Profiling of Unfolded Protein Response Markers and Effect of IRE1α-specific Inhibitor in Pituitary Neuroendocrine Tumor.

CONTEXT: Inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK), which are endoplasmic reticulum (ER) membrane proteins, regulate the unfolded protein response (UPR). These molecules have recently gained attention as a novel therapeutic target in secretory tumors. The roles of the UPR in pituitary neuroendocrine tumors (PitNETs) are unclear. OBJECTIVE: To clarify UPR profiling of PitNETs and to investigate the effect of pharmacological modulation of UPR by KIRA8, a newly developed IRE1α-specific inhibitor. METHODS: In 131 patients with PitNETs, we evaluated RNA expression of UPR markers in PitNETs and their clinical phenotypes. Using GH3 cells, we examined the effects of KIRA8 and its combination with octreotide on UPR profiling, cell growth, and apoptosis. RESULTS: Cytoprotective adaptive-UPR (A-UPR) markers were more increased in functioning PitNETs (FPitNETs, n = 112) than in nonfunctioning PitNETs (NFPitNETs, n = 19), while there was no difference in proapoptotic terminal-UPR (T-UPR) markers. Similarly, overt somatotroph tumors (STs, acromegaly, n = 11) increased A-UPR compared with silent STs (n = 10). In STs, serum IGF-1 levels were inversely correlated with Txnip mRNA expression, a representative T-UPR marker. KIRA8 inhibited cell growth and facilitated apoptosis in GH3 cells with increased expressions of T-UPR markers, which was enhanced by the combination with octreotide. Octreotide increased mRNA expression of Txnip and Chop, but decreased spliced Xbp1 under ER stress. Octreotide is suggested to inhibit activation of IRE1α but to reciprocally induce T-UPR under PERK. CONCLUSION: UPR markers in FPitNETs are implicated as dominant A-UPR but blunted T-UPR. KIRA8, enhanced with octreotide, unbalances the UPR, leading to antitumor effects. Targeting IRE1α may provide a novel strategy to treat PitNETs.

Renoprotective potential of concomittant medications with SGLT2 inhibitors and renin-angiotensin system inhibitors in diabetic nephropathy without albuminuria: a retrospective cohort study.

The renal protective effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors and renin-angiotensin system (RAS) inhibitors on diabetic nephropathy without albuminuria have not been fully investigated. This retrospective cohort study focused on patients with type 2 diabetes mellitus who had a baseline estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m2, and a urinary albumin-to-creatinine ratio < 30 mg/gCr. After propensity score matching, using covariates such as age, body mass index, systolic blood pressure, hemoglobin A1c levels, and prescription history of RAS inhibitors, we established a cohort of 58 patients: the SGLT2 inhibitor group (n = 28) and the control group (n = 28). In this cohort, we compared the annual eGFR decline rate between the two groups. The SGLT2 inhibitor group exhibited a significantly smaller eGFR change than the control group (- 1.15 vs. - 2.18 mL/min/1.73 m2/year). Within the SGLT2 inhibitor group, patients prescribed RAS inhibitors had demonstrated an even smaller eGFR change (- 0.70 mL/min/1.73 m2/year). In conclusion, SGLT2 inhibitors also have safeguarding effects in the stage of diabetic nephropathy without albuminuria, and the combined use of a SGLT2 inhibitor and a RAS inhibitor appears to be more effective than the single use of each.

Thyroid function, glycemic control, and diabetic nephropathy in patients with type 2 diabetes over 24 months: prospective observational study.

BACKGROUND: The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in type 2 diabetes patients. This study was conducted to reveal whether higher prevalence of thyroid dysfunction is observed in patients with type 2 diabetes. METHODS: We examined thyroid functions and thyroid autoantibodies in 200 patients with type 2 diabetes and 225 controls, with 24 months follow up for those with type 2 diabetes. RESULTS: Serum free triiodothyronine (fT3) levels and fT3/free thyroxine (fT4) ratio were significantly lower, while fT4 levels were significantly higher in patients with type 2 diabetes. The number of patients with thyroid dysfunction or patients positive for thyroid autoantibodies were not different between the two groups. The fT3/fT4 ratio was positively and negatively correlated with serum c-peptide and HbA1c levels, respectively, suggesting that the difference can be attributable to insulin resistance and diabetic control. In the follow-up observation, we found no significant correlation between basal thyrotropin (TSH), fT3, fT4 or fT3/fT4 ratio with the amounts of changes of HbA1c levels at 12 or 24 months after the basal measurements. There was a negative relationship between TSH levels and eGFR at baseline measurements, but TSH levels did not seem to predict future decline of eGFR levels. No relationship was observed between urine albumin/ g‧cre levels and thyroid function. CONCLUSION: Thyroid dysfunction and thyroid autoantibodies were not different in prevalence between patients with type 2 diabetes and controls, although in patients with type 2 diabetes, the fT3/fT4 ratio was decreased. Basal thyroid function did not predict future diabetes control or renal function within 24 months of follow-up.

