.

Fibrosis-4 Index Is Closely Associated with Arterial Damage and Future Risk of Coronary Heart Disease in Type 2 Diabetes.

This study evaluated the association between fibrosis-4 (FIB 4) index and arterial damage or future risk of coronary heart disease (CHD) in type 2 diabetes. The study subjects were 253 patients with type 2 diabetes. The FIB4 index, as a marker of hepatic fibrosis based on age, aspartate aminotransferase and alanine aminotransferase levels, and platelet count, was calculated for all subjects. Carotid intima-media thickness (IMT), carotid artery calcification (CAC), and aortic arch calcification (AAC) grade (0-2) were assessed as atherosclerotic variables. The Suita score was calculated as the future risk of coronary heart disease (CHD). We assessed whether the FIB4 index was associated with both atherosclerotic variables and the Suita score. FIB4 index was significantly associated with IMT (r = 0.241, P < 0.001) and Suita score (r = 0.291, P < 0.001). Subjects with CAC showed a significantly higher FIB4 index score compared to subjects without (1.70 ± 0.74 and 1.24 ± 0.69, respectively, P < 0.001), whereas the FIB4 index was significantly elevated with a higher grade of AAC (1.24 ± 0.74, 1.56 ± 0.66, and 1.79 ± 0.71, respectively, P < 0.001). Linear regression analysis adjusted for clinical characteristics indicated that the FIB4 index was positively associated with IMT, Suita score, CAC, and AAC grade (ß = 0.241, P=0.004; ß = 2.994, P < 0.001; ß = 0.139, P=0.001; and ß = 0.265, P < 0.001, respectively). FIB4 index is closely associated with arterial damage and future risk of CHD in type 2 diabetes.

Cardio-ankle vascular index is more closely associated than brachial-ankle pulse wave velocity with arterial damage and risk of cardiovascular disease in patients with diabetes.

BACKGROUND: This study aimed to compare the usefulness of arterial stiffness parameters, cardio-ankle vascular index (CAVI) and brachial-ankle pulse wave velocity (baPWV), for evaluating arterial damage and risk of cardiovascular disease (CVD) in subjects with diabetes. METHODS: The study subjects were 277 patients with type 1 or type 2 diabetes. All subjects were evaluated for vascular stiffness using CAVI (n = 154) or baPWV (n = 123). Carotid intima-media thickness (IMT) and the Suita score were also measured because these are established risk factors for future CVD. Associations of both CAVI and baPWV with these established parameters were evaluated in all subjects, and then in 174 subjects with adjustment for covariates by using propensity score matching. RESULTS: In all subjects, CAVI and baPWV correlated significantly with both IMT (r = 0.462, P < 0.001, and r = 0.212, P = 0.019, respectively) and the Suita score (r = 0.573, P < 0.001, and r = 0.373, P < 0.001, respectively). The correlation between CAVI and IMT was more significant than that between baPWV and IMT (Z = 2.33, P = 0.020). Similarly, the correlation between CAVI and the Suita score was more significant than that between baPWV and the Suita score (Z = 2.13, P = 0.033). After adjustment by propensity score matching, significant correlations between CAVI and IMT (r = 0.432 P < 0.001) and between CAVI and the Suita score (r = 0.544, P < 0.001) were preserved, though only the association between baPWV and the Suita score was significant (r = 0.289, P = 0.007) while that between baPWV and IMT showed no significance. Again, CAVI showed a significant association with the Suita score than baPWV (Z = 2.02, P = 0.043). CONCLUSIONS: CAVI is more closely associated than baPWV with arterial damage and risk of CVD in patients with diabetes.

Metabolism-secretion coupling in glucose-stimulated insulin secretion.

Pancreatic ß-cells in the islets of Langerhans secrete insulin in response to blood glucose levels. Precise control of the amount of insulin secreted is of critical importance for maintaining systemic carbohydrate homeostasis. It is now well established that glucose induced production of ATP from ADP and the KATP channel closure elevate cytosolic Ca2+, triggering insulin exocytosis in ß-cells. However, for full activation of insulin secretion by glucose, other mechanisms besides Ca2+ elevation are needed. These mechanisms are the targets of current research and include intracellular metabolic pathways branching from glycolysis. They are metabolic pathways originating from the TCA cycle intermediates, the glycerolipid/free fatty acid cycle and the pentose phosphate pathway. Signaling effects of these pathways including degradation (removal) of protein SUMOylation, modulation of insulin vesicular energetics, and lipid modulation of exocytotic machinery may converge to fulfill insulin secretion, though the precise mechanisms have yet to be elucidated. This mini-review summarize recent advances in research on metabolic coupling mechanisms functioning in insulin secretion.

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.

Glucagon Response to Glucose Challenge in Patients with Idiopathic Postprandial Syndrome.

