Expression of a PYCARD/ASC variant lacking exon 2 in Japanese patients with palindromic rheumatism increases interleukin-1ß secretion.

BACKGROUND: Palindromic rheumatism (PR) is a rare periodic arthritis characterized by relapsing short episodes of arthritis. Although the pathogenesis of PR is still unclear, the clinical condition is similar to that of autoinflammatory diseases caused by dysregulation of inflammasome-related genes. OBJECTIVE: We analyzed the inflammasome adapter PYD and CARD domain-containing protein/apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC) in Japanese patients with PR. METHODS: Serum interleukin (IL)-1ß concentrations in three Japanese patients with PR were measured. We also cloned PYCARD/ASC cDNA variants and expressed them in THP-1 cells to determine their effects on inflammasome activity following stimulation with phorbol 12-myristate 13-acetate and monosodium urate. Lysates of recombinant THP-1 cells were subjected to co-immunoprecipitation assays. RESULTS: Serum IL-1ß concentrations were significantly elevated in patients with PR, and a splice variant of PYCARD/ ASC mRNA lacking exon 2 (Δexon2) was dominantly expressed compared with that in controls. Moreover, IL-1ß secretion was significantly increased in THP-1 cells expressing Δexon2PYCARD/ASC compared with that in cells expressing the wild-type protein. The amount of NLRP3 bound to Δexon2PYCARD/ASC was increased after stimulation, whereas that bound to the wild-type protein was decreased. There were no differences in caspase-1 binding. CONCLUSIONS: Δexon2 PYCARD/ASC was associated with the pathogenesis of PR.

Reduction of Superoxide Dismutase 1 Delays Regeneration of Cardiotoxin-Injured Skeletal Muscle in KK/Ta-Ins2Akita Mice with Progressive Diabetic Nephropathy.

Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6-Ins2Akita and DN-prone KK/Ta-Ins2Akita mice. Here, we report that KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.

Severe hyponatremia with consciousness disturbance after receiving SARS-CoV-2 mRNA vaccination.

Summary: There are very few reports of syndrome of inappropriate antidiuresis hormone secretion (SIADH) after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Herein, we present the case of an 84-year-old woman who developed severe hyponatremia following the second administration of the SARS-CoV-2 mRNA vaccine. The patient presented with nausea, vomiting, and headache. Laboratory tests showed a plasma sodium level of 119 mmol/L. After receiving 500 mL of intravenous saline over a 2-h period, her plasma sodium level raised to 121 mmol/L, but her symptoms persisted. Considering that rapid plasma sodium correction was necessary, we started 3% saline solution overnight. Her plasma sodium level raised to 132 mmol/L and her symptoms completely resolved. Clinical and laboratory findings were consistent with a diagnosis of SIADH. In the absence of any other triggering factors, we concluded that the condition was likely associated with the vaccination. Clinicians should be aware of the potential for hyponatremia, particularly SIADH, associated with SARS-CoV-2 mRNA vaccination. Learning points: Reports of syndrome of inappropriate antidiuresis hormone secretion after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination are limited. If nausea, headache, and confusion are observed immediately after SARS-CoV-2 vaccination, clinicians should consider the presence of hyponatremia. As similar case reports to date have presented with severe hyponatremia, prompt treatment may be required.

A Pilot Study to Assess Glucose, Insulin, and Incretin Responses Following Novel High Resistant Starch Rice Ingestion in Healthy Men.

