Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ.

BACKGROUND: Imeglimin is a new anti-diabetic drug which promotes insulin secretion from pancreatic ß-cells and reduces insulin resistance in insulin target tissues. However, there have been no reports examining the possible anti-atherosclerotic effects of imeglimin. In this study, we investigated the possible anti-atherosclerotic effects of imeglimin using atherosclerosis model ApoE KO mice treated with streptozotocin (STZ). METHODS: ApoE KO mice were divided into three groups: the first group was a normoglycemic group without injecting STZ (non-DM group, n = 10). In the second group, mice were injected with STZ and treated with 0.5% carboxymethyl cellulose (CMC) (control group, n = 12). In the third group, mice were injected with STZ and treated with imeglimin (200 mg/kg, twice daily oral gavage, n = 12). We observed the mice in the three groups from 10 to 18 weeks of age. Plaque formation in aortic arch and expression levels of various vascular factors in abdominal aorta were evaluated for each group. RESULTS: Imeglimin showed favorable effects on the development of plaque formation in the aortic arch in STZ-induced hyperglycemic ApoE KO mice which was independent of glycemic and lipid control. Migration and proliferation of vascular smooth muscle cells and infiltration of macrophage were observed in atherosclerotic lesions in STZ-induced hyperglycemic ApoE KO mice, however, which were markedly reduced by imeglimin treatment. In addition, imeglimin reduced oxidative stress, inflammation and inflammasome in hyperglycemic ApoE KO mice. Expression levels of macrophage makers were also significantly reduced by imeglimin treatment. CONCLUSIONS: Imeglimin exerts favorable effects on the development of plaque formation and progression of atherosclerosis.

Dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor additively ameliorate hepatic steatosis through different mechanisms of action in high-fat diet-fed mice.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice. METHOD: C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated. RESULTS: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups. CONCLUSION: The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis.

C-peptide index at 2 h post-meal is a useful predictor of endogenous insulin secretory capacity and withdrawal from insulin therapy in subjects with type 2 diabetes.

AIMS: To evaluate the correlation between C-peptide index (CPI) at 2 h post-meal and endogenous insulin secretory capacity and to develop clinical models to predict the possibility of withdrawal from insulin therapy in patients with type 2 diabetes. METHOD: This was a single-centre retrospective study of patients with type 2 diabetes admitted to our hospital. Patients were divided into a withdrawal group (n = 72) and a non-withdrawal group (n = 75) based on whether they were able to withdraw from insulin therapy at discharge, and the correlation between CPI at 2 h after meal and diabetes-related parameters was evaluated. In addition, we created two clinical models to predict the possibility of withdrawal from insulin therapy using machine learning. RESULTS: The glycated haemoglobin values of the study participants were 87.8 ± 22.6 mmol/mo. The CPI at 2 h post-meal was 1.93 ± 1.28 in the non-withdrawal group and 2.97 ± 2.07 in the withdrawal group (p < 0.001). CPI at 2 h post-meal was an independent predictor of withdrawal from insulin therapy. In addition, CPI at 2 h post-meal was a better predictor than fasting CPI. Six factors associated with insulin therapy withdrawal (age, duration of diabetes, creatinine, alanine aminotransferase, insulin therapy until hospitalization, and CPI at 2 h post-meal) were used to generate two clinical models by machine learning. The accuracy of the generated clinical models ranged from 78.3% to 82.6%. CONCLUSION: The CPI at 2 h post-meal is a clinically useful measure of endogenous insulin secretory capacity under non-fasting conditions.

Clinical findings of acute necrotizing esophagitis complicated by diabetic ketoacidosis.

