Opioid-induced adrenal insufficiency in transdermal fentanyl treatment: a revisited diagnosis in clinical setting.

Opioids are widely used for treatment of acute and chronic pain. However, opioids have several well-known clinical adverse effects such as constipation, nausea, respiratory depression and drowsiness. Endocrine dysfunctions are also opioid-induced adverse effects but remain under-diagnosed in clinical settings, especially opioid-induced adrenal insufficiency (OIAI). A 46-year-old woman was treated with transdermal fentanyl at a dose of 90-120 mg daily morphine milligram equivalent for non-malignant chronic pain for four years. Fatigue, loss of appetite and decrease in vitality began about two years after starting fentanyl. Subsequently, constipation and abdominal pain appeared and became worse, which led to suspicion of adrenal insufficiency. Clinical diagnosis of OIAI was established based on laboratory findings of secondary adrenal insufficiency, including corticotropin-releasing hormone stimulation test, clinical history of long-term fentanyl use, and exclusion of other hypothalamic-pituitary diseases. Oral corticosteroid replacement therapy was unable to relieve her abdominal pain and constipation; opioid-rotation and dose-reduction of fentanyl were not feasible because of her persistent pain and severe anxiety. While her clinical course clearly suggested that long-term, relatively high-dose transdermal fentanyl treatment may have contributed to the development of secondary adrenal insufficiency, the symptoms associated with OIAI are generally non-specific and complex. Together with under-recognition of OIAI as a clinical entity, the non-specific, wide range of symptoms can impede prompt diagnosis. Thus, vigilance for early symptoms enabling treatments including corticosteroid replacement therapy is necessary for patients taking long-term and/or high dose opioid treatment.

Acromegaly accompanied by diabetes mellitus and polycystic kidney disease.

Acromegaly is characterized by autonomous excessive growth hormone (GH) secretion, generally due to GH-producing pituitary adenoma, and is associated with various systemic comorbidities including diabetes mellitus. Polycystic kidney disease (PKD) is characterized by the growth of numerous cysts in the kidneys that deteriorate renal function. While possible renal effects of excessive GH exposure have been a current issue in experimental medicine, only five cases of coexisting acromegaly and PKD have been reported previously, and little is known regarding the influence of acromegaly on renal disease. We treated a 50-year-old male with diabetes mellitus who showed a sudden and rapid decline of renal function along with increasing proteinuria, which led to diagnoses of PKD and acromegaly. His urinary protein levels were increased together with excessive GH secretion and worsening glycemic control. An increase of total kidney volume was also noted. Transsphenoidal surgery for the pituitary adenoma was successfully performed. Marked improvement of hyperglycemia and proteinuria were observed after the surgery, but renal function was unchanged. The patient's clinical course suggested common aspects of excessive GH secretion as an accelerating factor of the progression of diabetic nephropathy and PKD via direct and indirect pathways. Although coexisting acromegaly and PKD is clinically rare, vigilance for early diagnosis of acromegaly is appropriate in patients with diabetes and/or PKD, especially in those showing unexpected exacerbation of renal dysfunction.

Factory-calibrated continuous glucose monitoring and capillary blood glucose monitoring in a case with insulinoma: usefulness and possible pitfall under chronic hyperinsulinemic hypoglycemia.

The accuracy of factory-calibrated continuous glucose monitoring (fCGM) within hypoglycemic ranges, especially under the status of chronic hyperinsulinemic hypoglycemia like insulinomas, remains an issue. Even so, fCGM is known to be useful for detecting hypoglycemia unawareness in insulinoma cases. A 25-year-old woman presenting with sudden unconsciousness was diagnosed with insulinoma; fCGM facilitated diagnosis by continuous monitoring for hypoglycemia. Before surgery, she was treated with continuous and frequent bolus infusions of 50% glucose via central venous catheter. To evaluate the accuracy of fCGM values in this case, a comparison between fCGM and capillary blood glucose (CBG) values was also performed. According to the simultaneously measured values, those of fCGM were largely in accordance with those of CBG. Moreover, compared with the previously reported case not having glucose infusions via central venous catheter, both the mean absolute relative differences (MARDs) and the absolute differences (Δ glucose) between fCGM and CBG values were larger in the present case, although no significant differences of MARDs and Δ glucose between the two cases were observed in several different conditions including fasting, post-meal, hypoglycemia, and others. Therefore, we should note possible increased differences between fCGM and CBG values in cases using frequent intravenous glucose infusions as well as case-dependent differing levels of consistency between them.