INTRODUCTION: A newly developed resistant starch (RS) rice line with double mutation of starch synthase IIIa and branching enzyme IIb (ss3a/be2b) exhibits a tenfold greater percentage RS value than the wild-type rice line. Currently, the effects of cooked rice with such high RS content on secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are unclear. Therefore, we conducted a pilot study to assess postprandial responses of GLP-1 and GIP along with glucose and insulin and also gastric emptying after ingestion of the high-RS cooked rice with ss3a/be2b in healthy subjects. METHODS: In a non-randomized crossover design, five healthy men ingested two test foods, control (low-RS) and high-RS cooked rice, with at least 1-week washout period between testing days. Plasma glucose, serum insulin, plasma total GLP-1, plasma total GIP, and also gastric emptying rate were measured after ingestion of each test food, and the incremental area under the curves (iAUC) was calculated for each biochemical parameter using the values from 0 to 180 min after ingestion. RESULTS: The high-RS cooked rice ingestion tended to reduce iAUC-glucose (p = 0.06) and significantly reduced iAUC-insulin (p < 0.01) and iAUC-GLP-1 (p < 0.05) but not iAUC-GIP (p = 0.21) relative to control cooked rice ingestion. In addition, the high-RS cooked rice ingestion did not affect gastric emptying. CONCLUSIONS: The present results indicate that the suppressive effects of the high-RS cooked rice ingestion on postprandial responses of glucose and insulin may be provided through attenuation in GLP-1 secretion along with its low digestibility into glucose. We suggest that the high-RS rice with ss3a/be2b may serve as a better carbohydrate source and also as a novel functional food for dietary interventions to improve postprandial hyperglycemia and hyperinsulinemia without both enhancing GLP-1 secretion and affecting gastric emptying in patients with diabetes.

Cases of fulminant type 1 and type 2 diabetes mellitus whose HbA1c levels were unmeasurable due to increased labile HbA1c.

Although the measurement of hemoglobin A1c (HbA1c) using high-performance liquid chromatography (HPLC) is routinely used to estimate average blood glucose levels, it may not be accurately measured for various reasons, such as alteration of red blood cell lifespan and the existence of hemoglobin variants; including hemoglobin F (HbF). Here, we report cases of fulminant type 1 and type 2 diabetes mellitus in which HbA1c levels were unmeasurable because of increased labile HbA1c levels. Case 1 involved a 73-year-old man with fulminant type 1 diabetes mellitus, who was brought to our hospital with diabetic ketoacidosis. The patient's blood glucose level was 994 mg/dL, and HbA1c was unmeasurable, which turned out to be 6.2% on the next day when the blood glucose level was normalized. Case 2 involved a 72-year-old man with type 2 diabetes mellitus, whose blood glucose level was 767 mg/dL, and HbA1c was unmeasurable, which turned out to be 17.9% the following day. In both cases, the chromatograms showed that the HbA1c peaks overlapped with large labile HbA1c peaks, which decreased the next day. It is important to keep in mind that HbA1c levels may not be accurately measured in cases of extreme hyperglycemia because of an increase in labile HbA1c, regardless of the absolute HbA1c level.

Sodium-glucose cotransporter 2 inhibition attenuates protein overload in renal proximal tubule via suppression of megalin O-GlcNacylation in progressive diabetic nephropathy.

AIMS: The crosstalk between sodium-glucose cotransporter 2 (SGLT2) inhibition and a membrane-associated endocytic receptor megalin function involved in renal proximal tubular protein overload in progressive diabetic nephropathy (DN) is uncertain. Here, we determined whether SGLT2 inhibition affects megalin endocytic function through suppressing its O-linked ß-N-acetylglucosamine modification (O-GlcNAcylation) and protects the diabetic kidney from protein overload. MATERIALS AND METHOD: We treated 8-week-old male non-obese and hypoinsulinemic KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DN with an SGLT2 inhibitor ipragliflozin or insulin for 6 weeks, and investigated the endocytic function (proximal tubular protein reabsorption), renal expression and O-GlcNAcylation of megalin along with their effects on renal phenotypes including histology and biochemical markers. RESULTS: The treatment with ipragliflozin, but not insulin, suppressed megalin O-GlcNAcylation and accelerated its internalization, resulting in reduction in proximal tubular reabsorption of the highly filtered plasma proteins such as albumin and neutrophil gelatinase-associated lipocalin. These alterations following the ipragliflozin treatment contributed to amelioration of proximal tubular protein overload, mitochondrial morphological abnormality, and renal oxidative stress and tubulointerstitial fibrosis. CONCLUSIONS: The present study provides a novel crosstalk mechanism between SGLT2 inhibition and megalin underlying the potential renal benefits of SGLT2 inhibition in DN.

