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.

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.

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.

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.

Immune checkpoint inhibitor-induced hypothyroidism predicts treatment response in Japanese subjects.

Background: Immune checkpoint inhibitors (ICIs) cause a variety of immune-related adverse events (irAEs). Among them, thyroid dysfunction is most frequently observed. Patients with irAEs have higher survival rates than those without irAEs, but there is no certainty as to whether the degree of thyroid dysfunction is associated with treatment response or survival with ICIs. Method: This is a single-center, retrospective, observational study. The study included 466 patients who received ICI at Kawasaki Medical School Hospital from September 1, 2014, to May 31, 2022 and evaluated the degree of abnormal thyroid function and survival and remission rates after treatment with ICIs. Primary hypothyroidism of less than 10 µIU/mL TSH was classified as grade 1, and primary hypothyroidism requiring more than 10 µIU/mL TSH or levothyroxine as grade 2-4. Result: The mean age of the study participants was 68.2 ± 10.3 years, and the percentage of male participants was 72.6%. The frequency of ICI-induced thyroid dysfunction in the study participants was 28.2%. TSH levels were significantly higher in Grade 1 and Grades 2-4 when treated with ICI compared to NTF (p<0.0001). The survival rate at 1 year after ICI administration was significantly higher with 64.9% for grade 1 and 88.9% for grades 2-4 compared to 52.1% for NTF (p<0.0001). Cancer stage at the time of ICI administration did not differ among the groups (p=0.68). Nevertheless, the remission rate assessed by RECIST criteria was significantly higher in grades 2-4 compared to NTF (p<0.0001). Conclusion: ICI-induced thyroid dysfunction was significantly correlated with survival, mean observation time, and treatment remission rate. It is important to monitor thyroid hormone levels regularly in patients receiving ICIs.

Central Diabetes Insipidus Due to IgG4-related Hypophysitis That Required over One Year to Reach the Final Diagnosis Due to Symptoms Being Masked by Sialadenitis.

Pituitary inflammation due to IgG4-related disease is a rare condition and is sometimes accompanied by central diabetes insipidus. Central diabetes insipidus produces a strong thirst sensation, which may be difficult to distinguish when complicated by salivary insufficiency. A 45-year-old man was admitted to our department for a thorough examination of his thirst and polyuria. He had suddenly developed these symptoms more than one year earlier and visited an oral surgeon. Swelling of the left submandibular gland, right parotid gland, and cervical lymph nodes had been observed. Since his IgG4 level was relatively high at 792 mg/dL and a lip biopsy showed high plasmacytoid infiltration around the gland ducts, he had been diagnosed with IgG4-related disease. He had started taking 0.4 mg/kg/day of prednisolone, and his chief complaint temporarily improved. However, since the symptom recurred, he was referred to our institution. After admission, to examine the cause of his thirst and polyuria, we performed a water restriction test, vasopressin loading test, hypertonic saline loading test and pituitary magnetic resonance imaging. Based on the findings, we diagnosed him with central diabetes insipidus due to IgG4-related hypophysitis. We increased the dose of prednisolone to 0.6 mg/kg/day and started 10 µg/day of intranasal desmopressin. His symptoms were subsequently alleviated, and his serum IgG4 level finally normalized. We should remember that IgG4-related disease can be accompanied by hypophysitis and that central diabetes insipidus is brought about by IgG4-related hypophysitis. This case report should remind physicians of the fact that pituitary inflammation due to IgG4-related disease is very rare and can be masked by symptoms due to salivary gland inflammation, which can lead to pitfalls in the diagnosis in clinical practice.

Vitamin D deficiency osteomalacia triggered by long-term social withdrawal and unbalanced diet in a Japanese middle-aged subject: A case report.