Acute necrotizing esophagitis (ANE) is a rare and potentially life-threatening complication of diabetic ketoacidosis (DKA). While its association with DKA is established, specific clinical characteristics that predict ANE in DKA patients remain less understood. This study aimed to identify these characteristics by analyzing data from 30 DKA patients admitted from January 2018 to September 2022. Seven patients in this study presented with ANE, forming the ANE group. The remaining 23 constituted the non-ANE group. We compared the clinical parameters and computed tomography (CT) between the groups. The mean age of participants was 57.7 ± 20.4 years, and their mean HbA1c was 11.1 ± 3.3%. Notably, ethanol intake was significantly higher in the ANE group (44.4 ± 25.4 g/day) compared to the non-ANE group (6.8 ± 14.0 g/day; p = 0.013). Additionally, sodium-glucose transport protein 2 inhibitor use was significantly more prevalent in the ANE group (p = 0.013). Gastrointestinal symptoms were also significantly more pronounced in the ANE group, with vomiting occurring in 85.7% of patients compared to only 13.0% in the non-ANE group. Admission CT scans revealed further distinguishing features, with the ANE group showing significantly higher rates of esophageal wall thickening, intra-esophageal effusion, and calcification of the celiac artery origin (p < 0.0001, 0.0038, 0.0038, respectively). In conclusion, our study suggests that heavy alcohol consumption and strong gastrointestinal symptoms in DKA patients warrant a heightened suspicion of ANE. Early consideration of CT or upper gastrointestinal endoscopy is recommended in such cases.

The Impact of Hand Strength on HbA1c, Body Mass Index and Body Composition by Group According to Sedentary Behaviour: Cross-Sectional Study in Japanese Patients with Type 2 Diabetes Mellitus.

Background: The impact of hand strength in consideration of sedentary behaviour on diabetes management in patients with type 2 diabetes mellitus (T2DM) is unclear. The purpose of this study was to examine the impact of hand strength on HbA1c, body mass index (BMI) and body composition by group according to the duration of sedentary behaviour in Japanese patients with T2DM. Methods: In this retrospective, cross-sectional, single-centre study, hand strength standardised by bodyweight (GS) and sedentary time (ST), were obtained and analysed in a total of 270 Japanese T2DM outpatients in 2021. After dividing the patients into four categories of median values (high and low GS, and long and short ST), odds ratios (ORs) for good control of HbA1c, BMI, waist circumference (WC) and intra-abdominal fat (IAF) were investigated using logistic regression models. Results: The high GS/short ST group was found to have a significantly higher (OR = 2.01; 95% CI: 1.00, 4.03; P = 0.049) for controlled HbA1c compared with that of the low GS/long ST group. The high GS/short ST and the high GS/long ST groups had significantly higher ORs for controlled BMI, WC and IAF compared with the OR of the low GS/long ST group. In addition, the ORs were significantly increased with a positive trend in order from low GS/long ST, low GS/short ST, high GS/long ST, to high GS/short ST in all models (P < 0.001 for trend). Conclusion: Hand strength, with modest effects from sedentary behaviour, could be helpful for diabetes management in T2DM patients.

A preferred sequence for organelle inheritance during polarized cell growth.

Some organelles cannot be synthesized anew, so they are segregated into daughter cells during cell division. In Saccharomyces cerevisiae, daughter cells bud from mother cells and are populated by organelles inherited from the mothers. To determine whether this organelle inheritance occurs in a stereotyped manner, we tracked organelles using fluorescence microscopy. We describe a program for organelle inheritance in budding yeast. The cortical endoplasmic reticulum (ER) and peroxisomes are inherited concomitantly with bud emergence. Next, vacuoles are inherited in small buds, followed closely by mitochondria. Finally, the nucleus and perinuclear ER are inherited when buds have nearly reached their maximal size. Because organelle inheritance timing correlates with bud morphology, which is coupled to the cell cycle, we tested whether disrupting the cell cycle alters organelle inheritance order. By arresting cell cycle progression but allowing continued bud growth, we determined that organelle inheritance still occurs when DNA replication is blocked, and that the general inheritance order is maintained. Thus, organelle inheritance follows a preferred order during polarized cell division and does not require completion of S-phase.