Magnitude of slowing gastric emptying by glucagon-like peptide-1 receptor agonists determines the amelioration of postprandial glucose excursion in Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: Pharmacological levels of glucagon-like peptide-1 (GLP-1) can decelerate gastric emptying (GE) and reduce postprandial glucose levels. Most previous studies have used liquid meals to evaluate GE. We evaluated the effects of GLP-1 receptor agonists (GLP-1 RAs) on GE and postprandial glucose excursion in Japanese type 2 diabetes mellitus patients using a combination of solid and liquid meals. MATERIALS AND METHODS: In this single-center, prospective, open-label study, nine healthy individuals and 17 patients with type 2 diabetes mellitus consumed a 460-kcal combination of a solid and liquid meal labeled with 13 C-acetic acid. GE was measured from t = 0 to 150 min in a continuous 13 C breath test. Eight participants with type 2 diabetes mellitus were administered GLP-1 RAs, and we examined the relationship between GE and blood glucose excursion. RESULTS: There were no differences in the average GE coefficient (GEC) and lag time between the healthy and type 2 diabetes mellitus groups. However, the type 2 diabetes mellitus group showed larger GEC variations (P < 0.05). The coefficient of variation of R-R intervals was a significant predictor of GEC in type 2 diabetes mellitus patients (P < 0.01). The short-acting GLP-1 RA reduced the GEC at 1 month (P = 0.012), whereas the long-acting GLP-1 RA did not significantly change the GEC after treatment. A positive relationship was observed between postprandial glucose excursion from T0 min to T60 min and the GEC (r2  = 0.75; P < 0.01). CONCLUSIONS: The reduction in GE rate by the administration of GLP-1 RAs can predict the improvement in postprandial glucose excursion in type 2 diabetes mellitus patients.

Efficacy and safety of patient-directed titration of once-daily pre-dinner premixed biphasic insulin aspart 70/30 injection in Japanese type 2 diabetic patients with oral antidiabetic drug failure: STEP-AKITA study.

UNLABELLED: Aims/Introduction: To clarify clinical characteristics related to optimal glycemic control achieved after adding once-daily pre-dinner biphasic insulin aspart 70/30 (BIAsp 30) in Japanese type 2 diabetic (T2D) patients with oral antidiabetic drug (OAD) failure. MATERIALS AND METHODS: Under this regimen, we evaluated changes in HbA1c levels and daily self-monitoring blood glucose (BG) profiles, as well as the incidences of hypoglycemia and retinopathy progression. The patients adjusted BIAsp 30 dosages themselves every 3-4 days according to a pre-determined algorithm to achieve fasting BG levels of 101-120 mg/dL. HbA1c levels were expressed as Japan Diabetes Society values. RESULTS: Of 29 enrolled patients, 22 (HbA1c levels, 8.5 ± 1.5% [mean ± SD]) and 20 patients completed the 16- and 24-week follow-up, respectively. At 16 weeks 68.2 and 45.5%, and at 24 weeks 80.0 and 35% of patients had achieved HbA1c levels of <7.0 and <6.5%, respectively. The patients who had achieved optimal glycemic control, including daytime postprandial BG profiles after treatment, had lower post-breakfast BG excursions at baseline, shorter diabetes durations and younger age. No severe hypoglycemic episodes were recorded. Progression of retinopathy was observed in 3 of the 29 enrolled patients. CONCLUSIONS: Lower post-breakfast BG excursions, shorter diabetes duration and younger age in Japanese T2D patients with OAD failure might warrant optimal glycemic control with safety after adding once-daily pre-dinner BIAsp 30 initiating regimen. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00062.x, 2010).