INTRODUCTION: Osteomalacia is caused by an increase in the number of osteoids owing to mineralization failure. There are various causes of osteomalacia, such as hypophosphatemia due to excess production of fibroblast growth factor 23, vitamin D deficiency, insufficient vitamin D action, and renal tubular disorders. PATIENT CONCERNS: A 53-year-old man with bone pain and gait disturbance was referred to our institution. At the age of 35, he developed atopic dermatitis. He had eyesight deterioration due to atopic cataracts when he was 37 years old. Subsequently, he stayed home all the time, and his eating habits were unbalanced for a long period of time. Although he had atopic dermatitis, he did not take allergen-free diets, and he did not use sunscreen. Furthermore, when he was 43 years old, he failed to flex his legs and suffered gait disturbance. DIAGNOSIS: Hypocalcemia and hypophosphatemia were observed as follow: calcium, 5.5 mg/dL; adjusted calcium, 6.9 mg/dL; inorganic phosphorous, 1.9 mg/dL. In addition, intact parathyroid hormone levels were as high as 277.4 pg/mL, and 1, 25-(OH)2 vitamin D and 25-(OH) vitamin D levels were markedly reduced: 1, 25-(OH)2 vitamin D, ≤4 pg/mL; 25-(OH) vitamin D, 11.0 ng/mL. Fibroblast growth factor 23 levels did not increase. Alkaline phosphatase (ALP) and bone-type ALP (BAP) levels were high: ALP, 784 U/L; BAP, 159.2 µg/L (reference range: 3.7-20.9 µg/L). Based on these findings, we diagnosed this patient with vitamin D-deficient osteomalacia triggered by long-term social withdrawal and an unbalanced diet. INTERVENTIONS AND OUTCOMES: After hospitalization, to treat vitamin D-deficient osteomalacia, we started to administer 1 µg/day of alfacalcidol and 3 g/day of calcium lactate. Approximately one month later, 1,25-(OH)2 vitamin D levels increased to 214 pg/mL. Consequently, calcium and inorganic phosphorus were also increased up to 7.8 mg/dL and 3.9 mg/dL, respectively, and intact parathyroid hormone was decreased to 132.0 pg/mL. CONCLUSIONS: We should bear in mind the possibility of osteomalacia triggered by social withdrawal and vitamin D deficiency even in middle-aged subjects.

Effect of Hyperglycemia-Related Acute Metabolic Disturbance on Thyroid Function Parameters in Adults.

Non-thyroidal illness (NTI) is a condition in which the hypothalamic-pituitary-thyroid system and thyroid hormone metabolism are abnormal due to non-thyroidal diseases. Although NTI has been reported to occur in hyperglycemic emergencies in children, there have been few studies in adult cases. In this study, we examined adult patients with hyperglycemia regarding the frequency of NTI and its triggers. Adult diabetic patients who were hospitalized for diabetic ketosis (DK), diabetic ketoacidosis (DKA), or hyperglycemic hyperosmolarity syndrome (HHS) were included in the study. Compared with the DK group, the DKA and HHS groups had higher admission blood glucose, Anion Gap, serum osmolality, creatinine, and urea nitrogen, and lower pH and eGFR. The frequency of NTI in the DKA, HHS, and DK groups was 80%, 70%, and 50%, respectively, and thyroid stimulating hormone (TSH) and free thyroxine 3 (FT3) were significantly improved after treatment for hyperglycemia. Multiple regression analysis showed a significant correlation between the decrease in FT3 level and 3-hydroxybutyrate and albumin. Acute metabolic failure associated with hyperglycemia tends to be associated with a high rate of NTI and low FT3 levels at the start of treatment. The data in this study clearly shows that transient NTI is frequently observed in subjects with acute metabolic disorders such as DKA, HHS and DK. In addition, we should bear in mind that thyroid hormone replacement therapy is not necessary in subjects with NTI due to DKA, HHS and DK, especially when overt symptoms of hypothyroidism are not observed.

Association between changes in pancreatic morphology and vascular complications in subjects with type 2 diabetes mellitus: a retrospective study.

Decreased pancreatic volume, increased pancreatic fat mass, and serrated pancreatic margins are characteristic morphological changes of the pancreas in subjects with type 2 diabetes mellitus. This retrospective study aimed to clarify the clinical significance of pancreatic morphological changes in subjects with type 2 diabetes mellitus who underwent abdominal magnetic resonance imaging. The mean age and HbA1c value were 59.1 ± 16.3 years old and 8.9 ± 2.3%, respectively. Pancreatic body mass corrected for body surface area (BSA) in subjects with diabetes mellitus was lower compared to those in normal glucose tolerance (49.4 ± 15.3 cm3 vs. 60.9 ± 7.8 cm3), although it did not reach a statistic significance. There was a negative correlation between BSA-corrected pancreatic volume and age, duration of diabetes, glycoalbumin, mean and max IMT, and there was a positive correlation between BSA-corrected pancreatic volume and HOMA2-ß. Serration of the pancreatic limbus was more often observed in subjects with diabetes mellitus compared to those in normal glucose tolerance (74.1% vs. 14.3%). Subjects with serrated changes were older and had higher HbA1c, and visceral fat area was significantly larger in subjects with serrated changes. BSA-corrected pancreatic volume in subjects with serrated changes was significantly smaller, and mean IMT was significantly thicker in subjects with serrulation. Furthermore, advanced diabetic retinopathy and diabetic nephropathy were more often observed in subjects with serrated changes. Taken together, decreased BSA-corrected pancreatic volume and serrated changes were associated with the progression of vascular complications in subjects with type 2 diabetes mellitus.

Glucagon Test Is a Useful Predictor of Withdrawal From Insulin Therapy in Subjects With Type 2 Diabetes Mellitus.

There are many tests for evaluating endogenous insulin secretory capacity. However, there are only a limited number of studies that have examined in detail in clinical practice which method most accurately reflects the ability to secrete endogenous insulin especially in hyperglycemic state. The purpose of this study was to find the endogenous insulin secretory capacity and a possible predictor of insulin withdrawal in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia. In the endogenous insulin secretory test during hospitalization, CPR, CPR index, and ΔCPR after glucagon loading were all significantly higher in the insulin withdrawal group. On the other hand, there were no difference in fasting CPR index, HOMA-ß, SUIT, and 24-hour urinary CPR excretion between the two groups. In the glucagon test of the insulin withdrawal group, the cutoff value of ΔCPR was 1.0 ng/mL, the withdrawal rate of ΔCPR of 1.0 ng/mL or more was 69.2%, and the withdrawal rate of less than 1.0 ng/mL was 25.0%. In conclusion, it is likely that glucagon test is the most powerful tool for predicting the possibility of insulin withdrawal as well as for evaluating endogenous insulin secretory capacity in subjects with type 2 diabetes requiring hospitalization due to hyperglycemia.

Effects of sedentary behavior and daily walking steps on body mass index and body composition: Prospective observational study using outpatient clinical data of Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: This study examined the effect of daily walking steps on glycated hemoglobin, body mass index (BMI) and body composition while taking into consideration sedentary time (ST) in Japanese type 2 diabetes patients over a period of 12 months. MATERIALS AND METHODS: Self-administered ST values and information regarding daily walking steps were obtained and analyzed for 236 patients with type 2 diabetes who regularly visited the outpatient clinic. The patients - divided into three categories of daily walking steps: non-step counter user, <7,500 daily walking steps and ≥7,500 daily walking steps (HS) - were prospectively observed considering ST through the monitoring of glycated hemoglobin, BMI waist circumference (WC) and visceral fat accumulation (VFA) for 12 months. RESULTS: After 12 months, the participants categorized as the HS group had significantly reduced BMI and VFA independent of ST, as well as significantly reduced WC with high ST. WC and VFA disparities widened significantly at 12 months between the participants categorized as being in the non-step counter user group and the HS group with long ST. However, no difference in glycated hemoglobin levels and BMI were found among the three categories independent of ST. Compared with non-step counter users, the odds ratios with logistic regression models of improvement in BMI and VFA in the <7,500 daily walking steps and HS groups, and WC in the HS group after 12 months were significantly higher only among those with long ST. CONCLUSIONS: These results suggest that consideration of sedentary behavior in combination with daily walking steps might be essential for type 2 diabetes management.

Development of a simple device enabling percutaneous flow regulation for a small vascular graft for a Blalock­Taussig shunt capable of flow regulation: complete translation of an original article originally published in Pediatric Cardiology and Cardiac Surgery (154­159, 2016: vol. 32).

OBJECTIVES: The Blalock-Taussig shunt (BTS) operation is a cornerstone as initial palliative surgery for congenital heart disease with severely reduced pulmonary blood flow (PBF). The ideal PBF provided by BTS is crucial for an uneventful postoperative course, since excess PBF results in acute distress of the systemic circulation and insufficient PBF requires another BTS surgery. Therefore, the goal of this study was to develop a simple device to control the shunt graft flow percutaneously using a constrictor balloon connected to a subcutaneous port. METHODS: The device consists of a cylindrical balloon and an anti-bending structure extension connected to the balloon center. A PTFE vascular graft wrapped by the device was connected to a simulated closed circuit to measure the relationship between pressure and blood flow while changing the inner volume of the balloon. In a beagle model of replacement of the right carotid artery, blood flow velocity was measured in the carotid artery after saline injection into the balloon. The blood flow velocity before and after balloon inflation was compared immediately after implantation of the device and at 3 months after implantation. RESULTS: The device provided good flow control by inflating and deflating the balloon ex vivo and in vivo for up to 3 months in a canine model with a small graft wrapped with the device. CONCLUSIONS: The simple device developed in this study may enable regulation of PBF through a small vascular graft and help to prevent severe morbidity and mortality in the clinical setting of BTS.

Correction to: Development of a simple device enabling percutaneous flow regulation for a small vascular graft for a Blalock-Taussig shunt capable of flow regulation: complete translation of an original article originally published in Pediatric Cardiology and Cardiac Surgery (154-159, 2016: vol. 32).

In the original publication of the article, the title was incorrectly published.