Effect of SARS-CoV-2 BNT162b2 mRNA vaccine on thyroid autoimmunity: A twelve-month follow-up study.

Objectives: Graves' disease (GD) has been highlighted as a possible adverse effect of the respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. However, it is unknown if the SARS-CoV-2 vaccine disrupts thyroid autoimmunity. We aimed to present long-term follow-up of thyroid autoimmunity after the SARS-CoV-2 BNT162b2 mRNA vaccine. Methods: Serum samples collected from seventy Japanese healthcare workers at baseline, 32 weeks after the second dose (pre-third dose), and 4 weeks after the third dose of the vaccine were analyzed. The time courses of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibody, thyroid-stimulating hormone receptor antibody (TRAb), and thyroid function were evaluated. Anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were additionally evaluated in thirty-three participants. Results: The median age was 50 (IQR, 38-54) years and 69% were female. The median anti-spike IgG antibody titer was 17627 (IQR, 10898-24175) U/mL 4 weeks after the third dose. The mean TRAb was significantly increased from 0.81 (SD, 0.05) IU/L at baseline to 0.97 (SD, 0.30) IU/L 4 weeks after the third dose without functional changes. An increase in TRAb was positively associated with female sex (ß = 0.32, P = 0.008) and low basal FT4 (ß = -0.29, P = 0.02) and FT3 (ß = -0.33, P = 0.004). TgAb was increased by the third dose. Increase in TgAb was associated with history of the thyroid diseases (ß = 0.55, P <0.001). Conclusions: SARS-CoV-2 BNT162b2 mRNA vaccine can disrupt thyroid autoimmunity. Clinicians should consider the possibility that the SARS-CoV-2 vaccine may disrupt thyroid autoimmunity.

Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma.

Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic ß cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma.

Soluble T-cadherin promotes pancreatic ß-cell proliferation by upregulating Notch signaling.

Endogenous humoral factors that link systemic and/or local insulin demand to pancreatic ß-cells have not been identified. Here, we demonstrated that T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin primarily expressed in vascular endothelial cells and cardiac and skeletal muscle cells, but not in pancreatic ß-cells, was secreted as soluble forms and was important for ß-cell proliferation. Cdh13 (T-cadherin) knockout mice exhibited impaired glucose handling due to attenuated ß-cell proliferation under high-fat diet conditions. The gene expression analyses indicated the impairment in cell cycle and Notch signaling in the islets of T-cadherin knockout mice under high-fat diet conditions. In streptozotocin-induced diabetes, the replacement of soluble T-cadherin improved ß-cell mass and blood glucose levels in T-cadherin knockout mice. Recombinant soluble T-cadherin upregulated Notch signaling in cultured murine islets. We concluded that soluble T-cadherin could work as an endogenous humoral factor whose signaling pathways including Notch signaling regulate ß-cell proliferation under diabetic conditions in mice.

Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report.

BACKGROUND: The global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19. CASE PRESENTATION: A healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH < 1.5 pg/ml, cortisol 1.6 µg/dl). He was diagnosed with adrenal crisis and was emergently treated with hydrocortisone. The symptoms responded well and he recovered within a few days. Magnetic resonance images after the replacement with hydrocortisone revealed an atrophic pituitary gland. The patient was referred to our tertiary hospital for further endocrinological examination. Pituitary endocrine load tests revealed isolated adrenocortical response deficiency. After other clinical assessments, he was diagnosed as having isolated ACTH deficiency. After initiation of hydrocortisone replacement, there has been no recurrence of symptoms related to adrenocortical insufficiency nor involvement of other pituitary functions. CONCLUSION: This is the first reported case of IAD potentially associated with COVID-19 immunization. Recent reports have emphasized the importance of adjuvants in the mRNA vaccine that induce the endocrinological adverse effects through disturbance of the autoimmune system, but details are still unclear. Given the broad and rapid spread of vaccinations against COVID-19, it is clinically important to consider that there could be cases with a rare but emergent adrenal crisis even among those who present common symptoms of adverse effects following inactive SARS-CoV-2 mRNA vaccination.