Protein hypoacylation induced by Sirt5 overexpression has minimal metabolic effect in mice.

Sirtuins are a family of evolutionary conserved enzymes that dynamically regulate cellular physiology. Mammals have 7 sirtuins, which are located in different cellular compartments. Sirt5, a sirtuin isoform located in multiple subcellular sites, is involved in regulating a diverse range of cellular and metabolic processes through the removal of a range of acyl-lysine modifications on target proteins. Loss of Sirt5 leads to hyper-malonylation and hyper-succinylation of both mitochondrial and extra-mitochondrial proteins, influencing oxidative phosphorylation, the TCA cycle and glycolysis. However despite these findings, the effect of Sirt5 overexpression on metabolism remains poorly investigated. Here we report that overexpression of Sirt5 has minimal effect on mitochondrial metabolism and overall physiology in mice, despite inducing widespread decreases in protein acylation. Our data confirms the role of Sirt5 as an important demalonylase and desuccinylase enzyme in vivo, but questions the relevance of physiological changes in protein acylation levels in the regulation of cellular metabolism.

DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells.

Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy.

An exploratory study of factors in disordered eating behavior in diabetes self-management in Japan.

AIMS/INTRODUCTION: Diet directly affects glucose metabolism, and eating behavior is influenced by various daily life stressors. This study was conducted to investigate the relationship between common psychosomatic stressors on endocrine hormones and eating behavior in patients with type 2 diabetes. MATERIALS AND METHODS: This cross-sectional study was performed in 40 patients with type 2 diabetes. Resting hormone blood sampling and four self-reported questionnaires were employed. RESULTS: Patients who scored higher on the 'anger/hostility' (AH) subcategory of the profile of mood state (POMS) questionnaire had significantly higher serum cortisol (ß = 0.40, P = 0.01 by least squares adjusted for age and sex). In the eating behavior questionnaire, the subcategories of 'feeling of hunger/satiation' (ß = 0.49, P < 0.01) and 'eating as diversion' (ß = 0.39, P = 0.03) were associated with higher serum cortisol. Resting morning cortisol levels were higher in participants who rated high on the POMS-AH and in those who reported 'irritated when hungry' and 'tend to eat when irritated or anxious'. Sleep quality showed no association with eating behavior. CONCLUSIONS: Mood state is associated with eating behavior. Anger increases cortisol levels and may lead to compulsive eating. Various forms of hostility are important factors in appetite control and increased cortisol secretion, and can be an impediment to successful dietary self-management in patients with type 2 diabetes. Thus, assessment of mood state and control of negative mood are important therapeutic targets in diabetes management.

A Case Report of Diabetes in a Patient with Glycogen Storage Disease Type 1a.

Glycogen storage disease type 1a (GSD-1a) is a rare congenital disease. Recently, life expectancy with GSD-1a has been improved by its early diagnosis and management. Complications of diabetes with GSD-1a are extremely rare. The optimal treatment for glucose control using this disease combination remains unclear. The existence of GSD-1a and diabetes can cause both hypoglycemia and hyperglycemia, making glucose control especially problematic. In the present report, α-glucosidase inhibitor (α-GI) and dipeptidyl peptidase-4 (DPP-4) inhibitors improved hyperglycemia without symptoms of hypoglycemia in a patient with diabetes and GSD-1a using intermittent continuous glucose monitoring (isCGM).

Self-monitoring of blood glucose (SMBG) improves glycaemic control in oral hypoglycaemic agent (OHA)-treated type 2 diabetes (SMBG-OHA study).

