Retrospective study of factors associated with progression and remission/regression of diabetic kidney disease-hypomagnesemia was associated with progression and elevated serum alanine aminotransferase levels were associated with remission or regression.

AIM: This study was aimed at retrospectively investigating some common clinical factors, including the serum level of magnesium (Mg), associated with progression and remission/regression of diabetic kidney disease (DKD). METHODS: The subjects were 690 Japanese patients with type 2 diabetes mellitus who were receiving treatment with oral antidiabetic drugs other than SGLT2 inhibitors. Routine clinical data were collected on the first and last day of the observation period. The prognosis of DKD is categorized into four stages according to the Kidney Disease Improving Global Outcomes classification. Progression was defined as transition from any of the lower three risk categories (LR, MIR, HR) at the start of the observation period, to the VHR stage/category at the end of the observation period. Remission/regression was defined as improvement of the risk category by at least one stage from the start to the end of the observation period. Factors associated with progression and regression/remission were investigated using Cox proportional hazards analysis. Furthermore, the factors associated with the annual decrease in eGFR of 5 ml/min/1.73 m2 or more were examined by logistic regression analysis. Factors associated with transition of urinary protein negative to trace or positive, or transition of negative or trace to positive, were investigated by Cox proportional hazard analysis. RESULTS: The observation period was 2251 ± 1614 days. Age (Exp [B] = 1.10, 95% CI; 1.06-1.14; P < 0.01; 1 year old), serum Mg (Exp [B] = 0.82, 95% CI; 0.71-0.95; P < 0.01); 0.1 mg/dl), and serum HbA1c (Exp [B] = 1.03, 95% CI; 1.01-1.05; P < 0.01: 0.1%) were associated with progression of DKD; on the other hand, serum ALT was associated with the likelihood of remission/regression of DKD (Exp [B] = 1.01, 95% CI; 1.002-1.018; P < 0.05; 1 IU/L). The decline in eGFR was associated with higher HbA1c levels, hypomagnesemia, and lower ALT. The new appearance of trace or overt proteinuria was correlated with higher HbA1c levels, advancing age, hypomagnesemia and hypertriglycemia. CONCLUSION: Our findings confirmed previous reports that advancing age and serum HbA1c levels were associated with an increased risk of progression of DKD. Lower serum Mg concentrations were also found to be associated with a high risk of progression of DKD, and interventional studies are needed to confirm a causal relationship. Elevated HbA1c levels and hypomagnesemia were common factors in the decline in eGFR and the appearance of trace or overt proteinuria. Lower serum ALT levels were associated with the decline in eGFR. Since serum ALT is known to decrease as the renal function deteriorates, serum ALT is considered to be a marker of renal function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-020-00483-1.

Suppression of Blue Light at Night Ameliorates Metabolic Abnormalities by Controlling Circadian Rhythms.

Purpose: Light-emitting diodes that emit high-intensity blue light are associated with blue-light hazard. Here, we report that blue light disturbs circadian rhythms by interfering with the clock gene in the suprachiasmatic nucleus (SCN) and that suppression of blue light at night ameliorates metabolic abnormalities by controlling circadian rhythms. Methods: C57BL/6J mice were exposed to 10-lux light for 30 minutes at Zeitgeber time 14 for light pulse with blue light or blue-light cut light to induce phase shift of circadian rhythms. Phase shift, clock gene expression in SCN, and metabolic parameters were analyzed. In the clinical study, healthy participants wore blue-light shield eyewear for 2 to 3 hours before bed. Anthropometric data analyses, laboratory tests, and sleep quality questionnaires were performed before and after the study. Results: In mice, phase shift induced with a blue-light cut light pulse was significantly shorter than that induced with a white light pulse. The phase of Per2 expression in the SCN was also delayed after a white light pulse. Moreover, blood glucose levels 48 hours after the white light pulse were higher than those after the blue-cut light pulse. Irs2 expression in the liver was decreased with white light but significantly recovered with the blue-cut light pulse. In a clinical study, after 1 month of wearing blue-light shield eyeglasses, there were improvements in fasting plasma glucose levels, insulin resistance, and sleep quality. Conclusions: Our results suggest that suppression of blue light at night effectively maintains circadian rhythms and metabolism.

