Age and sex are excellent predictors of bone complications in patients with type 2 diabetes with no history of osteoporotic fracture or treatment for osteoporosis.

OBJECTIVE: To identify patients with type 2 diabetes mellitus (T2DM) with no history of fracture or osteoporosis treatment who are at risk of bone complications through the assessment of bone quality and quantity. METHODS: Of the outpatients attending our clinic during 2021 to 2022, we retrospectively enrolled 137 (men/women: 85/52, median age: 65 years) consecutive patients aged ≥40 years who had T2DM but no history of fracture or osteoporosis treatment. The lumbar spine and femoral neck bone mineral density and the trabecular bone score were determined using dual-energy X-ray absorptiometry. Independent factors associated with bone disease were identified using logistic regression analysis, and odds ratios (ORs) were calculated. RESULTS: Age and female sex were significantly associated with high ORs for development of bone disease. The integrated risk of bone complications was nearly 40-fold higher in older (≥65 years) women than in younger (<65 years) men. This difference remained after adjustment for the duration of T2DM, body mass index, and HbA1c level. CONCLUSIONS: Older women have the highest risk of osteopenia and osteoporosis among patients with T2DM who have no history of fracture or osteoporosis treatment. These patients should undergo intensive monitoring for bone fragility from an early stage of their disease.

Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk.

Objective: In primary aldosteronism (PA), renal impairment has been identified as an important comorbidity. Excess cortisol production also may lead to renal damage; thus, concomitant mild autonomous cortisol secretion (MACS) may predispose PA patients to renal disorders. However, there is limited evidence to support this claim. Therefore, this study aimed to determine whether the concurrence of MACS and PA increases the risk of renal complications. Design: This study is a retrospective cross-sectional study. Methods: A total of 1310 patients with PA were stratified into two groups according to 1 mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS (n = 340) and non-MACS (n = 970). The prevalence of renal complications was compared between the group. We also performed multiple logistic regression analysis to determine factors that increase the risk for renal complications. Results: The prevalence of lowered estimated glomerular filtration rate (eGFR) and proteinuria was nearly twice higher in the MACS group than in the non-MACS group. Not only plasma aldosterone concentration (PAC) but also the presence of MACS was selected as independent factors that were associated with the two renal outcomes. The risk of lower eGFR or proteinuria in patients who had MACS and higher levels PAC was several folds higher than in those who had an absence of MACS and lower levels of PAC. Conclusions: MACS is an independent risk factor for renal complications in patients with PA, and MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal complications.

Development of a simple prediction model for adrenal crisis diagnosis.

To develop a prediction model for adrenal crisis (AC) diagnosis among individuals with adrenal insufficiency that relies on the values of routinely measured clinical parameters, for application in standard clinical practice. We retrospectively analysed data from five referral centres in Japan. Multivariate binary logistic regression was used to identify independent predictors of AC, and receiver operating characteristic curve analysis was used to determine their optimal cut-off points. The analysis included data from 54 patients with 90 AC events. Logistic regression revealed that serum sodium and C-reactive protein (CRP) levels were independent predictors of AC. Serum sodium levels < 137 mEq/L had a sensitivity of 71.1% and specificity of 95.6%. CRP levels > 1.3 mg/dL had a sensitivity of 84.4% and specificity of 94.9%. In combination, serum sodium levels < 137 mEq/L or CRP levels > 1.3 mg/dL for AC diagnosis had sensitivity and specificity values of 97.8% and 94.4%, respectively. The combined use of serum sodium and CRP levels had high sensitivity and specificity, and can be used for AC screening in standard clinical practice. The model can assist in identifying AC among high-risk individuals. A larger prospective study is needed to validate these results.

Liraglutide Reduces Visceral and Intrahepatic Fat Without Significant Loss of Muscle Mass in Obese Patients With Type 2 Diabetes: A Prospective Case Series.