BACKGROUND: We conducted a clinical research study to determine the effect of self-monitoring of blood glucose (SMBG) on glycaemic control and the value of a putatively less painful blood sampling technique on SMBG in oral hypoglycaemic agent-treated type 2 diabetes patients; SMBG has not been broadly applied in non-insulin-treated patients in Japan. METHODS: One hundred thirty-seven subjects were recruited for the 24-week, prospective, comparison study and randomized into three groups: 46, no SMBG group; 46, fingertip group; and 45, palm group. The primary endpoint was change in HbA(1c). The secondary endpoints were SMBG compliance, dropout rate, treatment changes, and patient's and physician's satisfaction. RESULTS: Six subjects in the fingertip group (13.2%) and one subject in the palm group (2.2%) were dropped because of pain. A(1C) level of all subjects at 24-week was decreased more in the fingertip (-0.23%) and palm (-0.16%) groups than that in the no SMBG group (+0.31%) (p < 0.05). SMBG compliance was higher in the fingertip group (2.17 times/day) than that in the palm group (1.65 times/day) (p < 0.05). A(1C) level of treatment-unchanged subjects was decreased more in the fingertip (-0.25%) and palm (-0.21%) groups than that in the no SMBG group (+0.30%) (p < 0.05). SMBG compliance was higher in the fingertip group (2.24 times/day) than that in the palm group (1.65 times/day) (p < 0.05). Patient's questionnaire showed that 84.1% of the fingertip group and 90.2% of the palm group were satisfied with SMBG. Physician's satisfaction was higher in the palm group (94.0%) than that in the fingertip group (80.0%) (p < 0.05). CONCLUSION: SMBG is beneficial for glycaemic control, and palm blood sampling is a useful procedure for oral hypoglycaemic agent-treated type 2 diabetes.

Psychological Factors Motivating Male Japanese Workers With Type 2 Diabetes to Engage in Dietary Modifications: A Qualitative Descriptive Study.

Introduction: Japanese men with type 2 diabetes mellitus (T2DM) usually encounter work-related difficulties when engaging in dietary modifications. Hence, healthcare providers must understand the psychological factors, such as the needs and goals, that motivate them to engage in dietary modifications. Objective: We aimed to describe the psychological factors motivating male Japanese workers with T2DM to engage in dietary modifications. Methods: Using a qualitative descriptive design, we conducted semi-structured interviews with 11 male Japanese workers with T2DM and identified categories based on semantic differences using qualitative content analysis. Results: The following eight categories emerged: (I want to) demonstrate my skills at work, be able to engage in dietary modifications on my own, avoid unpleasant symptoms caused by eating, avoid burdensome treatment, maintain my healthy life, get positive results in medical examinations, maintain my relationships with others, and enjoy healthy food. Conclusion: The factors motivating the participants to engage in dietary modifications were realistic and sincere desires rooted in their ideal lives. Their desire to prioritize work emerged as an important factor. Healthcare providers should identify an individual's ideal daily life, including work aspects, and encourage individuals to set realistic and valuable goals.

Big insulin-like growth factor 2-producing multiple solitary fibrous tumors treated with debulking surgery: A case report.

Background: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulin-like growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no standard treatment strategy for multiple tumors has been established. The effects of pharmacological therapies including somatostatin analogs are often inefficient and remain difficult to predict. Case description: A 68-year-old man was admitted to our hospital due to impaired consciousness and severe hypoglycemia. His medical history included diagnosis of a left temporal solitary fibrous tumor (SFT) at the age of 48 years, after which local recurrent and metastatic tumors were repeatedly resected. Four years before admission, multiple intraabdominal and subcutaneous tumors were detected and, being asymptomatic, were managed conservatively. Laboratory exam on admission demonstrated hypoglycemia accompanied with low serum insulin and IGF1 levels. Computed tomography (CT) scan revealed multiple intraabdominal and subcutaneous tumors increasing in size. Serum big IGF2 was detected on immunoblot analysis, and he was diagnosed as NICTH. In addition, tumor uptake was observed on 68Ga-labelled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-d-Phe1-Tyr3-octreotide positron emission tomography/CT (DOTATOC-PET/CT). Since larger tumor is more suspicious about responsible producibility of big IGF2, we planned to resect large ones preferentially and reduce the amounts of residual tumors. Debulking surgery was performed by removing eleven intraabdominal tumors; the hypoglycemia was then completely corrected. Histological analyses revealed the resected tumors to be metastases of SFT having somatostatin receptor 2 expression. In immunoblot analysis, the resected tumors were found to be positive for big IGF2; serum big IGF2 was undetectable after surgery. Conclusion: We present a case of NICTH with multiple metastatic SFTs. We strategically performed debulking surgery, which led to remission of hypoglycemia. This result demonstrates a pioneering practical solution for NICTH cases with multiple tumors. In addition, in cases of SFTs presenting with NICTH, positivity of DOTATOC-PET/CT as well as single-dose administration of octreotide may be predictive of the efficacy of somatostatin-based therapy.