Risk factors for pseudoaldosteronism with rhabdomyolysis caused by consumption of drugs containing licorice and differences between incidence of these conditions in Japan and other countries: case report and literature review.

BACKGROUND: The pathogenesis of licorice-induced pseudoaldosteronism is thought to involve the inhibition of 11ß-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid. Some risk factors have been reported, but differences between Japan and other countries have not been reported. CASE PRESENTATION: A 79-year-old woman was hospitalized because of pseudoaldosteronism with rhabdomyolysis caused by ingestion of herbal medicines containing licorice. She had been prescribed shakuyakukanzobushito (decocted, 3 g of licorice) and keishikajutsubuto (decocted, 2 g of licorice) for the treatment of lower back pain and had been taking antihypertensive agents for the treatment of essential hypertension. After taking the herbal medicines for 2 weeks, the patient developed weakness of the extremities and pain in both thighs. On admission, she had hypertension, oliguria, an elevated serum creatine kinase level, hypokalemia, alkalemia associated with metabolic alkalosis, low plasma renin activity, and low plasma aldosterone levels. Intravenous and oral potassium supplementation and the administration of spironolactone resulted in the normalization of her condition within approximately 2 weeks. DISCUSSION: An analysis of case reports of pseudoaldosteronism with rhabdomyolysis revealed that in Japan, most cases occurred in elderly women with essential hypertension and were caused by drugs such as herbal medicines. In contrast, in other countries, many cases involved younger men, and the dominant causes were foods containing licorice. The use of herbal medicines is increasing all over the world, and when a patient with risk factors is prescribed an herbal medicine containing licorice, careful follow-up is required.

A patient who experienced thyroid storm complicated by rhabdomyolysis, deep vein thrombosis, and a silent pulmonary embolism: a case report.

BACKGROUND: Thyroid storm is a serious condition of thyrotoxicosis. Hyperthyroidism often presents with thrombotic events, especially at cerebral sites; however, the possible association between a lower extremity deep vein thrombosis (LEDVT) and thyroid storm has not been previously reported. We encountered a patient who developed thyroid storm, associated with rhabdomyolysis, followed by LEDVT and a small silent pulmonary embolism (PE). The case is discussed with references to the pertinent literature. CASE PRESENTATION: A 50-year-old woman with no past medical history was referred to our hospital because of severe diarrhea, muscle weakness in her lower limbs (manual muscle testing: MMT 3), and disturbances of consciousness. She was diagnosed as having Graves' disease based on the presence of struma, exophthalmos, and hyperthyroidism with TSH receptor antibody positivity; we further determined that the patient was experiencing thyroid storm based on the results of the Burch-Wartofsky scoring system and a Japanese diagnostic criteria. Treatment with steroids, iodine potassium, methimazole, and propranolol was initiated. Severe watery diarrhea continued, and the laboratory data revealed hypokalemia (2.0 meq/L). On day 14, a blood analysis showed a sudden elevation in her creatinine kinase (CK) level, leading to a diagnosis of rhabdomyolysis. Thereafter, the muscle weakness in her lower limbs advanced to a degree of MMT 1. Seven days after the diagnosis of rhabdomyolysis, pitting edema began to appear in bilateral lower extremities. Contrast-enhanced CT scans revealed a LEDVT involving the left common iliac vein, bilateral femoral veins, and left popliteal vein. Furthermore, a small PE was identified. Hyperthyroidism often presents with thrombotic events, especially at cerebral sites, but few reports of PE or LEDVT have been made. CONCLUSION: This case suggests that the occurrence of thyroid storm may be associated with a risk of LEDVT and/or PE. We suggest that DVT preventive measures are undertaken, and that a lower limb venous echo or contrast-enhanced CT examination would be considered if LEDVT is suspected.

A patient with Graves' disease who survived despite developing thyroid storm and lactic acidosis.