Comparison of clinical efficacy and safety of weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in Japanese patients with type 2 diabetes: Randomized, parallel-group, multicentre, open-label trial (COMING study).

AIM: To compare the clinical usefulness of once-weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes. METHODS: In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24-week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks. RESULTS: HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%-6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%-7.4 ± 0.8%) (p < .0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p < .05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p < .0001). The parameters such as low-density lipoprotein cholesterol, alanine aminotransferase and γ-glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p < .01). The Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group. CONCLUSIONS: This prospective trial showed that semaglutide has more pronounced glucose- and body mass index-lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms.

Efficacy and safety of pemafibrate in patients with hypertriglyceridemia in clinical settings: A retrospective study.

BACKGROUND AND AIMS: Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings. METHODS AND RESULTS: We evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved. CONCLUSION: In this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis.

Addison's disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculosis or MAC pulmonary disease, in a subject with type 2 diabetes mellitus: case report.

BACKGROUND: Addison's disease is primary adrenal dysfunction and is characterized by decrease of cortisol level and increase of adrenocorticotropic hormone (ACTH) level. It is known that infection is one of main causes of Addison's disease. Among various infections, tuberculous infection accounts for the majority of them. Recently the number of subjects with non-tuberculous mycobacterial infection has been increased, and the infection can also bring about Addison's disease. Mycobacterium avium complex (MAC) pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection. CASE PRESENTATION: An 83-year-old female was suspected of having adrenal failure in our outpatient care and hospitalized in our institution. There was pigmentation in her face, hands and legs, especially in auricle and nail beds in her hands and legs. In rapid ACTH load test (0.25 mg of 1-24 ACTH), cortisol level was not increased at all. An abdominal computed tomography (CT) showed swelling of both adrenal glands accompanied by calcification. QuantiFERON test was negative and mycobacterium tuberculosis complex was negative in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of adrenal tuberculosis. It is known that MAC pulmonary disease accounts for the majority of non-tuberculous mycobacterial infection. In this subject, however, anti-MAC antibody was negative and MAC-related bacteria were not detected in PCR test using bronchial lung lavage fluid. These data ruled out the possibility of MAC pulmonary disease. Mycobacterium abscessus (Mab) was positive in bronchial lung lavage fluid culture. Based on these data, we diagnosed this subject with Addison's disease triggered by infection with mycobacterium abscessus, but not by adrenal tuberculous or MAC pulmonary disease. Decreased sodium level and increased eosinophil number were normalized and appetite loss was markedly mitigated after starting hydrocortisone therapy. A chest CT which was taken about 6 months later showed drastic reduction of consolidation in the upper lobe of the left lung although calcification in the adrenal gland was still observed. CONCLUSIONS: We should bear in mind the possibility of Addison's disease triggered by another type of infection rather than adrenal tuberculosis or MAC pulmonary disease.

Sudden extensive bloody pleural and pericardial effusion in a subject with untreated known hypothyroidism after total thyroidectomy, triggered by pneumonia.