Initiating SGLT2 inhibitor therapy to improve renal outcomes for persons with diabetes eligible for an intensified glucose-lowering regimen: hypothetical intervention using parametric g-formula modeling.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are now recommended in guidelines for persons with type 2 diabetes mellitus (T2DM) and at risk of advanced kidney disease as part of the glucose-lowering regimen. RESEARCH DESIGN AND METHODS: To explore the optimal threshold at which to initiate SGLT2 inhibitor therapy, we conducted an observational study analyzed under a counterfactual framework. This study used the electronic healthcare database in Japan, comprising data from approximately 20 million patients at approximately 160 medical institutions. Persons with T2DM with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 in April 2014 were eligible. The primary end point was the composite of renal deterioration (>40% decline in eGFR) and the development of eGFR<30 mL/min/1.73 m2. We estimated the risk of the composite end point occurring over 77 months in different scenarios, such as early or delayed intervention with SGLT2 inhibitors for uncontrolled diabetes at different hemoglobin A1c (HbA1c) thresholds. The parametric g-formula was used to estimate the risk of the composite end point, adjusting for time-fixed and time-varying confounders. RESULTS: We analyzed data from 36 237 persons (149 346 person-years observation), of whom 4679 started SGLT2 inhibitor therapy (9470 person-years observation). Overall, initiating SGLT2 inhibitor therapy was associated with a 77-month risk reduction in the end point by 1.3-3.7%. The largest risk reduction was observed within 3 months of initiation once the HbA1c level exceeded 6.5% (risk reduction of 3.7% (95% CI 1.6% to 6.7%)) compared with a threshold of 7.0% or higher. CONCLUSIONS: Our analyses favored early intervention with SGLT2 inhibitors to reduce the renal end point, even for persons with moderately controlled HbA1c levels. Our findings also suggest caution against clinical inertia in the care of diabetes.

A unique profile of insulin antibody titer in islet-transplanted patients.

Insulin antibodies (IAs) can cause glycemic variability. Islet transplantation (ITx) is a treatment for insulin-deficient diabetes that aims to establish on-target glycemic control in the absence of hypoglycemia. To date, there has not been a detailed case study of the association between ITx and IA levels. In this study, we identified a unique profile of IA titers, which differed from glutamic acid decarboxylase antibody titers, in four ITx patients. IA levels decreased with intensified immunosuppressive therapy, whereas glutamic acid decarboxylase antibodies increased transiently after ITx. These data suggest the possibility that IAs, unlike other islet autoantibodies, were eliminated due to immunosuppression after transplantation therapy. The disappearance of IAs, as well as the restoration of regulated insulin secretion after ITx, might have a positive effect on glycemic control in recipients with diabetes. Furthermore, this unique feature is suggestive of immunological pathogenesis and has implications for the treatment of IA-causing disease conditions.

Preservation effect of imeglimin on pancreatic ß-cell mass: Noninvasive evaluation using 111In-exendin-4 SPECT/CT imaging and the perspective of mitochondrial involvements.