A 56-year-old woman with Graves' disease presented with the complaints of diarrhea and palpitations. Physical examination and laboratory data revealed hypothermia and signs of mild hyperthyroidism, heart failure, hepatic dysfunction with jaundice, hypoglycemia, and lactic acidosis. The patient was diagnosed as having developed the complication of thyroid storm in the absence of marked elevation of the thyroid hormone levels, because of the potential hepatic and cardiac dysfunctions caused by heavy alcohol drinking. A year later, after successful treatment, the patient remains well without any clinical evidence of heart failure or hepatic dysfunction. Thyroid storm associated with lactic acidosis and hypothermia is a serious condition and has rarely been reported. Prompt treatment is essential even if the serum thyroid hormone levels are not markedly elevated. We present a report about this patient, as her life could eventually be saved.

Genetic variations of the ABC transporter gene ABCC3 in a Japanese population.

An ATP-binding cassette transporter, multidrug resistance-related protein 3 (MRP3), is encoded by the ABCC3 gene. The MRP3 protein is expressed in several tissues, and functions as an efflux transporter for conjugated as well as unconjugated substrates. In this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects. Forty-six genetic variations, including 21 novel ones, were found: 8 were located in the 5'-flanking region, 14 in the coding exons (8 synonymous and 6 nonsynonymous variations), and 24 in the introns. Of these 46 variations, five novel nonsynonymous variations, 2221C>T (Gln741Stop), 2395G>A (Val799Met), 2798_2799delAG (Gln933ArgfsX64), 3657C>A (Ser1219Arg), and 4217C>T (Thr1406Met), were found as heterozygous variations. The allele frequencies were 0.011 for Ser1219Arg and 0.006 for the other four variations. Gln741Stop induces a stop codon at codon 741. Gln933ArgfsX64 causes a frame-shift at codon 933, resulting in early termination at codon 997. Both variations result in loss of 6 transmembrane helices (from the 12th to 17th helices) in the C-terminus and all regions of nucleotide binding domain 2. Thus, both variant proteins are assumed to be inactive. These data provide fundamental and useful information for pharmacogenetic studies on MRP3-transported drugs in Japanese.

Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population.

Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.

Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese.

Genetic variations in cytochrome P450 2C9 (CYP2C9) are known to contribute to interindividual and interethnic variability in response to clinical drugs such as warfarin. In the present study, CYP2C9 from 263 Japanese subjects was resequenced, resulting in the discovery of 62 variations including 32 novel ones. In addition to the two known non-synonymous single nucleotide polymorphisms (SNPs), Ile359Leu (*3; allele frequency=0.030) and Leu90Pro (*13; 0.002), seven novel non-synonymous SNPs, Leu17Ile (0.002), Lys118ArgfsX9 (*25; 0.002), Thr130Arg (*26; 0.002), Arg150Leu (*27; 0.004), Gln214Leu (*28; 0.002), Pro279Thr (*29; 0.002) and Ala477Thr (*30; 0.002), were found. Functional characterization of novel alleles using a mammalian cell expression system in vitro revealed that *25 was a null allele and that *26, *28 and *30 were defective alleles. The *26 product showed a 90% decrease in the Vmax value but little change in the Km value towards diclofenac. Both *28 and *30 products showed two-fold higher Km values and three-fold lower Vmax values than the *1 allele, suggesting the importance of Gln214 and Ala477 for substrate recognition. Linkage disequilibrium and haplotype analyses were performed using the detected variations. Only five haplotypes (frequency >0.02) accounted for most (>87%) of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. Although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans. Taken together, novel defective alleles and detailed haplotype structures would be useful for determining metabolic phenotypes of CYP2C9 substrate drugs in Japanese and probably Asians.

Atorvastatin lowers plasma low-density lipoprotein cholesterol and C-reactive protein in Japanese type 2 diabetic patients.