BACKGROUND: In subjects with hypothyroidism, edema is often observed, and pleural effusion and pericardial fluid could be also observed. The color of such fluid retention is usually yellow. Here we show a very rare case with hypothyroidism who had bloody pleural effusion and bloody pericardial fluid. CASE PRESENTATION: A 42-year-old male noticed chest pain and the aggravation of exertional dyspnea, and he was transported to our institution by emergency. He had Graves' disease and underwent total thyroidectomy about 4 years before. After then, he had been treated with 200 µg/day of levothyroxine sodium for the maintenance of thyroid function. However, he self-interrupted such medication about 2 years before. Thyroid function on admission was reduced as follows: free triiodothyronine, 1.60 pg/mL; free thyroxine < 0.40 ng/dL; thyroid-stimulating hormone 25.50 µU/mL. Inflammation markers were increased: white blood cells 25,280 /µL; C-reactive protein 18.66 mg/dL. A large amount of pericardial fluid and pleural effusion were observed in chest and abdominal computer tomography and echocardiography. In addition, we performed pleural effusion and pericardial fluid collection. Pleural effusion in this subject showed bloody color, but not yellow. In cell block specimen of pleural effusion and pericardial fluid, red blood cells, neutrophils and lymphocyte component were observed. In this subject, however, we were unable to find any obvious background disease causing bloody pericardial effusion. Finally, we concluded that bloody pleural effusion and bloody pericardial fluid were brought about in a subject with untreated known hypothyroidism after total thyroidectomy, triggered by pneumonia. CONCLUSIONS: In subjects with hypothyroidism, fluid and mucopolysaccharide are stored in interstitial space and protein osmolality is increased, thus leading to edema and fluid retention. It is noted here that pleural effusion and pericardial fluid in this subject showed bloody color and included red blood cells. There are no reports of bloody pericardial fluid with hypothyroidism. Therefore, it is important to keep in mind that a subject with some trigger, such as infection, may have a hematologic fluid retention that is not seen when hypothyroidism is present alone, as observed in this subject.

How HIV Nef Proteins Hijack Membrane Traffic To Promote Infection.

The accessory protein Nef of human immunodeficiency virus (HIV) is a primary determinant of viral pathogenesis. Nef is abundantly expressed during infection and reroutes a variety of cell surface proteins to disrupt host immunity and promote the viral replication cycle. Nef counteracts host defenses by sequestering and/or degrading its targets via the endocytic and secretory pathways. Nef does this by physically engaging a number of host trafficking proteins. Substantial progress has been achieved in identifying the targets of Nef, and a structural and mechanistic understanding of Nef's ability to command the protein trafficking machinery has recently started to coalesce. Comparative analysis of HIV and simian immunodeficiency virus (SIV) Nef proteins in the context of recent structural advances sheds further light on both viral evolution and the mechanisms whereby trafficking is hijacked. This review describes how advances in cell and structural biology are uncovering in growing detail how Nef subverts the host immune system, facilitates virus release, and enhances viral infectivity.

Clustering of IRE1α depends on sensing ER stress but not on its RNase activity.

The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades. In addition, the sensor IRE1α exhibits stress-induced clustering in a transient time frame similar to activation of its endoRNase activity. Previous work had suggested that the clustering response and RNase activity of IRE1α are functionally linked, but here we show that they are independent of each other and have different behaviors and modes of activation. Although both clustering and the RNase activity are responsive to luminal stress conditions and to depletion of the ER chaperone binding protein, RNase-inactive IRE1α still clusters and, conversely, full RNase activity can be accomplished without clustering. The clusters formed by RNase-inactive IRE1α are much larger and persist longer than those induced by ER stress. Clustering requires autophosphorylation, and an IRE1α mutant whose RNase domain is responsive to ligands that bind the kinase domain forms yet a third type of stress-independent cluster, with distinct physical properties and half-lives. These data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor.-Ricci, D., Marrocco, I., Blumenthal, D., Dibos, M., Eletto, D., Vargas, J., Boyle, S., Iwamoto, Y., Chomistek, S., Paton, J. C., Paton, A. W., Argon, Y. Clustering of IRE1α depends on sensing ER stress but not on its RNase activity.

Basedow's disease with associated features of Hashimoto's thyroiditis based on histopathological findings.