BACKGROUND: Postprandial syndrome is characterized by hunger, weakness, and anxiety neurosis after meals. Although abnormal glucagon response is a suggested mechanism, inaccuracies in conventional glucagon measurement methods have prevented precise analysis. Recently, a more reliable dual-antibody sandwich enzyme-linked immunosorbent assay for glucagon was developed. METHODS: We conducted a 75-g oral glucose tolerance test (OGTT) extending to 4 hours in 14 patients with idiopathic postprandial syndrome. In addition to blood glucose and insulin, glucagon concentration was measured with the novel method and analyzed retrospectively. RESULTS: Median (lower quartile, upper quartile) age and body-mass index were 40 years (30, 49) and 24.9 (23.1, 26.2), respectively. The OGTT revealed that one patient had a diabetic pattern, and two were glucose intolerant. Fasting insulin was 7.6 µU/mL (6.8, 8.8) and reached 73.7 µU/mL (54.3, 82.6) at 30 min. Insulin remained elevated until 180 min. Fasting glucagon was 21.1 pg/mL (16.1, 33.8), reached a nadir of 6.9 (3.5, 10.3) at 60 min, one-third the baseline level, and remained suppressed until 180 min. We observed two types of glucagon dynamics: a lower fasting glucagon with further suppression and a normal or higher fasting glucagon with a subsequent large decrease. CONCLUSIONS: These data suggest that glucagon suppression is greater in patients with idiopathic postprandial syndrome than in previously studied healthy subjects. The present data will contribute to our understanding and future research of this syndrome.

Aortic arch calcification with pericardial fat mass detected on a single chest X-ray image is closely associated with the predictive variables of future cardiovascular disease.

This study evaluated the associations between aortic arch calcification (AAC) with pericardial fat (PF) mass detected on a single chest X-ray image and predictive variables of future cardiovascular disease (CVD). The subjects were 353 patients treated with at least one of the hypertension, dyslipidemia or diabetes. All subjects were evaluated for AAC; divided into 3 groups with AAC grades of 0, 1, or 2; and examined for the presence of PF. Carotid intima-media thickness (IMT, n = 353), cardio-ankle vascular index (CAVI, n = 218), the Suita score (n = 353), and cardiovascular risk points defined in the Hisayama study (n = 353), an assessment of the risk of future cardiovascular disease, were measured. The relationship of AAC grades, with or without PF, and CVD risks was evaluated. The IMT (1.62 ± 0.74 mm, 2.33 ± 1.26, and 2.43 ± 0.89 in patients with AAC grade 0, 1 and 2, respectively, p < 0.001), CAVI (8.09 ± 1.32, 8.71 ± 1.32, and 9.37 ± 1.17, respectively, p < 0.001), the Suita score (46.6 ± 10.7, 51.8 ± 8.3, and 54.2 ± 8.2, respectively, p < 0.001), and cardiovascular risk points (8.5 ± 2.6, 10.6 ± 2.3, and 11.5 ± 2.3, respectively, p < 0.001) were significantly elevated with AAC progression. Multinomial logistic regression analysis adjusted for clinical characteristics showed that the relative risk ratios of the Suita score or cardiovascular risk points were elevated according to the progress of AAC grade with PF. Therefore, aortic arch calcification with pericardial mass detected on a single chest X-ray image is closely associated with the predictive variables of future CVD.

Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic ß-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.

Using recombinase-mediated cassette exchange to engineer MIN6 insulin-secreting cells based on a newly identified safe harbor locus.

AIMS/INTRODUCTION: Recent studies have identified genomic and transcript level changes along with alterations in insulin secretion in patients with diabetes and in rodent models of diabetes. It is important to establish an efficient system for testing functional consequences of these changes. We aimed to generate such a system using insulin-secreting MIN6 cells. MATERIALS AND METHODS: MIN6 cells were first engineered to have a tetracycline-regulated expression system. Then, we used the recombination-mediated cassette exchange strategy to explore the silencing-resistant site in the genome and generated a master cell line based on this site. RESULTS: We identified a site 10.5 kbps upstream from the Zxdb gene as a locus that allows homogenous transgene expression from a tetracycline responsible promoter. Placing the Flip/Frt-based platform on this locus using CRISPR/Cas9 technology generated modified MIN6 cells applicable to achieving cassette exchange on the genome. Using this cell line, we generated MIN6 subclones with over- or underexpression of glucokinase. By analyzing a mixed population of these cells, we obtained an initial estimate of effects on insulin secretion within 6 weeks. Furthermore, we generated six MIN6 cell sublines simultaneously harboring genes of inducible overexpression with unknown functions in insulin secretion, and found that Cited4 and Arhgef3 overexpressions increased and decreased insulin secretion, respectively. CONCLUSIONS: We engineered MIN6 cells, which can serve as a powerful tool for testing genetic alterations associated with diabetes, and studied the molecular mechanisms of insulin secretion.

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.

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.

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.

A rare case of fulminant type 1 diabetes mellitus accompanied by both acute pancreatitis and myocarditis - case report.

BACKGROUND: Fulminant type 1 diabetes mellitus (FT1D) is a newly established subtype of type 1 diabetes. Its etiology has not been fully elucidated. Several cases with FT1D have exhibited pancreatitis or myocarditis. CASE PRESENTATION: We report a 31-year-old Japanese woman who showed upper abdominal pain and was admitted to a local hospital. She was initially diagnosed with acute pancreatitis based on serum amylase elevation and swelling of the pancreas on computed tomography. Four days after admission, she developed diabetic ketoacidosis and was transferred to our hospital. Her symptoms and laboratory findings met the FT1D criteria. On the 3rd hospital day, electrocardiography (ECG) showed ST-segment elevation, and serum cardiac enzymes were markedly elevated. Because she exhibited late gadolinium enhancement in the apical wall on contrast-enhanced cardiac magnetic resonance imaging, she was diagnosed as acute myocarditis. Abnormal ECG findings and elevations of biomarkers associated with myocarditis showed improvement on the next day. CONCLUSIONS: This is the first case of FT1D accompanied by both pancreatitis and myocarditis and suggests that the pathophysiology of FT1D is related to the common etiology of acute pancreatitis and myocarditis.

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.

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.