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.

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.

Clinical course of different long-acting insulin therapies-glargine U100, U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes: a multicenter retrospective observational study (JDDM65 study).

This study aimed to retrospectively compare the clinical efficacy of different types of long-acting insulin therapies-glargine U100, glargine U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes after insulin use was initiated in an outpatient setting. The study consisted of 822 insulin-naïve patients in Japan who started using long-acting insulin for treatment of type 2 diabetes and continued for over 12 months. In addition, the impact of insulin type on insulin withdrawal was investigated by dividing the participants into two groups: those who achieved insulin withdrawal and those who did not, during the 12-month observation period based on a Cox proportional hazards model. As a result, HbA1c was decreased, and BMI was increased in all participants regardless of the insulin type used. A total of 185 participants succeeded in insulin withdrawal. After adjustment was made for several confounders, the positive determinant factors for withdrawal were short duration of diabetes and the choice of IDegAsp when compared with Gla100; the negative determinant factor was use of insulin secretagogues at the start of the study. In conclusion, all long-acting insulins were a powerful tool for treatment of type 2 diabetes, and patients with short duration of diabetes and/or no usage of insulin secretagogues resulted in favorable outcomes in terms of insulin withdrawal within a year in an outpatient setting. In addition, insulin degludec/insulin aspart was found to possibly be a better choice for treatment when it was compared with glargine U100 among the four types of insulin.

Concurrence of overt Cushing's syndrome and primary aldosteronism accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex: case report.

BACKGROUND: Various adrenal disorders including primary aldosteronism and Cushing's syndrome lead to the cause of hypertension. Although primary aldosteronism is sometimes complicated with preclinical Cushing's syndrome, concurrence of overt Cushing's syndrome and primary aldosteronism is very rare. In addition, it has been drawing attention recently that primary aldosteronism is brought about by the presence of aldosterone-producing cell cluster in adjacent adrenal cortex rather than the presence of aldosterone-producing adenoma. CASE PRESENTATION: A 67-year-old Japanese female was referred to our institution due to moon face and central obesity. Based on various clinical findings and data, we diagnosed this subject as overt Cushing's syndrome and primary aldosteronism. Furthermore, in immunostaining for cytochrome P450 (CYP) 11B1, a cortisol-producing enzyme, diffuse staining was observed in tumorous lesion. Also, in immunostaining for CYP11B2, an aldosterone-producing enzyme, CYP11B2 expression was not observed in tumorous lesion, but strong CYP11B2 expression was observed in adjacent adrenal cortex, indicating the presence of aldosterone-producing cell cluster. CONCLUSIONS: We should bear in mind the possibility that concurrence of overt Cushing's syndrome and primary aldosteronism is accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex.

Multiple endocrine neoplasia type 1 with a frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas: case report.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by pituitary neoplasia, primary hyperparathyroidism and pancreatic endocrine tumor. Here we show a case of MEN1 with a germline frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas. CASE PRESENTATION: A 28-year-old man noticed the decreased visual acuity of both eyes and visited our institution. Since he was diagnosed as visual disturbance and brain computer tomography (CT) showed a mass in the pituitary fossa, he was hospitalized in our institution. Endoscopic trans-sphenoidal hypophysectomy and total parathyroidectomy with auto-transplantation were performed, and a giant cervical lipoma was resected. Furthermore, in genetic search, we found a germline frameshift mutation in MEN1 gene leading to the appearance of a new stop codon. CONCLUSIONS: We should bear in m ind that giant skin lipoma and multiple abnormal fatty deposits in the pancreas could be complicated with MEN1.

A case of tamoxifen-induced hypertriglyceridemia monitoring the changes in lipoprotein fractions over time.

BACKGROUND: Tamoxifen, which is one of the selective estrogen receptor modulators (SERMs), can bring out life-threatening complication, e.g. hypertriglyceridemia-induced acute pancreatitis, although it is rare. We precisely report changes in lipoprotein metabolism before and after tamoxifen discontinuation because there have been few reports of it. CASE PRESENTATION: 47-year-old premenopausal woman with dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and chronic kidney disease was prescribed tamoxifen as adjuvant therapy after operation of breast cancer. She experienced severe tamoxifen-induced hypertriglyceridemia several months after dosing tamoxifen. Before cessation of tamoxifen, lipoprotein fraction test revealed marked stagnation of VLDL and IDL metabolisms, resulting in severe hypertriglyceridemia (serum triglyceride level was 1881 mg/dL). Seven days after tamoxifen withdrawal, lipoprotein fraction test showed that the metabolisms of endogenous lipoproteins were changed drastically. CONCLUSIONS: From these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through suppression of post-heparin lipolytic activity. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.