Progressive loss of ß-cell mass (BCM) has a pernicious influence on type 2 diabetes mellitus (T2DM); evaluation of BCM has conventionally required an invasive method that provides only cross-sectional data. However, a noninvasive approach to longitudinal assessment of BCM in living subjects using an indium 111-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) (111In-exendin-4) has been developed recently. Imeglimin is a novel antidiabetic agent that is reported to improve glycemic control and glucose-stimulated insulin secretion (GSIS) via augmentation of mitochondrial function. However, the influence of imeglimin on BCM is not fully understood. We have investigated the effects of imeglimin on BCM in vivo in prediabetic db/db mice using a noninvasive 111In-exendin-4 single-photon emission computed tomography/computed tomography (SPECT/CT) technique. During the 5-week study period, imeglimin treatment attenuated the progression of glucose intolerance, and imeglimin-treated mice retained greater BCM than control, which was consistent with the results of 111In-exendin-4 SPECT/CT scans. Furthermore, immunohistochemical analysis revealed reduced ß-cell apoptosis in the imeglimin-treated db/db mice, and also lowered release of cytosolic cytochrome c protein in the ß cells. Furthermore, electron microscopy observation and membrane potential measurement revealed improved structural integrity and membrane potential of the mitochondria of imeglimin-treated islets, respectively. These results demonstrate attenuation of progression of BCM loss in prediabetic db/db mice partly via inhibition of mitochondria-mediated apoptosis.

Year-long effects of COVID-19 restrictions on glycemic control and body composition in patients with glucose intolerance in Japan: A single-center retrospective study.

AIMS/INSTRUCTION: During the coronavirus disease 2019 (COVID-19) pandemic, the lockdowns in Europe raised concerns about negative effects on glycemic control and body composition in patients with diabetes. In Japan, voluntary-based restrictions were imposed as the declaration of a state of emergency (DSE), whose metabolic consequences have not been fully investigated. We carried out a single-center retrospective study to evaluate changes in glycemic control and body composition in outpatients with glucose intolerance after the DSE. MATERIALS AND METHODS: We enrolled outpatients with glucose intolerance: (i) for whom longitudinal data about body composition were available; (ii) who participated in dietary follow up with nutritionists; and (iii) whose laboratory data included glycated hemoglobin (HbA1c) levels before and after the DSE. RESULTS: Among 415 patients, we found no significant changes in HbA1c overall after the DSE. Bodyweight and fat mass increased significantly, whereas skeletal mass decreased significantly. HbA1c changes after the DSE were significantly correlated with changes in bodyweight and fat mass. In 128 patients whose HbA1c levels increased ≥0.3%, changes in bodyweight and fat mass were significantly larger than those in the other 287 patients. With regard to lifestyle changes, increased snacking was likely to worsen glycemic control (odds ratio 1.76, P = 0.036). CONCLUSIONS: COVID-19 restrictions in Japan had unfavorable metabolic consequences for patients with glucose intolerance, highlighted by increased bodyweight and body fat, and decreased skeletal muscle. In addition, lifestyle changes, such as increased snacking, might worsen glycemic control. Clinical attention and interventions are required to prevent such metabolic changes.

Voxel-based specific regional analysis system for Alzheimer's disease utility as a screening tool for unrecognized cognitive dysfunction of elderly patients in diabetes outpatient clinics: Multicenter retrospective exploratory study.

AIMS/INTRODUCTION: An efficient screening strategy for identification of cognitive dysfunction remains a clinical issue in the management of elderly adults with diabetes. A magnetic resonance imaging voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) has been developed as an automated brain morphometry system that includes the hippocampus. We carried out a multicenter retrospective study to evaluate the utility of VSRAD for screening cognitive dysfunction in diabetes outpatient clinics. MATERIALS AND METHODS: We enrolled patients with diabetes aged >65 years who underwent brain magnetic resonance imaging scans for the purpose of a medical checkup between November 2018 and May 2019. Patients who were already suspected or diagnosed with mild cognitive impairment and/or dementia as well as those with a history of cerebrovascular disease were excluded. RESULTS: A total of 67 patients were enrolled. Five patients were diagnosed with mild cognitive impairment or dementia (clinical cognitive dysfunction). Patients with clinical cognitive dysfunction showed a significantly higher z-score in VSRAD analysis (2.57 ± 0.47 vs 1.15 ± 0.55, P < 0.01). The sensitivities and specificities for diagnosis of clinical cognitive dysfunction were 80 and 48% for the Mini-Mental State Examination, 100 and 89% for the z-score, and 100 and 90% for the combination of the Mini-Mental State Examination score and z-score, respectively. CONCLUSIONS: VSRAD analysis can distinguish patients with clinical cognitive dysfunction in the elderly with diabetes, and also shows reasonable sensitivity and specificity compared with the Mini-Mental State Examination alone. Thus, VSRAD analysis can be useful for early identification of clinical cognitive dysfunction in the elderly with diabetes.