Molecular Mechanism of Pancreatic ß-Cell Failure in Type 2 Diabetes Mellitus.

Various important transcription factors in the pancreas are involved in the process of pancreas development, the differentiation of endocrine progenitor cells into mature insulin-producing pancreatic ß-cells and the preservation of mature ß-cell function. However, when ß-cells are continuously exposed to a high glucose concentration for a long period of time, the expression levels of several insulin gene transcription factors are substantially suppressed, which finally leads to pancreatic ß-cell failure found in type 2 diabetes mellitus. Here we show the possible underlying pathway for ß-cell failure. It is likely that reduced expression levels of MafA and PDX-1 and/or incretin receptor in ß-cells are closely associated with ß-cell failure in type 2 diabetes mellitus. Additionally, since incretin receptor expression is reduced in the advanced stage of diabetes mellitus, incretin-based medicines show more favorable effects against ß-cell failure, especially in the early stage of diabetes mellitus compared to the advanced stage. On the other hand, many subjects have recently suffered from life-threatening coronavirus infection, and coronavirus infection has brought about a new and persistent pandemic. Additionally, the spread of coronavirus infection has led to various limitations on the activities of daily life and has restricted economic development worldwide. It has been reported recently that SARS-CoV-2 directly infects ß-cells through neuropilin-1, leading to apoptotic ß-cell death and a reduction in insulin secretion. In this review article, we feature a possible molecular mechanism for pancreatic ß-cell failure, which is often observed in type 2 diabetes mellitus. Finally, we are hopeful that coronavirus infection will decline and normal daily life will soon resume all over the world.

Hypopituitarism and cranial nerve involvement mimicking Tolosa-Hunt syndrome as the initially presenting feature of diffuse large B-cell lymphoma: a case report.

BACKGROUND: Early diagnosis of lymphoma involving the central nervous system is sometimes difficult but emergent to avoid the delay of therapeutic initiation. Pituitary insufficiencies are usually associated with lymphoma in the pituitary gland. There have been no cases of lymphoma originating from extra pituitary gland with hypopituitarism that simultaneously presenting unilateral upper cranial nerve palsies and ophthalmalgia. These symptoms are mostly caused by neoplastic involvement of the skull base or benign diseases such as Tolosa-Hunt syndrome (THS). We report a case of lymphoma with unique clinical courses initially presenting hypopituitarism and symptoms mimicking THS with a mass in sphenoidal and cavernous sinuses accompanying sphenoidal bone erosion. CASE PRESENTATION: A 71-year-old woman visited our hospital with left ophthalmalgia, ptosis, and diplopia. Neurological findings revealed left oculomotor, trochlear and abducent nerve palsies. Endocrine tests indicated partial hypopituitarism. Initial CT and MRI revealed that a mass in sphenoidal and cavernous sinuses had invaded the sella with osteolysis of the sphenoid bone. At around four weeks, almost all the symptoms of cranial nerve palsies were relieved. Seven weeks later, she had a high fever and cervical lymph node (CLN) swellings. CLN biopsy revealed CD20-positive B-cells. She was diagnosed with diffuse large B-cell lymphoma (DLBCL). 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) revealed elevated uptake at the erosion lesion of the sphenoidal bone, but not the pituitary gland. After chemotherapy, all the symptoms related to systemic lymphoma were relieved, but partial hypopituitarism remained. The mass in sphenoidal and cavernous sinuses and elevated uptake by PET/CT were dissolved. CONCLUSION: This case of DLBCL had a unique clinical course; initial presentation of hypopituitarism and symptoms mimicking THS. There was also rare demonstration of mass lesions related to DLBCL in the sphenoidal and cavernous sinuses compressing the pituitary gland through an eroded area of the sphenoidal bone. It should be clinically cautioned that DLBCL can be associated with erosion of the sphenoidal bone and cause both hypopituitarism and THS-mimicking symptoms.

Spatial and transcriptional heterogeneity of pancreatic beta cell neogenesis revealed by a time-resolved reporter system.