BACKGROUND: Basedow's disease and Hashimoto's thyroiditis are autoimmune thyroid disorders and usually diagnosed with elevation of serum autoimmune antibodies. Thyrotropin receptor antibodies (TRAb) and/or thyroid-stimulating antibody (TSAb) are usually used for diagnosis of Basedow's disease, and thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies (TgAb) are for diagnosis of Hashimoto's thyroiditis. However, it is difficult to diagnose a subject as Basedow's disease with associated features of Hashimoto's thyroiditis only with elevation of such autoimmune antibodies. CASE PRESENTATION: A 44-year-old woman with 5-year history of Basedow's disease underwent a total thyroidectomy. She did not have a goiter. TRAb, TSAb, TPOAg and TgAb were all positive before a total thyroidectomy. In histopathological macroscopic examination, diffuse hyperplasia of the thyroid gland was observed. Furthermore, in histopathological microscopic examination, both characteristics of Basedow's disease and Hashimoto's thyroiditis were observed. After a total thyroidectomy, titers of all thyroid-associated autoimmune antibodies were markedly reduced. CONCLUSION: Herein, we report a subject with Basedow's disease without a goiter whose TPOAb and TgAb were relatively high at the onset of Basedow's disease. In addition, interestingly, the histopathological findings of this subject showed direct signs of Basedow's disease and Hashimoto's thyroiditis in the same thyroid gland. Considering from such findings, she seemed to have Basedow's disease with associated features of Hashimoto's thyroiditis. In conclusion, we should bear in mind the possibility of Basedow's disease with associated features of Hashimoto's thyroiditis in subjects with Basedow's disease, particularly when TPOAb and TgAb as well as TRAb and TSAb are positive.

Eicosapentaenoic acid/arachidonic acid ratio and weight loss during hospitalization for glycemic control among overweight Japanese patients with type 2 diabetes: a retrospective observational study.

BACKGROUND: The study aimed to examine the relationship between levels of serum eicosapentaenoic acid (EPA), arachidonic acid (AA), as well as EPA/AA ratio and weight loss during hospitalization in participants considered to be overweight, with type 2 diabetes. METHODS: The study participants included 142 patients who were hospitalized for treatment of type 2 diabetes. We divided the participants into two groups depending on the achievenemt in reduction of bodyweight 3% or more during hospitalization and examined the relationship between serum levels of EPA and AA, as well as ratio of EPA/AA on admission and effectiveness of weight loss under strict dietary therapy during hospitalization, using Cox proportional hazard models. RESULTS: After adjustment was made for several confounders, the hazard ratio of effective weight loss for logarithmical serum EPA was 1.59 (95% CI 1.02-2.49, P = 0.04) and for logarithmical EPA/AA ratio 1.64 (1.03-2.61, P = 0.04), whereas the hazard ratio for effective weight loss for logarithmical serum AA was 1.11 (0.45-2.78, P = 0.82). In addition, after dividing EPA/AA ratio and serum EPA into quartiles based on participant number, the hazard ratio for the highest quartile of EPA/AA ratio was 2.33 (1.14-4.77, P = 0.02), and for the highest quartile of serum EPA 1.60 (0.80-3.19, P = 0.18) compared with the lowest quartile. CONCLUSION: These results suggest the possibility that EPA is involved in bodyweight change under a caloric-restriction regimen. In addition, EPA/AA ratio was found to be a better predictor of medical intervention for weight loss among overweight patients with type 2 diabetes, compared with serum EPA level.

Intersectin1 promotes clathrin-mediated endocytosis by organizing and stabilizing endocytic protein interaction networks.

During clathrin-mediated endocytosis (CME), dozens of proteins are recruited to nascent CME sites on the plasma membrane. Coordination of endocytic protein recruitment in time and space is important for efficient CME. Here, we show that the multivalent scaffold protein intersectin1 (ITSN1) promotes CME by organizing and stabilizing endocytic protein interaction networks. By live-cell imaging of genome-edited cells, we observed that endogenously labeled ITSN1 is recruited to CME sites shortly after they begin to assemble. Knocking down ITSN1 impaired endocytic protein recruitment during the stabilization stage of CME site assembly. Artificially locating ITSN1 to the mitochondria surface was sufficient to assemble puncta consisting of CME initiation proteins, including EPS15, FCHO, adaptor proteins, the AP2 complex and epsin1 (EPN1), and the vesicle scission GTPase dynamin2 (DNM2). ITSN1 can form puncta and recruit DNM2 independently of EPS15/FCHO or EPN1. Our work redefines ITSN1's primary endocytic role as organizing and stabilizing the CME protein interaction networks rather than a previously suggested role in initiation and provides new insights into the multi-step and multi-zone organization of CME site assembly.