Efficacy and safety of adding ipragliflozin to insulin in Japanese patients with type 1 diabetes mellitus: a retrospective study.

Advances in insulin preparations and administration methods have produced a gradual improvement in glycemic control in patients with type 1 diabetes mellitus (DM). Nevertheless, glycated hemoglobin (HbA1c) levels in patients with type 1 DM are still poor compared to those in patients with type 2 DM. Here, we sought to assess the efficacy and safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin (IPRA) in patients with type 1 DM. This study was retrospectively conducted with data from type 1 DM patients who had a history of IPRA therapy. The primary endpoint was HbA1c level at 24 weeks. The baseline characteristics of a total of 12 subjects were as follows: age, 50.1 ± 13.2 years; diabetes duration, 17.3 ± 10.5 years; body mass index (BMI), 22.9 ± 2.1 kg/m2; HbA1c, 8.8 ± 1.3%; and daily insulin dose, 0.60 ± 0.21 units/kg. IPRA decreased HbA1c levels to 8.2 ± 1.2% (p < 0.05) and reduced insulin dose to 0.52 ± 0.17 units/kg (p < 0.01) after 24 weeks. HbA1c value was particularly reduced in subjects with preserved C-peptide index. IPRA significantly reduced body weight by -1.4 ± 1.4 kg (p < 0.01) 16 weeks after starting treatment, with no further weight loss after 24 weeks. There were no instances of diabetic ketoacidosis or severe hypoglycemia. IPRA exerted beneficial effects on glycemic control without any severe adverse effects, and should be safe and effective when used in patients with type 1 DM with understanding of correspondence in sick day.

Favorable Effects of GLP-1 Receptor Agonist against Pancreatic ß-Cell Glucose Toxicity and the Development of Arteriosclerosis: "The Earlier, the Better" in Therapy with Incretin-Based Medicine.

Fundamental pancreatic ß-cell function is to produce and secrete insulin in response to blood glucose levels. However, when ß-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic ß-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the ß-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of ß-cells. However, GLP-1R expression in ß-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on ß-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of ß-cells against glucose toxicity in routine medical care.

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.

Correction to: Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice.

It has been brought to our attention that Fig. 5a showing the vasculature in islets of control flox mice is not in fact an endocrine cell but rather exocrine tissue.

Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice.