BACKGROUND: Glucagon-like peptide-1 receptor agonists have been reported to reduce body fat as well as improving glycemic control in obese patients with type 2 diabetes. However, the maximum dose of liraglutide is limited to 0.9 mg in Japan, while the international dose is 1.8 mg; and the effect of this low dose on body composition has not been assessed in detail. Accordingly, this study was performed to evaluate the effect of liraglutide on body composition when administered at 0.9 mg once daily for 24 weeks. METHODS: Nine patients were enrolled and started liraglutide at 0.3 mg once daily, which was titrated to 0.9 mg once daily after 1 - 2 weeks and continued for 24 weeks. To comprehensively investigate changes of body composition, the body fat and muscle weight were determined by dual energy absorptiometry, visceral fat volume (VFV) and abdominal subcutaneous fat volume (SFV) were measured by abdominal computed tomography (CT), and the intrahepatic lipid content (IHL) was assessed by proton magnetic resonance spectroscopy. Measurements were obtained before starting liraglutide therapy and after 12 and 24 weeks of treatment. RESULTS: Fasting plasma glucose was significantly reduced from 127 ± 22 to 101 ± 14 mg/dL at 24 weeks and hemoglobin A1c (HbA1c) showed significant reduction from 6.4±0.9% to 5.2±0.5%. Body weight was reduced from 103.4 ± 14.7 to 97.0 ± 12.4 kg (mean reduction: 11.7%) and BMI decreased from 37.4 ± 6.4 to 35.0 ± 5.3 kg/m2 (mean reduction: 5.8%). Furthermore, VFV and IHL decreased from 5,192 ± 1,730 to 4,513 ± 1,299 cm3 (mean reduction: 11.9%) and 32.1±12.6% to 15.2±9.2% (mean reduction: 49.2%), respectively, but SFV did not change. Moreover, the fat index was reduced from 14.8 ± 4.4 to 12.9 ± 3.4 kg/m2 (mean reduction: 10.9%), but the skeletal muscle index did not change. CONCLUSIONS: In obese Japanese drug-naive patients who had type 2 diabetes, treatment with liraglutide (0.9 mg once daily for 24 weeks) reduced body fat, especially visceral fat and intrahepatic fat, while having no significant effect on skeletal muscle.

Effects of a novel selective peroxisome proliferator-activated receptor-α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance.

AIMS/INTRODUCTION: Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator with potent triglyceride-lowering and high-density lipoprotein cholesterol-raising effects. We showed that pemafibrate decreased the homeostatic model assessment for insulin resistance in patients with dyslipidemia. To investigate how pemafibrate improves insulin sensitivity, we used a hyperinsulinemic-euglycemic clamp technique to determine the splanchnic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. MATERIALS AND METHODS: A total of 27 patients with hypertriglyceridemia and insulin resistance were randomly assigned to receive pemafibrate (0.4 mg/day, b.i.d.) or placebo treatment for 12 weeks. The hyperinsulinemic-euglycemic clamp test combined with oral glucose loading was carried out at weeks 0 and 12 to evaluate the splanchnic and peripheral glucose uptake. RESULTS: Pemafibrate, but not the placebo, significantly increased the splanchnic glucose uptake rate from baseline (19.6 ± 5.9% with P = 0.005 and 2.1 ± 7.4% with P = 0.78, respectively), although no significant difference between the groups was observed (P = 0.084). Conversely, peripheral glucose uptake rate was not significantly altered. Pemafibrate, compared with the placebo, significantly decreased plasma triglycerides (-61.4 ± 16.4% vs -2.5 ± 41.4%, P = 0.001), free fatty acids (-24.8 ± 23.2% vs 2.0 ± 26.8%, P = 0.016) and gamma-glutamyl transpeptidase (-30 ± 46 vs 10 ± 19 U/L, P = 0.009) levels, and significantly increased fibroblast growth factor 21 (457.7 ± 402.1 vs -41.7 ± 37.4 pg/mL, P = 0.007) levels. CONCLUSIONS: Pemafibrate increased splanchnic glucose uptake from baseline in patients with hypertriglyceridemia.

Tofogliflozin decreases body fat mass and improves peripheral insulin resistance.

The impact of tofogliflozin, a sodium-glucose co-transporter-2 inhibitor, on peripheral glucose uptake in patients with type 2 diabetes mellitus (T2DM) was investigated using the hyperinsulinaemic-euglycaemic clamp method in a single-arm, open-label study. The following variables were compared between before and after tofogliflozin administration for 12 weeks in 16 patients with T2DM who were receiving dipeptidyl peptidase-4 inhibitor treatment: body weight (BW); blood pressure; glucose metabolism; liver function; lipid profile; and body composition. Peripheral glucose uptake (M value and M/I ratio) was examined by the hyperinsulinaemic-euglycaemic clamp method. After 12 weeks, there was a significant decrease (P < .001) in glycated haemoglobin, BW, body fat mass and lean body mass. Peripheral glucose uptake, which indicates insulin sensitivity, increased significantly (M value by 0.90 and M/I ratio by 0.49; both P < .05). The change in the M value after 12 weeks of tofogliflozin therapy was correlated with the change in body fat mass (P < .05). Tofogliflozin significantly improved insulin sensitivity and peripheral glucose uptake in patients with T2DM. These improvements were significantly correlated with reduction in body fat mass.

Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies.

AIM: We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. METHODS: We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. RESULTS: Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019-1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026-1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. CONCLUSIONS: Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population.

Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes.

AIM: We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes. METHODS: We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis. RESULTS: All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10(-4), binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037-1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10(-4), adjusted for sex, age and BMI). CONCLUSIONS: ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.