We investigated the meaning and the worth of lowering low-density lipoprotein cholesterol (LDL-C) to less than 100 mg/dL in Japanese type 2 diabetic patients using atorvastatin. As a multicenter open-labeled study, 84 type 2 diabetic Japanese patients with hypercholesterolemia were enrolled between September 2003 and April 2004. Subjects received 16 weeks of treatment with atorvastatin. High-sensitive C-reactive protein (hs-CRP), plasminogen activator inhibitor 1, monocyte chemotactic protein 1, interleukin 6, urine albumin-creatinine ratio, hemoglobin A(1c), total cholesterol, and LDL-C were measured at baseline and after 8 and 16 weeks of treatment. According to the Adult Treatment Panel III of the National Cholesterol Education Program, we divided the subjects into responders (final LDL-C <100 mg/dL) and nonresponders (final LDL-C > or =100 mg/dL). After 16 weeks of atorvastatin treatment, as well as a reduction of total cholesterol and LDL-C, a significant reduction of hs-CRP was observed. Plasminogen activator inhibitor 1, monocyte chemotactic protein 1, and interleukin 6 were not changed. After stratification, hs-CRP declined only in responders. We concluded that atorvastatin not only improved hypercholesterolemia, but also reduced CRP even in Japanese diabetic patients. The results of this stratified study suggest that achievement of the Adult Treatment Panel III treatment goal of LDL-C might assure a reduction of inflammation, which is associated with cardiovascular events.

Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes.

Glimepiride, a sulfonylurea hypoglycemic agent, is metabolized by cytochrome P450 2C9 (CYP2C9) which is known to have genetic polymorphisms. To examine the effects of CYP2C9 genetic polymorphisms on the safety and efficacy of glimepiride in patients with type 2 diabetes, the responses to the glimepiride were measured in Japanese type 2 diabetic patients with the different CYP2C9 genotype. The reduction in the HbA(1c) was significantly larger (P<0.05) among the CYP2C9*1/*3 subjects than among the CYP2C9*1/*1 subjects. The long-term observations of 2 patients with a CYP2C9*1/*3 suggested that subjects with a CYP2C9*1/*3 respond well to glimepiride during the initial phase of treatment, but 1 patient have shown the weight gain over the long-term treatment. The pharmacokinetic study showed that the area under the concentration-time curve for glimepiride in the CYP2C9*1/*3 subjects was approximately 2.5-fold higher than that of the CYP2C9*1/*1 subjects. The intrinsic clearance of glimepiride by the CYP2C9*3 enzyme was lower than that by the CYP2C9*1 enzyme. These results suggested that the lower hydroxylation activity of glimepiride in the subject with type 2 diabetes and CYP2C9*1/*3 led to a marked elevation in the plasma concentrations of glimepiride and a stronger pharmacological effect of glimepiride.

Genetic variations and haplotypes of CYP2C19 in a Japanese population.

Forty-eight single nucleotide variations, including 27 novel ones, were found in the 5'- regulatory region, all of the exons and their surrounding introns of CYP2C19 in 253 Japanese subjects (134 diabetic patients and 119 healthy volunteers). Identified novel variations were as follows: -2772G>A, 2767_-2760delGGTGAACA, -2720T>C, -2547delG, -2545G>T, -2545_-2544 delGC, and -2040C>T in the enhancer region; -778C>T, -777G>A, -529G>C, -189C>A, and -185A>G in the promoter region; 151A>G (S51G), 481G>C (A161P), 986G>A (R329H), 1078G>A (D360N), and 1119C>T (D373D) in the exons, and IVS1+128T>A, IVS3+163G>A, IVS4+271A>G, IVS5-49A>G, IVS6-210C>T, IVS6-196T>A, IVS6-32T>A, IVS7+84G>A, IVS7-174C>T, and IVS8+64C>T in the introns. Since we found no significant differences in the variation frequencies between healthy volunteers and diabetic patients, the data for all subjects were treated as one group in further analysis. The allele frequencies were 0.265 for IVS6-196T>A, 0.045 for -2772G>A and -2720T>C, 0.024 for -2040C>T, 0.014 for IVS7-174C>T, 0.010 for -529G>C, 0.006 for IVS1+128T>A and 481G>C (A161P), 0.004 for -2767_-2760delGGTGAACA and IVS6-210C>T, and 0.002 for the other 17 variations. In addition, the two known nonsynonymous single nucleotide polymorphisms, 681G>A (splicing defect, (*)2 allele) and 636G>A (W212X; (*)3 allele) were detected at 0.267 and 0.128 frequencies, respectively. No variation was detected in the known binding sites for constitutive androstane receptor and glucocorticoid receptor. Linkage disequilibrium analysis showed several close linkages of variations throughout the gene. By using the variations, thirty-one haplotypes of CYP2C19 and their frequencies were estimated. Our results would provide fundamental and useful information for genotyping CYP2C19 in the Japanese and probably other Asian populations.