AIMS/HYPOTHESIS: While pancreatic beta cells have been shown to originate from endocrine progenitors in ductal regions, it remains unclear precisely where beta cells emerge from and which transcripts define newborn beta cells. We therefore investigated characteristics of newborn beta cells extracted by a time-resolved reporter system. METHODS: We established a mouse model, 'Ins1-GFP; Timer', which provides spatial information during beta cell neogenesis with high temporal resolution. Single-cell RNA-sequencing (scRNA-seq) was performed on mouse beta cells sorted by fluorescent reporter to uncover transcriptomic profiles of newborn beta cells. scRNA-seq of human embryonic stem cell (hESC)-derived beta-like cells was also performed to compare newborn beta cell features between mouse and human. RESULTS: Fluorescence imaging of Ins1-GFP; Timer mouse pancreas successfully dissected newly generated beta cells as green fluorescence-dominant cells. This reporter system revealed that, as expected, some newborn beta cells arise close to the ducts (ßduct); unexpectedly, the others arise away from the ducts and adjacent to blood vessels (ßvessel). Single-cell transcriptomic analyses demonstrated five distinct populations among newborn beta cells, confirming spatial heterogeneity of beta cell neogenesis such as high probability of glucagon-positive ßduct, musculoaponeurotic fibrosarcoma oncogene family B (MafB)-positive ßduct and musculoaponeurotic fibrosarcoma oncogene family A (MafA)-positive ßvessel cells. Comparative analysis with scRNA-seq data of mouse newborn beta cells and hESC-derived beta-like cells uncovered transcriptional similarity between mouse and human beta cell neogenesis including microsomal glutathione S-transferase 1 (MGST1)- and synaptotagmin 13 (SYT13)-highly-expressing state. CONCLUSIONS/INTERPRETATION: The combination of time-resolved histological imaging with single-cell transcriptional mapping demonstrated novel features of spatial and transcriptional heterogeneity in beta cell neogenesis, which will lead to a better understanding of beta cell differentiation for future cell therapy. DATA AVAILABILITY: Raw and processed single-cell RNA-sequencing data for this study has been deposited in the Gene Expression Omnibus under accession number GSE155742.

Correction to: Glycemic control of people with diabetes over months after the 2018 North Osaka Earthquake.

[This corrects the article DOI: 10.1007/s13340-020-00438-6.].

Reduced Fat Taste Sensitivity in Obese Japanese Patients and Its Recovery after a Short-Term Weight Loss Program.

Fat taste has recently attracted attention as the 'sixth taste.' However, the relationship between fat and sweet taste in Japanese obesity has not yet been examined, and no reports have ascertained whether improvement of fat taste can be obtained by weight loss. Patients were recruited into obesity group (BMI≥30 kg/m2; n=15) or control group (BMI<25 kg/m2; n=11). They answered a questionnaire on smoking, eating behavior, lifestyle, and food frequency, and their taste thresholds were measured (fat, umami, and sweet). The obesity group was tested twice (on admission and before discharge). They showed several eating behavior abnormalities, higher total energy intake, and less physical activity. There were some gender differences: physical inactivity was more prominent in females, and high total energy intake in males, which correlates with fat taste rank. Fat taste rank was significantly higher in obesity group, whereas taste rank of umami and sweet were not significantly different. Gender-specific analysis of fat taste rank revealed only male obesity showed significant difference. Reduced sensitivity of fat may be specific to male gender or obesity by overeating, but not by physical inactivity. Multiple logistic regression analysis revealed that fat taste was a factor relevant to obesity. Fat taste significantly improved after a weight loss program, with average duration of 11.3 d. Japanese obese people, especially males and those who are obese by overeating, have reduced sensitivity to fat taste. This can be recovered by even a short-term weight loss program.

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice.

AIMS/HYPOTHESIS: Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. METHODS: We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. RESULTS: Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12-15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. CONCLUSIONS/INTERPRETATION: Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes. DATA AVAILABILITY: The single-cell RNA sequence (scRNA-seq) analysis datasets generated in this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE166164 ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166164 ).

Association of abdominal obesity with crossing capillaries in the finger nailfold in type 2 diabetes mellitus.

AIM: Increased crossing of finger nailfold capillaries could be a novel visual marker of early microvascular damage among type 2 diabetes mellitus patients. Although abdominal obesity is an important driver of early microvascular damage, its association with an increase in the percentage of crossing capillaries remains uncertain. We investigated the association between abdominal obesity and an increase in the percentage of crossing capillaries in the finger nailfold in patients with type 2 diabetes mellitus. METHODS: This cross-sectional study enrolled 123 type 2 diabetes mellitus patients (age 40-75 years) who visited the outpatient diabetic clinic at Osaka University Hospital between May and October 2019. Abdominal obesity was defined as a waist circumference ≥ 90 cm in women and ≥ 85 cm in men. Capillary morphology was assessed by nailfold capillaroscopy based on the simple capillaroscopic definitions of the European League Against Rheumatism Study Group. The association between abdominal obesity and a high percentage of crossing capillaries in the finger nailfold (defined as the highest tertile of crossing capillaries) was analyzed using multivariable logistic regression. RESULTS: After adjusting for age, sex, smoking status, regular exercise, duration of diabetes, glycated hemoglobin, hypertension, and dyslipidemia, abdominal obesity was significantly associated with a high percentage of crossing capillaries (multivariable-adjusted odds ratios [95% confidence interval] = 2.70 [1.05-6.90], p = 0.038). CONCLUSIONS: Abdominal obesity may play an important role in the increase in the percentage of crossing capillaries in the finger nailfold in patients with type 2 diabetes mellitus.

