Comparison over Time of Adverse Drug Reactions in Diabetes Patients Treated with Sodium-Glucose Cotransporter 2 Inhibitors.

BACKGROUNDS: The prescription of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been increasing due to their additional benefits, including weight loss, cardioprotection and renoprotection. Accordingly, there are concerns about the potential rise in severe adverse drug reactions (ADRs), such as urinary tract infections, diabetic ketoacidosis, volume depletion, and hypoglycemia. The Society has announced recommendations on the proper use of SGLT2 inhibitors. We aimed to elucidate the recent occurrence of severe ADRs which need discontinuation of SGLT2 inhibitors or hospitalization. METHODS: In this retrospective cohort study, we identified 391 diabetic patients who were prescribed SGLT2 inhibitors upon admission to our hospital between April 2017 and March 2023. Of these, 68 patients who discontinued SGLT2 inhibitors for reasons other than ADRs were excluded. Patients were classified into the 2017 group and the 2020 group based on the treatment period of SGLT2 inhibitors, and the occurrence of ADRs and patient backgrounds were compared between the two groups. RESULTS: A total of 323 eligible patients were identified. Discontinuations of SGLT2 inhibitors decreased in the 2020 group (p < 0.05). However, discontinuations due to frailty increased (p < 0.05). Hospitalization due to ADRs, specifically those due to urinary tract infections, diabetic ketoacidosis, or volume depletion, did not specifically decrease (p = 0.273). CONCLUSIONS: This study indicated that there has been some improvement in the awareness of the proper use of SGLT2 inhibitors and there is still a need to continue enlightenment activities.

Usefulness of immature platelet fraction for the clinical evaluation of myelodysplastic syndromes.

Ratios of young platelets or reticulated platelets can be routinely obtained as an immature platelet fraction (IPF) with the XE-2100 automated hematology analyzer (Sysmex, Kobe, Japan). We combined IPF analysis of 31 patients with myelodysplastic syndrome (MDS) with a complete blood count, a bone marrow examination, and a chromosome analysis. The patients with >40 x 10(9)/L platelets were classified as group A, and those with > or =40 x 10(9)/L were placed in group B. The 2 groups were subclassified as A1 or B1 for patients with an IPF of <10% and as A2 or B2 for those with an IPF > or =10%. Categories A1, A2, B1, and B2 comprised 12 patients, 6 patients, 7 patients, and 6 patients, respectively. Patients with a relatively high IPF (>10%) (category A2 or B2) showed distinctive characteristics. Group B2 showed a higher frequency of chromosomal abnormalities than B1 (P = .029), and group A2 tended to show a higher incidence of clinical improvement than A1 (P = .08). IPF determination may be clinically useful for the assessment of prognosis for MDS patients.

Association of serum MCP-1 concentration and MCP-1 polymorphism with insulin resistance in Japanese individuals with obese type 2 diabetes.

Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) secreted by adipocytes is a member of the CC chemokine family and plays a pivotal role in the inflammatory process. A polymorphism, the -2518 A/G of MCP-1 gene, has been associated with type 2 diabetes, type 1 diabetes, parameters of insulin resistance and obesity. Therefore, we investigated the effects of MCP-1 single nucleotide polymorphisms (SNPs) on the susceptibility to type 2 diabetes or insulin resistance in the Japanese population. We also assessed the correlation between serum MCP-1 concentration and other clinical characteristics in Japanese type 2 diabetic subjects. The serum MCP-1 concentration was significantly correlated with HOMA-IR and the visceral fat area, but not with BMI. Although there was no association between this SNP and type 2 diabetes, the -2518A/G polymorphism was associated with the serum MCP-1 concentration. In subgroup analysis, Japanese obese diabetic -2518AA carriers had a higher MCP-1 concentration and increased insulin resistance than obese diabetic -2518G carriers. These data indicated that the MCP-1 polymorphism was associated with insulin resistance in Japanese obese diabetic subjects and that MCP-1 was implicated in the pathogenesis of insulin resistance, especially associated with obesity, in humans.

Lack of association of LRP5 and LRP6 polymorphisms with type 2 diabetes mellitus in the Japanese population.

AIMS: A missense mutation in the low density lipoprotein receptor-related protein 6 gene (LRP6) was recently shown to be responsible for a disorder characterized by early-onset coronary artery disease as well as diabetes mellitus (DM), hyperlipidemia, hypertension, and osteoporosis. Mice deficient in LRP5, a closely related paralog of LRP6, manifest a marked impairment in glucose tolerance. The aim of the present study was to examine whether common variants of LRP5 and LRP6 are associated with Type 2 DM or dyslipidemia in Japanese individuals. METHODS: Thirteen single nucleotide polymorphisms (SNPs) of LRP6 and nine SNPs of LRP5 were genotyped in a total of 608 Type 2 DM patients and 366 nondiabetic control subjects (initial study). An association analysis was then performed for each SNP and for haplotypes. For some of the SNPs, we provided another sample panel of 576 cases and 576 controls for the replication study. The relation to clinical characteristics was also examined in diabetic subjects. RESULTS: In the initial study, three SNPs of LRP6 were found to be associated with susceptibility to Type 2 DM. However, this association was not detected in the replication panel. None of SNPs in LRP5 were associated with Type 2 DM in the initial panel. Neither LRP6 nor LRP5 was associated with body mass index, HOMA-beta, HOMA-IR or serum lipid concentrations. CONCLUSIONS: We found no evidence for a substantial effect of LRP5 or LRP6 SNPs on susceptibility to type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population.

Association study of the effect of WFS1 polymorphisms on risk of type 2 diabetes in Japanese population.