Association of HLA-DR, -DQ genotype and CTLA-4 gene polymorphism with Graves' disease in Japanese children.

OBJECTIVE: Childhood onset Graves' disease (GD) has been documented to be clinically distinct from adult onset GD, and an association with the genes encoding HLA and CTLA-4 (cytotoxic T lymphocyte antigen-4) has been reported in both Caucasian and Japanese adult GD patients. The aim of this study was to determine whether HLA-DR, -DQ and CTLA-4 are associated with childhood onset GD in Japanese individuals. METHODS: We investigated the genotype of HLA class II (DRB1, DQB1) and the A/G transition polymorphism of CTLA-4 exon 1 position 49 in 43 GD patients and in healthy controls for comparison. The CTLA-4 alleles were identified by the polymerase chain reaction (PCR) of genomic DNA and restriction fragment-length polymorphism analysis (PCR-RFLP) with Ita1. RESULTS: The frequency of both HLA-DRB1*0405 and DQB1*0401 was increased in the patient group (DRB1*0405: 26.7%, p < 0.001; DQB1*0401: 25.6%, p < 0.005) compared with the controls. Patients with GD had a significantly lower frequency of the AA genotype of CTLA-4 than the controls, but there was no difference in allele frequency between the G and A allele. CONCLUSIONS: the association of HLA-DRB1 and DQB1 genotype with susceptibility to childhood onset GD differs from that in adult onset GD, whereas the association between CTLA-4 gene polymorphism and childhood onset GD is similar to that in adult onset GD in Japanese individuals, but the association is weak.

Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes.

The progression of diabetes and hypertension complications is associated with microalbuminuria. Intensive glycemic control prevents or retards microalbuminuria in patients with type 2 diabetes, but little is known about the respective benefits of different antidiabetic drugs. We studied the effect of gliclazide and pioglitazone on microalbuminuria in patients with type 2 diabetes. We excluded patients with very poor glycemic control (glycated hemoglobin [HbA(1c)] >10%), impaired liver function, nondiabetic renal diseases, and those whose urine contained red blood cells, hemoglobin, or casts. Each patient received the designated drug for 12 weeks and their body weight, blood pressure (BP), fasting plasma glucose (FPG), HbA(1c), lipids (triglycerides [TG], total, and high-density lipoprotein-cholesterol [HDL-C]), 1,5 anhidroglucitol (1,5-AG), immunoreactive insulin (IRI), and urinary albumin to creatinine ratio (UACR) were measured every month. The effects of the drugs were analyzed using 2-way repeated measures analysis of variance (ANOVA). The 2 groups of patients were well matched for age, duration of diabetes, retinal status, blood pressure, body mass index (BMI), IRI, FPG, HBA(1c), 1,5-AG, lipids, and UACR, as well as the use of antihypertensive drugs. After treatment, no significant differences were seen in drug efficacy between the 2 groups. Gliclazide and pioglitazone significantly reduced FPG (F = 26.0, P <.0001), HBA(1c) (F = 48.1, P <.0001), and total cholesterol (TC) levels (F = 3.5, P <.05). Decrements in these metabolic parameters were comparable between the groups. 1,5-AG increased in both groups (F = 27.5, P <.0001), and the increment was comparable in both groups. Gliclazide and pioglitazone significantly reduced UACR (F = 15.7, P <.0001) with a comparable decrement in both groups. No other variables changed significantly throughout the 12-week treatment. These results suggest that 12 weeks of treatment with gliclazide or pioglitazone are equally effective in reducing microalbuminuria with similar improvements in blood glucose and cholesterol levels, independent of their mechanisms of actions.

Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes.

Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.