AIMS/HYPOTHESIS: The aim of this study was to elucidate the impact of 3'-phosphoinositide-dependent protein kinase-1 (PDPK1) in vascular endothelial cells on the maintenance of pancreatic beta cell mass and function. METHODS: Male vascular endothelial cell-specific Pdpk1-knockout mice (Tie2+/-/Pdpk1flox/flox mice) and their wild-type littermates (Tie2-/-/Pdpk1flox/flox mice; control) were used for this study. At 12 weeks of age, an IPGTT and OGTT were conducted. Pancreatic blood flow was measured under anaesthesia. Thereafter, islet blood flow was measured by the microsphere method. Mice were killed for islet isolation and further functional study and mRNA was extracted from islets. Pancreases were sampled for immunohistochemical analyses. RESULTS: During the IPGTT, the blood glucose level was comparable between knockout mice and control flox mice, although serum insulin level was significantly lower in knockout mice. During the OGTT, glucose tolerance deteriorated slightly in knockout mice, accompanied by a decreased serum insulin level. During an IPGTT after pre-treatment with exendin-4 (Ex-4), glucose tolerance was significantly impaired in knockout mice. In fact, glucose-stimulated insulin secretion of isolated islets from knockout mice was significantly reduced compared with control flox mice, and addition of Ex-4 revealed impaired sensitivity to incretin hormones in islets of knockout mice. In immunohistochemical analyses, both alpha and beta cell masses were significantly reduced in knockout mice. In addition, the CD31-positive area was significantly decreased in islets of knockout mice. The proportion of pimonidazole-positive islets was significantly increased in knockout mice. mRNA expression levels related to insulin biosynthesis (Ins1, Ins2, Mafa, Pdx1 and Neurod [also known as Neurod1]) and beta cell function (such as Gck and Slc2a2) were significantly decreased in islets of knockout mice. Microsphere experiments revealed remarkably reduced islet blood flow. In addition, mRNA expression levels of Hif1α (also known as Hif1a) and its downstream factors such as Adm, Eno1, Tpi1 (also known as Ets1), Hmox1 and Vegfa, were significantly increased in islets of knockout mice, indicating that islets of knockout mice were in a more hypoxic state than those of control flox mice. As a result, mRNA expression levels related to adaptive unfolded protein response and endoplasmic reticulum stress-related apoptotic genes were significantly elevated in islets of knockout mice. In addition, inflammatory cytokine levels were increased in islets of knockout mice. Electron microscopy revealed reduced endothelial fenestration and thickening of basal membrane of vascular endothelium in islets of knockout mice. CONCLUSIONS/INTERPRETATION: Vascular endothelial PDPK1 plays an important role in the maintenance of pancreatic beta cell mass and function by maintaining vascularity of pancreas and islets and protecting them from hypoxia, hypoxia-related endoplasmic reticulum stress, inflammation and distortion of capillary structure.

Severe hypertriglyceridemia in a subject with disturbed life style and poor glycemic control without recurrence of acute pancreatitis: a case report.

BACKGROUND: Hypertriglyceridemia is often observed as the result of lipid abnormality and frequently associated with other lipid and metabolic disorders. Aggravation of hypertriglyceridemia is caused by various conditions. However, severe hypertriglyceridemia is usually induced by an addition of some secondary clinical conditions such as uncontrolled type 2 diabetes mellitus (T2DM) and obesity with insulin resistance. CASE PRESENTATION: A 40-year-old man with 4-year history of dyslipidemia and T2DM visited after his interruption of therapy for about 1.5 years. His past history was acute pancreatitis. His life style was markedly disturbed, and he had a lot of risk factors for hypertriglyceridemia. Surprisingly, his serum triglyceride level was as high as 16,900 mg/dL. His aggravation and remission of hypertriglyceridemia were closely associated with the alteration of RLP-cholesterol levels in dyslipidemia and glycoalbumin and ketone body levels in T2DM. CONCLUSION: We report very severe hypertriglyceridemia, which seemed to be caused by markedly disturbed life style and poorly controlled T2DM. Total therapy with diet and drug for each disease is very important for the improvement of very severe hypertriglyceridemia. This case report suggests that very severe hypertriglyceridemia alone does not necessarily bring out acute pancreatitis, although it is very important to check pancreatitis markers in such a situation.

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.

Protective effects of the SGLT2 inhibitor luseogliflozin on pancreatic ß-cells in db/db mice: The earlier and longer, the better.

AIMS: We compared the protective effects of sodium glucose co-transporter (SGLT) 2 inhibitor luseogliflozin on pancreatic ß-cells between early and advanced stages of diabetes and between short- and long-term use. MATERIALS AND METHODS: Diabetic db/db mice were treated with luseogliflozin for 2 weeks in an early stage of diabetes (7-9 weeks of age) and an advanced stage of diabetes (16-18 weeks) for a longer period of time (7-18 weeks). We performed various morphological analyses of pancreatic islets and examined gene expression profiles in islets after such treatment. RESULTS: In diabetic db/db mice, insulin biosynthesis and secretion were markedly increased by luseogliflozin in an early stage of diabetes but not in an advanced stage. In addition, ß-cell mass was preserved by luseogliflozin only in an early stage. Furthermore, when db/db mice were treated with luseogliflozin for a longer period of time, starting from an early stage, ß-cell function and mass were markedly preserved even after a longer period of time compared to untreated db/db mice. CONCLUSION: Luseogliflozin exerts more protective effects in an early stage of diabetes compared to an advanced stage, and longer-term use of luseogliflozin exerts more beneficial effects on pancreatic ß-cells compared to short-term use.