Psychosocial conditions and the progression of diabetic nephropathy in Japanese with type 2 diabetes mellitus.

We previously reported the association of positive psychosocial conditions with diabetic nephropathy (DN) in patients with type 2 diabetes in a cross-sectional setting. In the present study, we evaluated the association between six indicators related to psychosocial conditions and the progression of DN assessed by estimated glomerular filtration rate (eGFR) and albuminuria during 2-year observation period in 252 patients with type 2 diabetes. In unadjusted model, the subjects with higher happiness score attenuated reduced eGFR, and those with more social support attenuated increase in alubuminuria and decline eGFR. However, in adjusted model for happiness score and social support, only happiness score indicated the significant association with reduced eGFR. Gender-segregated analysis showed a significant association between happiness score and ΔeGFR in male but not in female subjects. On the other hand, decrease in eGFR was significantly attenuated in the subjects with more social support as compared to those with less social support in women but not in men. These results suggested that that psychosocial conditions could be related to the progression of DN, and that the psychosocial factors that influence in DN might differ between men and women, in Japanese patients with type 2 diabetes.

Evaluation of change in metabolome caused by comprehensive diabetes treatment: A prospective observational study of diabetes inpatients with gas chromatography/mass spectrometry-based non-target metabolomic analysis.

AIMS/INTRODUCTION: Diabetes patients develop a variety of metabolic abnormalities in addition to hyperglycemia. However, details regarding change in various metabolites after comprehensive diabetes treatment remain unknown. This study aimed to identify the short-term change in metabolome in inpatients who were subject to comprehensive diabetes treatment, using gas chromatography/mass spectrometry-based non-target metabolomics techniques. MATERIALS AND METHODS: Participants of the present study were randomly recruited from the patients with type 2 diabetes hospitalized due to problems with glycemic control (n = 31) and volunteers without diabetes (n = 30), both of whom were aged between 20 and 75 years. A metabolomic analysis of fasting plasma samples on the 2nd (pre-treatment) and 16th hospital (post-treatment) day with gas chromatography/mass spectrometry using a multiple reaction monitoring mode was carried out. RESULTS: A principal component analysis showed that metabolome of fasting plasma was different between individuals with and without diabetes. The metabolome of fasting plasma in diabetes patients after treatment was different from that of pre-treatment, as well as individuals without diabetes. Many amino acids (proline, glycine, serine, threonine, methionine, pyroglutamic acid, glutamine and lysine) were significantly increased by >10% after administering the inpatient diabetes treatment. A hierarchical clustering analysis showed that in the case of patients with markedly decreased monosaccharide levels and increased 1,5-anhydroglucitol, the levels of amino acids increased more significantly. CONCLUSIONS: After a 2-week comprehensive treatment, the plasma levels of various amino acids increased in conjunction with the reduction in monosaccharide levels in poorly controlled type 2 diabetes patients.

Unexpected Pleiotropic Effects of SGLT2 Inhibitors: Pearls and Pitfalls of This Novel Antidiabetic Class.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors facilitate urine glucose excretion by reducing glucose reabsorption, leading to ameliorate glycemic control. While the main characteristics of type 2 diabetes mellitus are insufficient insulin secretion and insulin resistance, SGLT2 inhibitors have some favorable effects on pancreatic ß-cell function and insulin sensitivity. SGLT2 inhibitors ameliorate fatty liver and reduce visceral fat mass. Furthermore, it has been noted that SGLT2 inhibitors have cardio-protective and renal protective effects in addition to their glucose-lowering effect. In addition, several kinds of SGLT2 inhibitors are used in patients with type 1 diabetes mellitus as an adjuvant therapy to insulin. Taken together, SGLT2 inhibitors have amazing multifaceted effects that are far beyond prediction like some emerging magical medicine. Thereby, SGLT2 inhibitors are very promising as relatively new anti-diabetic drugs and are being paid attention in various aspects. It is noted, however, that SGLT2 inhibitors have several side effects such as urinary tract infection or genital infection. In addition, we should bear in mind the possibility of diabetic ketoacidosis, especially when we use SGLT2 inhibitors in patients with poor insulin secretory capacity.