Pemafibrate improves hepatic inflammation, function and fibrosis in patients with non-alcoholic fatty liver disease: a one-year observational study.

AIM OF THE STUDY: To optimize the long-term outcomes of patients with non-alcoholic fatty liver disease (NAFLD), long-term therapy is important to prevent cirrhosis and hepatocellular carcinoma. Pemafibrate, a novel selective peroxisome proliferator-activated receptor-α modulator, is a promising therapeutic agent for patients with NAFLD. However, only short-term clinical studies are currently available. The aim of this study is to evaluate the long-term outcomes of patients with NAFLD treated with pemafibrate. MATERIAL AND METHODS: This is a retrospective observational study. Patients with NAFLD treated with pemafibrate 0.1 mg twice daily for one year were retrospectively reviewed. RESULTS: Twenty-two patients without diabetes mellitus were included and analyzed. Regarding hepatic inflammation markers, alanine aminotransferase (ALT) significantly decreased during the first three months and was maintained. Low-density lipoprotein and triglycerides significantly decreased at three months and were maintained. Regarding markers of hepatic function, the albumin-bilirubin score decreased significantly during one year of therapy due to significantly elevated serum albumin and decreased total bilirubin levels. Regarding markers of fibrosis, Mac-2 binding protein glucosylation isomer (M2BPGi) significantly decreased, and platelet count increased significantly. Next, we performed correlation analysis between changes in M2BPGi and other parameters. Changes in aspartate aminotransferase, ALT and triglycerides positively correlated with the change in M2BPGi. CONCLUSIONS: One-year pemafibrate therapy improves markers of hepatic inflammation, function and fibrosis in non-diabetic patients with NAFLD. Improvement of hepatic fibrosis markers significantly correlates with improvement of hepatic inflammation markers and triglyceride levels.

Clinical Practice Changes After Post-Market Safety Reports on Desmopressin Orally Disintegrating Tablet in Japan: A Single-Center Retrospective Study.

BACKGROUND: Desmopressin orally disintegrating tablet (ODT) was approved in March 2012 in Japan; the post-market safety reports, which warned about adequate initial dose of desmopressin ODT, were published in 2014. However, it is unclear how the warning affected physician and patient behavior. METHODS: We performed a retrospective single-center study to compare the clinical situation of Japanese central diabetes insipidus patients before and after the report. RESULTS: Thirty-four patients before October 2014 and 16 patients after November 2014 switched from intranasal desmopressin to desmopressin ODT. The mean follow-up period after the switch to desmopressin ODT was 38 ± 3 months. Patients switching after November 2014 tended to have lower ratios of oral to nasal desmopressin dose at switching and 3 months after the switch (at switching; P = 0.20, 3 months; P = 0.42, respectively), and higher ratios from 6 to 12 months than before October 2014 (6 months; P = 0.93, 9 months; P = 0.52, 12 months; P = 0.80, respectively). Relative doses per initial desmopressin ODT at 9 and 12 months were significantly higher in patients switching after November 2014 than in patients switching before October 2014 (9 months; P = 0.02, 12 months; P = 0.04, respectively). Moreover, logistic regression analysis revealed that the incidence of hyponatremia was dependent on the ratio of nasal to oral desmopressin dose (P = 0.02). In addition, in four out of six patients who had serum sodium level reduced below 130 mEq/L, hyponatremia occurred within 1 month after the switch. CONCLUSIONS: A more gradual dose titration after the safety reports was performed, which involved the long-term safety of desmopressin ODT use. Vigilance of hyponatremia in early phase of desmopressin ODT use should be noted.

Overexpression of SIRT5 confirms its involvement in deacetylation and activation of carbamoyl phosphate synthetase 1.