Kinetic investigation reveals an HIV-1 Nef-dependent increase in AP-2 recruitment and productivity at endocytic sites.

The HIV-1 accessory protein Nef hijacks clathrin adaptors to degrade or mislocalize host proteins involved in antiviral defenses. Here, using quantitative live-cell microscopy in genome-edited Jurkat cells, we investigate the impact of Nef on clathrin-mediated endocytosis (CME), a major pathway for membrane protein internalization in mammalian cells. Nef is recruited to CME sites on the plasma membrane, and this recruitment is associated with an increase in the recruitment and lifetime of the CME coat protein AP-2 and the late-arriving CME protein dynamin2. Furthermore, we find that CME sites that recruit Nef are more likely to recruit dynamin2 and transferrin, suggesting that Nef recruitment to CME sites promotes site maturation to ensure high efficiency in host protein downregulation. Implications of these observations for HIV-1 infection are discussed.

The impact of grip strength, waist circumference, and body mass index on Hemoglobin A1c value: Cross-sectional study using outpatient clinical data in Japanese elderly patients with type 2 diabetes mellitus.

AIM: Grip strength (GS) as a surrogate for muscular strength, waist circumference (WC) as a surrogate marker of visceral fat, and body mass index (BMI) as a surrogate marker of obesity should also be considered markers for the management of risks associated with type 2 diabetes mellitus (T2DM). However, in terms of the management of T2DM in elderly patients, the accentuated heterogeneity of sarcopenic change might modify the associations between those factors and glycemic control. In this cross-sectional study, we aimed to clarify the impact of GS, WC, and BMI on hemoglobin A1c (HbA1c) in elderly Japanese patients with T2DM. METHODS: GS, WC, and BMI were measured in 327 patients. Odds ratios (ORs) and 95% confidence intervals (CIs) for good glycemic control (HbA1c < 7.0%) were investigated to analyze the three variables as numerical values by dividing them into tertiles. All results were expressed after adjustment was made for the confounders of age, sex, and number of diabetes medications being used by the study participants. RESULTS: The ORs of GS, WC, and BMI for well-controlled HbA1c were 1.056 (95% CI, 1.016-1.098), 0.986 (95% CI, 0.960-1.013), and 1.032 (95% CI, 0.959-1.111), respectively. The OR of 3.726 (95% CI, 1.831-7.581) in the high tertile for GS was significantly higher than the OR in the low tertile, and no differences were observed among the tertiles for WC and BMI. CONCLUSIONS: Based on that result, GS was found to have more potential as an effective marker of glycemic control than WC or BMI among elderly Japanese patients with T2DM. Geriatr Gerontol Int 2024; 24: 410-414.

The impact of handgrip strength and waist circumference on glycemic control: Prospective, observational study using outpatient clinical data in Japanese patients with type 2 diabetes mellitus.

INTRODUCTION: Loss of muscle mass and the accumulation of visceral fat are known risk factors for the deterioration of glycemic control in type 2 diabetes mellitus. This study looked at the effects of such factors on glycemic control in Japanese patients with type 2 diabetes mellitus in the form of handgrip strength (HGS) and waist circumference (WC). MATERIALS AND METHODS: In this prospective, observational study, 233 patients with type 2 diabetes mellitus and a HbA1c level of ≥7.0% were followed for around 1 year, during which time they were studied for an understanding of the association between handgrip strength, waist circumference, and glycemic control (HbA1c <7.0%). Hazard ratios (HRs) and 95% confidence intervals (CIs) for glycemic control improvement by Cox hazards models were analyzed for handgrip strength and waist circumference. RESULTS: Compared with the low tertile, patients in the middle and high tertiles of handgrip strength when adjustment was carried out for waist circumference were 2.117 (1.142-3.924) and 4.670 (2.526-8.632), respectively. The HRs of patients in the middle and high tertiles of WC when adjustment was made for HGS were 0.442 (0.269-0.725) and 0.339 (0.191-0.604), respectively. Within the low, middle, and high HGS tertiles, the HRs for WC were 0.863 (0.797-0.934), 0.940 (0.899-0.982), and 1.009 (0.984-1.035), respectively, although the HRs for HGS within each WC tertile remained significant. CONCLUSIONS: Handgrip strength and waist circumference demonstrated independent associations for glycemic control, but the effect of waist circumference appeared to be at least partially canceled out by increased handgrip strength. The data suggest that handgrip strength might help to mitigate the negative impact of waist circumference on glycemic control.