Mutations of WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder characterized by juvenile diabetes mellitus, optic atrophy, deafness and diabetes insipidus. The product encoded by WFS1 gene, wolframin, could be involved in ER stress response causing beta-cell loss through impaired cell cycle progression and increased apoptosis. Recently, polymorphisms in the WFS1 gene were strongly associated with type 2 diabetes in Caucasians. The aim of the present study was to examine whether the variants of WFS1 are associated with risk of type 2 diabetes in Japanese individuals. Four single nucleotide polymorphisms, rs6446482, rs12511742, rs1801208 (R456H) and rs734312 (H611R) were genotyped in a total of 536 diabetic patients and 398 nondiabetic control subjects. Among the four variants, rs12511742 showed a marginal association with susceptibility to type 2 diabetes (odds ratio = 1.32, 95% confidence interval = 1.02-1.71, P = 0.033). Carriers of the risk allele at rs12511742 exhibited lower pancreas beta-cell function (P = 0.017). However, this association disappeared after adjustment for sex, age and BMI (Adjusted P = 0.24). Although we found no evidence for a substantial effect of WFS1 polymorphisms on risk of type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population, this gene is still a good candidate for a type 2 diabetes susceptibility gene, potentially, through impaired insulin secretion.

Effects of pioglitazone and metformin on intracellular lipid content in liver and skeletal muscle of individuals with type 2 diabetes mellitus.

Both ectopic fat accumulation and changes of the amount of several adipocyte secreting proteins (adipokines) are thought to contribute to the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now investigated the effects of 2 insulin-sensitizing drugs, pioglitazone and metformin, on body fat composition and serum adipokine concentrations in individuals with type 2 diabetes mellitus. A total of 41 diabetic patients were treated with pioglitazone (n =21) or metformin (n =20) for 6 months. Intramyocellular lipid content (IMCL) and hepatic lipid content as well as the areas of subcutaneous and visceral fat deposits in the abdomen were determined by nuclear magnetic resonance spectroscopy before and after drug treatment. The serum concentrations of adiponectin and retinol binding protein 4 were also determined by enzyme-linked immunosorbent assays. Pioglitazone treatment reduced both hepatic lipid content (12.0 +/- 6.1 vs 8.4 +/- 3.7 arbitrary units [AU], P < .01) and IMCL (8.4 +/- 3.6 vs 6.3 +/- 2.4 AU/creatine, P < .01), whereas metformin reduced only IMCL (7.0 +/- 3.6 vs 5.8 +/- 2.0 AU/creatine, P < .05). Although the areas of visceral and subcutaneous fat were not significantly affected by treatment with either drug, pioglitazone induced a significant reduction in the ratio of visceral to subcutaneous fat area (0.92 +/- 0.41 vs 0.85 +/- 0.41, P < .05). Pioglitazone treatment also resulted in a marked increase in serum adiponectin concentration (5.6 +/- 4.1 vs 16.2 +/- 9.9 microg/mL, P < .0001) and a small but significant decrease in serum retinol binding protein 4 concentration (73.4 +/- 25.1 vs 65.1 +/- 23.7 microg/mL, P < .05). These results suggest that pioglitazone may improve insulin sensitivity both by affecting serum adipokine concentrations and by reducing the intracellular triglyceride content of liver and skeletal muscle in individuals with type 2 diabetes mellitus.

Lack of association of CPT1A polymorphisms or haplotypes on hepatic lipid content or insulin resistance in Japanese individuals with type 2 diabetes mellitus.

Accumulation of fat in the liver is associated with insulin resistance and type 2 diabetes mellitus. The carnitine palmitoyltransferase (CPT) enzyme system facilitates the transport of long-chain fatty acids into mitochondria, and the gene for the hepatic isoform of CPT1 (CPT1A) is a candidate gene for metabolic disorders such as insulin resistance associated with fatty liver. We have now investigated the contribution of the CPT1A locus to hepatic lipid content (HLC), insulin resistance, and susceptibility to type 2 diabetes mellitus. A total of 324 type 2 diabetic patients and 300 nondiabetic individuals were enrolled in the study. Eighty-seven of the type 2 diabetic patients who had not been treated with insulin or lipid-lowering drugs were evaluated by homeostasis model assessment for insulin resistance and were subjected to nuclear magnetic resonance for determination of HLC. A total of 19 single nucleotide polymorphisms (SNPs) were identified at the CPT1A locus, and linkage disequilibrium analysis revealed a strong linkage disequilibrium block between SNP8 (intron 5) and SNP17 (intron 14). Neither haplotypes nor SNPs of CPT1A were found to be associated either with susceptibility to type 2 diabetes mellitus or with HLC or insulin resistance in type 2 diabetic patients.

Association of the -112A>C polymorphism of the uncoupling protein 1 gene with insulin resistance in Japanese individuals with type 2 diabetes.

The -112A>C polymorphism (rs10011540) of the gene for uncoupling protein 1 (UCP1) has been associated with type 2 diabetes mellitus in Japanese individuals. The aim of the present study was to investigate the effects of this polymorphism, as well as the well-known -3826A>G polymorphism (rs1800592), on clinical characteristics of type 2 diabetes. We determined the genotypes of the two polymorphisms in 93 Japanese patients with type 2 diabetes. Intramyocellular lipid content and hepatic lipid content (HLC) were measured by magnetic resonance spectroscopy. No significant differences in age, sex, BMI, or HbA1c level were detected between type 2 diabetic patients with the -112C allele and those without it. However, homeostasis model assessment for insulin resistance (p=0.0089) and HLC (p=0.012) was significantly greater in patients with the -112C allele. We did not detect an association of the -3826A>G polymorphism (rs1800592) of UCP1 gene with any measured parameters. These results suggest that insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes.