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.

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.

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.

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 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.

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.

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.

Structural and functional differences in auto-antibody positive compared to auto-antibody negative hypothyroid patients with chronic thyroiditis.

Most primary hypothyroidism in adults is caused by chronic thyroiditis. Autoantibodies such as anti-thyroglobulin antibody (TgAb) and anti-thyroid peroxidase antibody (TPOAb) are involved in the pathogenesis of chronic thyroiditis. On the other hand, the clinical features of antibody-negative hypothyroidism are not clear. In this study, we aimed to determine the prevalence of thyroid-related autoantibodies in patients with primary hypothyroidism and to evaluate the differences in thyroid structure between antibody-positive and antibody-negative hypothyroidism. Among 804 patients who attended Kawasaki Medical School Hospital for thyroid hormone abnormalities or thyroid gland enlargement between January 1, 2010 and December 31, 2021, 237 patients with primary hypothyroidism who underwent thyroid antibody measurement and thyroid ultrasound examination were included. Participants were divided into groups according to antibody positivity/negativity, and differences in antibody positivity and thyroid structure were evaluated. In this study, 34.6% of patients had antibody-negative hypothyroidism. The positive rate of each antibody was 62.0% for TgAb and 49.4% for TPOAb. The participants with antibody-positive hypothyroidism had significantly larger thyroid gland on thyroid ultrasound examination (p < 0.05). Thyroid-stimulating hormone was significantly higher in participants with antibody-positive compared to antibody-negative hypothyroidism. The present study reveals a positive rate of thyroid-related autoantibodies in patients with hypothyroidism and the differences in thyroid structure between patients with and without antibodies. This study clearly show that the prevalence of antibody-negative chronic thyroiditis is quite high among hypothyroid patients, although this point needs confirmation by further investigations. The data in this study would be useful for the treatment of antibody-negative hypothyroid patients.

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.

Simple standing test without furosemide is useful in the diagnosis of primary aldosteronism.

Primary aldosteronism (PA) is a well-known cause of secondary hypertension. We have long performed the simple standing test in patients with PA. On the other hand, there are few reports on the usefulness of the simple standing test in PA. This study is a single-center, retrospective, observational study. A total of 173 patients with hypertension or adrenal tumor admitted to Kawasaki Medical School were included. Eighty patients who met the exclusion criteria were excluded, and 31 patients without PA (non-PA), 26 patients with unilateral PA, and 36 patients with bilateral PA were included in the study. The simple standing test was performed after 120 min of standing or sitting followed, and the aldosterone/renin ratio (ARR) and percentage of increase plasma aldosterone concentration (%increase of PAC) was calculated. The mean ARR in the simple standing test in unilateral PA (1143 (528-2200)) and bilateral PA subjects (521 (374-765)) were significantly higher compared to non-PA subjects (152 (102-240)) (p < 0.0001, p = 0.0013, respectively). The percentage increase of PAC after standing loading was significantly lower in unilateral PA subjects (110 (96-140)) compared to non-PA subjects (187 (155-244)) (p = 0.0003), with no difference between non-PA and bilateral PA subjects (p = 0.99). The cutoff value of the ARR in the simple standing test for diagnosis of PA in this study was 364 (AUC = 0.948, sensitivity = 83.8%, specificity = 93.5%, false positive rate = 3.7%, false negative rate = 25.6%, p < 0.001), which was not inferior to the diagnostic performance of the captopril loading test. The diagnostic performance of the simple standing test for PA was not inferior to that of the captopril loading test. The percentage increase of PAC in unilateral PA subjects was significantly lower compared to bilateral PA subjects. These results demonstrate the usefulness of the simple standing test, which can be performed simultaneously with general screening tests of PA.

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.

Incidence of endocrine-related immune-related adverse events in Japanese subjects with various types of cancer.

Background: Immune checkpoint inhibitors (ICIs), such as cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed cell death protein 1 ligand 1 (PD-L1) inhibitors, are often used to treat a variety of malignancies. ICIs are known to cause endocrine-related immune-related adverse events (irAEs), but the incidence varies among reports and/or agents. This study evaluated the incidence of endocrine-related irAEs in patients who were treated with ICIs in Japan. Method: This single-center, retrospective, observational study examined the incidence and clinical characteristics of endocrine-related irAEs in 466 participants who were treated with ICIs at Kawasaki Medical School Hospital. Result: The mean age of participants with and without endocrine-related irAEs was 69.1 ± 1.8 years and 68.1 ± 1.1 years, respectively, with no difference between them. The overall incidence of any endocrine-related irAEs among the participants was 25.5%. Hypothyroidism was prevalent in 24.3%, hypoadrenocorticism in 3.2%, hypopituitarism in 0.9%, and insulin-dependent diabetes mellitus in 1.1%. Participants receiving combination therapy with CTLA-4 and PD-1 inhibitors had a significantly higher incidence of endocrine-related irAEs than those receiving monotherapy. Conclusion: Endocrine-related irAEs correlated significantly with survival and mean observation period. There was substantial difference in the incidence of endocrine-related irAEs among various types of ICIs and types of cancer. We should bear in mind that endocrine testing is necessary during the treatment with ICIs.

Influence of Nutritional Guidance/Consulting on Glycemic Control during the Coronavirus Disease 2019 Pandemic in Patients with Type 2 Diabetes Mellitus.

Objective The coronavirus disease 2019 (COVID-19) pandemic has led to a global restriction of public behavior due to lockdowns in various major cities. Lifestyle changes and reduced rates of outpatient lifestyle guidance/consulting may have had some impact on glycemic control in patients with type 2 diabetes. This study analyzed the impact of changes in the frequency of nutritional guidance/consulting (NGC) during the COVID-19 pandemic on outpatient care for type 2 diabetes. Methods Among 785 patients, 67 who received regular NGC during the COVID-19 pandemic were assigned to the continuation group (CG), 143 whose NGC was discontinued after the pandemic were assigned to the discontinuation group (DG), and 575 who did not receive regular NGC regardless of the COVID-19 pandemic status were assigned to the irregular NGC group (IGG). The three groups were followed up for two years. Analyses among the three categories were performed using the chi-square test or an analysis of covariance. Results The number of diabetes medications after the declaration of the COVID-19 emergency did not markedly increase in the CG (2.0±1.4 to 2.1±1.5, p>0.05) but significantly increased from 2.2±1.4 to 2.6±1.4 in the DG (p<0.005) and from 2.2±1.4 to 2.4±1.4 in the IGG (p<0.005). The increase in HbA1c adjusted for confounders was unchanged at 0.12±1.06% for the CG and -0.07±1.29% for the IGG but was significantly increased at 0.19±1.49% for the DG (p<0.05). Conclusion In patients with type 2 diabetes mellitus, regular nutritional guidance may be important for maintaining good glycemic control, even during the COVID-19 pandemic.

Correlation of Baba's diabetic neuropathy classification with various diabetes-related complications.

It is known that Baba's diabetic neuropathy classification (BDC) is useful in quantitative evaluation of Diabetic polyneuropathy (DPN). In this study, we aimed to investigate the possible association between BDC and various diabetic microvascular and macrovascular complications in patients whose neuropathy was evaluated with BDC. As the results, BDC was significantly correlated with the severity of diabetic retinopathy and nephropathy. BDC was also significantly correlated with history of myocardial infarction or cerebral infarction, carotid IMT, and ABI. These data suggest that BDC may be useful in predicting the presence of various diabetic microvascular and macrovascular complications. The data also support the idea that we should perform further investigation of other diabetes-related complications in patients with severe DPN.

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.

Usefulness of cortisol/ACTH ratio (CAR) for diagnosis of cushing's syndrome: comparison of CAR with findings in dexamethasone suppression test.

Cushing's syndrome and subclinical Cushing's syndrome (SCS) are conditions of increased cortisol secretion from the adrenal glands. Cushing's syndrome includes adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (Cushing's disease) and ACTH-independent Cushing's syndrome (AICS). The purpose of this study was to investigate the diagnostic potential of the cortisol / adrenocorticotropic hormone (ACTH) ratio (CAR) for diagnosis of Cushing's syndrome or SCS in adult subjects. This was a single-center, retrospective, observational study. This study enrolled 44 subjects with SCS, 14 AICS, 10 CD, and 248 non-Cushing's syndrome subjects who had undergone a 1 mg dexamethasone suppression test (1 mg DST). Definition of SCS was as follows: no physical signs characteristic of Cushing syndrome and cortisol was ≥ 83 nmol/L in 1 mg DST. The diagnostic potential of CAR for diagnosis of Cushing's syndrome was evaluated by comparing the correlation between CAR and after-load cortisol level in 1 mg DST. As the results, there was a strong positive correlation between CAR and after-load cortisol level in subjects with AICS (r = 0.800, p < 0.005). CAR was 10,040 ± 4170 nmol/pmol in subjects with NCS, 17,535 ± 10,246 nmol/pmol in SCS, 101,221 ± 18,009 nmol/pmol in AICS, and 4324 ± 2051 nmol/pmol in CD, all of which were significantly higher compared to those with AICS (p < 0.0005). The cutoff values of CAR for screening at our institution were 11,849.6 nmol/pmol for AICS (AUC 0.935, p < 0.005, sensitivity 92.3%, specificity 83.5%) and 7006.1 nmol/pmol for CD (AUC 0.714, p < 0.05, sensitivity 100.0%, specificity 46.8%). There was a positive correlation between CAR and adrenal adenoma diameter in subjects with AICS (r = 0.508, p < 0.05), but there was no correlation between tumor diameter and CAR in subjects with SCS and CD. In conclusion, high CAR indicates increased cortisol secretion from the adrenal glands. Since CAR is a simple indicator that can be easily evaluated by general practitioners as well as endocrinologists, we think CAR would be useful for the early detection of Cushing's syndrome.

Imeglimin exerts favorable effects on pancreatic ß-cells by improving morphology in mitochondria and increasing the number of insulin granules.

Imeglimin is a new anti-diabetic drug commercialized in Japan (Twymeeg®) and has been drawing much attention in diabetes research area as well as in clinical practice. In this study, we evaluated the effect of imeglimin on pancreatic ß-cells. First, single-dose administration of imeglimin enhanced insulin secretion from ß-cells and decreased blood glucose levels in type 2 diabetic db/db mice. In addition, single-dose administration of imeglimin significantly augmented insulin secretion in response to glucose from islets isolated from non-diabetic db/m mice. Second, during an oral glucose tolerance test 4-week chronic treatment with imeglimin enhanced insulin secretion and ameliorated glycemic control in diabetic db/db mice. Furthermore, the examination with electron microscope image showed that imeglimin exerted favorable effects on morphology in ß-cell mitochondria and substantially increased the number of insulin granules in type 2 diabetic db/db and KK-Ay mice. Finally, imeglimin reduced the percentage of apoptotic ß-cell death which was accompanied by reduced expression levels of various genes related to apoptosis and inflammation in ß-cells. Taken together, imeglimin directly enhances insulin secretion in response to glucose from ß-cells, increases the number of insulin granules, exerts favorable effects on morphology in ß-cell mitochondria, and reduces apoptotic ß-cell death in type 2 diabetic mice, which finally leads to amelioration of glycemic control.

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.

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.