Glucotoxicity-induced suppression of Cox6a2 expression provokes ß-cell dysfunction via augmented ROS production.

Oxidative stress is a deteriorating factor for pancreatic ß-cells under chronic hyperglycemia in diabetes. However, the molecular mechanism underlying the increase in oxidative stress in ß-cells under diabetic conditions remains unclear. We demonstrated previously that the selective alleviation of glucotoxicity ameliorated the downregulation of several ß-cell factors, including Cox6a2. Cox6a2 encodes a subunit of the respiratory chain complex IV in mitochondria. In this study, we analyzed the role of Cox6a2 in pancreatic ß-cell function and its pathophysiological significance in diabetes mellitus. Cox6a2-knockdown experiments in MIN6-CB4 cells indicated an increased production of reactive oxygen species as detected by CellROX Deep Red reagent using flow cytometry. In systemic Cox6a2-knockout mice, impaired glucose tolerance was observed under a high-fat high-sucrose diet. However, insulin resistance was reduced when compared with control littermates. This indicates a relative insufficiency of ß-cell function. To examine the transcriptional regulation of Cox6a2, ATAC-seq with islet DNA was performed and an open-chromatin area within the Cox6a2 enhancer region was detected. Reporter gene analysis using this area revealed that MafA directly regulates Cox6a2 expression. These findings suggest that the decreased expression of Cox6a2 increases the levels of reactive oxygen species and that Mafa is associated with decreased Cox6a2 expression under glucotoxic conditions.

Association of obesity, diabetes, and physical frailty with dental and tongue-lip motor dysfunctions in patients with metabolic disease.

OBJECTIVE: This study aimed to reveal the clinical features associated with decreased dental (or shearing/crushing) and tongue-lip motor functions in patients with metabolic diseases. METHODS: One thousand patients with metabolic diseases including diabetes, dyslipidemia, hypertension, and hyperuricemia were recruited. Dental function was assessed with a gummy jelly test, wherein glucose elution from a chewed gummy jelly was measured. Tongue-lip motor function was measured as repeatedly pronounced syllables per second. The association of clinical variables with the two functions was analyzed using multivariate linear regression models. RESULTS: The mean measurement of dental function was 202 ± 73 mg/dL, and that of tongue-lip motor function was 5.5 ± 1.0 times/s. Clinical variables independently associated with dental function (mg/dL) were age (adjusted regression coefficient ß = -9.8 per standard deviation [SD]), smoking (ß = -14.4 and -25.9 for past and current smoking, respectively), body mass index (BMI) 25-30 and ≥30 versus 20-25 kg/m2 (ß = -14.7 and -23.1, respectively), diabetes (ß = -11.9), hemoglobin A1c level ≥64 mmol/mol (ß = -14.6), gait speed (ß = 6.2 per SD), and handgrip strength (ß = 7.5 and 7.7 per SD for males and females, respectively) (all P < 0.05). Clinical variables independently associated with tongue-lip motor function (times/s) were age (ß = -0.31 per SD), BMI ≥ 30 versus 20-25 kg/m2 (ß = -0.24), diabetes (ß = -0.22), dyslipidemia (ß = 0.16), gait speed (ß = 0.12 per SD), and handgrip strength (ß = 0.18 and 0.13 per SD for males and females, respectively) (all P < 0.05). CONCLUSIONS: Obesity, diabetes, physical frailty, and old age were shared risk factors for decreased dental and tongue-lip motor functions in patients with metabolic diseases.

Coincidence of Large Adrenal Cyst and Prominent Hyporeninemic Hyperaldosteronism.

A 67-year-old Japanese woman who had end-stage renal disease was referred to our hospital for kidney transplantation. Abdominal CT revealed a large adrenal mass with inhomogeneity. She had a history of hospitalization for stroke and heart failure and exhibited prominent hyporeninemic hyperaldosteronism. Histological examination of the resected tumor with anti-CYP11B2 antibody indicated that she had a vascular endothelial cyst with primary aldosteronism (PA) due to multiple adrenocortical micronodules. This report implicates the pathological interaction between adrenal vascular cysts and PA-mediated vascular damage of the adrenal vein.