A case of Empty Sella syndrome with adrenal insufficiency masked by prednisolone after administration of immune checkpoint inhibitors.

INTRODUCTION: The use of immune checkpoint inhibitors (ICIs) is gradually increasing; ICIs produce a variety of immune-related adverse events (irAEs), especially ICI-induced hypoadrenocorticism, which can be a lethal complication if treatment is delayed. PATIENT CONCERNS: A 63-year-old man received chemotherapy with pembrolizumab for nonsmall cell lung cancer. He developed drug-induced interstitial pneumonia 366 days after receiving pembrolizumab and was treated with prednisolone. Five hundred thirty-seven days later, he developed drug-induced eosinophilic enteritis, and pembrolizumab was discontinued and prednisolone was continued. After discontinuation of prednisolone, general malaise and edema of the lower extremities appeared, and adrenal insufficiency was suspected. DIAGNOSIS: In blood tests on admission adrenocorticotropic hormone (ACTH) was 2.2 pg/mL and cortisol was 15 µg/dL, with no apparent cortisol deficiency. However, the cortisol circadian rhythm disappeared and remained low throughout the day; a corticotropin-releasing hormone stimulation test showed decreased reactive secretion of ACTH. Pituitary magnetic resonance imaging showed pituitary emptying, suggesting Empty Sella syndrome. INTERVENTIONS AND OUTCOMES: We started hydrocortisone and his symptoms were improved. CONCLUSIONS: The administration of high-dose steroids after ICI administration may mask the symptoms of hypoadrenocorticism as irAEs. Therefore, we should bear in mind the possibility of hypoadrenocorticism when we stop steroid therapy in patients who are treated with steroids after ICI administration.

Usefulness of Once-Weekly GLP-1 Receptor Agonist Semaglutide on Glycemic Control in Subjects with Type 2 Diabetes Mellitus: Switching from the Same Class Dulaglutide in a Retrospective Observation Study.

Recently, the development of once-weekly incretin-based injections dulaglutide and semaglutide has drawn a great deal of attention. This study is aimed at comparing the efficacy of once-weekly GLP-1 receptor activator (GLP-1RA) dulaglutide and semaglutide on glycemic control and several metabolic parameters in patients with type 2 diabetes mellitus. We compared various clinical parameters between before and after switching from dulaglutide to semaglutide in "study 1" (pre-post comparison) and set the control group using propensity score matching method in "study 2." In "study 1," six months after the switching, HbA1c was significantly reduced from 8.2% to 7.6% and body mass index was also decreased from 30.4 kg/m2 to 30.0 kg/m2. Such effects were more pronounced in subjects whose glycemic control was poor. In "study 2," after 1 : 1 propensity score matching, glycemic control and body weight management were improved in the switching group compared with the dulaglutide continuation group. In this study including obese subjects with poor glycemic control, switching dulaglutide to semaglutide showed more beneficial effects on both glycemic and weight control irrespective of age, body weight, and diabetes duration. Therefore, we should bear in mind that it would be better to start using a relatively new once-weekly GLP-1RA semaglutide in clinical practice, especially in obese subjects with poor glycemic control with other GLP-1RAs.