SIR2 protein, an NAD-dependent deacetylase, is localized to nucleus and is involved in life span extension by calorie restriction in yeast. In mammals, among the seven SIR2 homologues (SIRT1-7), SIRT3, 4, and 5 are localized to mitochondria. As SIRT5 mRNA levels in liver are increased by fasting, the physiological role of SIRT5 was investigated in liver of SIRT5-overexpressing transgenic (SIRT5 Tg) mice. We identified carbamoyl phosphate synthetase 1 (CPS1), a key enzyme of the urea cycle that catalyzes condensation of ammonia with bicarbonate to form carbamoyl phosphate, as a target of SIRT5 by two-dimensional electrophoresis comparing mitochondrial proteins in livers of SIRT5 Tg and wild-type mice. CPS1 protein was more deacetylated and activated in liver of SIRT5 Tg mice than in wild-type. In addition, urea production was upregulated in hepatocytes of SIRT5 Tg mice. These results agree with those of a previous study using SIRT5 knockout (KO) mice. Because ammonia generated during fasting is toxic, SIRT5 protein might play a protective role by converting ammonia to non-toxic urea through deacetylation and activation of CPS1.

Pemafibrate decreases markers of hepatic inflammation in patients with non-alcoholic fatty liver disease.

AIM OF THE STUDY: Non-alcoholic fatty liver disease (NAFLD) is frequently complicated by dyslipidemia and is considered to be a hepatic manifestation of metabolic syndrome. Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator. There are no reports of the clinical effects of pemafibrate in patients with NAFLD. The aim of this study is to determine the effect of pemafibrate on patients with NAFLD. MATERIAL AND METHODS: This is an observational study of patients with NAFLD complicated by dyslipidemia treated with pemafibrate for three months. Patient medical records were retrospectively reviewed. RESULTS: Thirty-eight patients were included, and all patients had dyslipidemia without diabetes. Changes in parameters after three months of pemafibrate therapy were evaluated. Weight was not significantly changed. Alanine aminotransferase, a marker of hepatic inflammation, significantly improved. Remarkably, alkaline phosphatase and γ-glutamyl transpeptidase decreased in all patients. The albumin-bilirubin score, a marker of hepatic function, improved due to significant elevation of serum albumin and decrease in total bilirubin. Lipid profiles including high-density lipoprotein cholesterol and triglycerides significantly decreased. Low-density lipoprotein cholesterol did not significantly change. The NAFLD fibrosis score significantly improved, but the FIB-4 index did not significantly change. CONCLUSIONS: Three months of pemafibrate treatment of patients with NAFLD improves markers of hepatic inflammation, function and fibrosis. This is the first clinical study evaluating the effect of pemafibrate in patients with NAFLD.

Long-term empagliflozin therapy improves levels of hepatic fibrosis marker in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus.

The long-term outcomes of patients with non-alcoholic fatty liver disease (NAFLD) treated with sodium-glucose cotransporter-2 inhibitors remain indeterminate. Empagliflozin improves hyperglycemia by increasing glucose excretion in the urine, and it reduces fat volume and insulin resistance. The aim of this study is to assess the effect of long-term empagliflozin therapy on hepatic inflammation, function and fibrosis in patients with NAFLD. This is a two-center retrospective observational study including patients with NAFLD complicated by type 2 diabetes mellitus. We retrospectively reviewed the medical records. Changes in parameters were investigated over one-year empagliflozin treatment. Twenty-four patients treated with empagliflozin were evaluated. Weight, body mass index, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, fasting plasma glucose, hemoglobin A1c, serum insulin and homeostasis model assessment insulin resistance significantly decreased during treatment (p < 0.05). Albumin-bilirubin (ALBI) score, a marker of hepatic function, was significantly improved (p < 0.01). The FIB-4 index and Mac-2 Binding Protein Glucosylation Isomer, markers of hepatic fibrosis, significantly improved (p < 0.01). One-year empagliflozin treatment of patients with NAFLD complicated by type 2 diabetes mellitus significantly improves markers of hepatic inflammation, function and fibrosis. J. Med. Invest. 67 : 280-284, August, 2020.