Genetic factors are involved in the etiology of most diseases, but prior to 2000, the methods for identifying such factors were very limited. Genome-wide association study (GWAS), developed in the 2000s, is an analytical method that can be applied to most diseases, including endocrine disorders. GWAS has provided a wealth of information on disease risks and the molecular pathogenesis of many human diseases. This review summarizes key findings from GWAS for thyroid physiology and diseases, and illustrates how GWAS is a powerful research tool to elucidate the molecular mechanisms of the diseases.

Type 2 diabetes (T2D) is a polygenic disease and studies to understand the etiology of the disease have required selectively bred animal models with polygenic background. In this review, we present two models; the Goto-Kakizaki (GK) rat and the Oikawa-Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mouse. The GK rat was developed by continuous selective breeding for glucose tolerance from the outbred Wistar rat around 50 years ago. The main cause of spontaneous hyperglycemia in this model is insulin secretion deficiency from pancreatic β-cells and mild insulin resistance in insulin target organs. A disadvantage of the GK rat is that environmental factors have not been considered in the selective breeding. Hence, the GK rat may not be suitable for elucidating predisposition to diabetes under certain environmental conditions, such as a high-fat diet. Therefore, we recently established two mouse lines with different susceptibilities to diet-induced diabetes, which are prone and resistant to the development of diabetes, designated as the ON-DP and ON-DR mouse, respectively. The two ON mouse lines were established by continuous selective breeding for inferior and superior glucose tolerance after high-fat diet feeding in hybrid mice of three inbred strains. Studies of phenotypic differences between ON-DP and ON-DR mice and their underlying molecular mechanisms will shed light on predisposing factors for the development of T2D in the modern obesogenic environment. This review summarizes the background and the phenotypic differences and similarities of GK rats and ON mice and highlights the advantages of using selectively bred rodent models in diabetes research.

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone secreted by the bone in response to dietary phosphate intake. Since the phosphate content in the diet correlates with the protein content, both plant- and animal-based protein intake can increase the serum FGF23 level. However, a higher percentage of energy from plant protein than from animal protein is associated with a lower serum FGF23 level in patients with chronic kidney disease (CKD) in the United States. Since dietary habits differ between Asian and Western populations, we performed a cross-sectional study to determine the association between the percentages of energy from plant and animal proteins and the serum FGF23 level in Japanese CKD patients. In 107 non-dialysis CKD patients (age: 66 ± 9 years; estimated glomerular filtration rate: 56 ± 21 mL/min/1.73 m²), the percentages of energy from plant and animal proteins were assessed using a food frequency questionnaire based on food groups. Venous blood samples were used to measure the serum FGF23, phosphate, 1,25-dihydroxyvitamin D, and intact parathyroid hormone levels. The percentages of energy from plant and animal proteins showed a negative and positive association, respectively, with the serum FGF23 level. Furthermore, isocaloric substitution modeling showed that replacing animal protein with plant protein was associated with a low serum FGF23 level. Our findings suggest that encouraging diets with high plant protein level may prevent an increase in the serum FGF23 level in Japanese CKD patients.

Adrenal incidentaloma is a clinically unapparent adrenal mass more than one cm in diameter detected during imaging performed not for adrenal disease. A 34-year-old man was evaluated for AI with a diameter of 3.5 cm in the left adrenal. He was obese with body mass index of 33,9. Blood pressure was 110–120/90 mmHg. The general laboratory tests were unremarkable. An adrenal hormone screening set revealed that ACTH was 6.9 pg/mL, cortisol 14.9 μg/dL, renin activity 0.9 ng/mL/h, aldosterone 79.4 pg/mL, dehydroepiandrosterone-sulfate (DHEA-S) measured on two occasions 5,217 ng/mL and 6,477 ng/mL (gender- and age-adjusted reference values, 1,060–4,640 ng/mL). The levels of metanephrine and normetanephrine were normal. The tumor was thought to produce solely DHEA-S. The excised left adrenal tissue contained a tumor with a diameter of 26 mm and neighboring adrenal tissue. The tumor consisted mostly of acidophil cells without necrosis, capsular or vascular invasion, and mitosis. Immunohistochemical study revealed followings: the cells of the tumors were stained positive for 3β-hydroxysteroid dehydrogenase, and 17α-hydroxylase, and 11β-hydroxylase, weakly positive for DHEA sulphotransferase, and negative for aldosterone synthetase. The atrophy of neighboring tissue was presumably caused by excess cortisol production. Four months after surgery, the cortisol level was 11.2 μg/dL and DHEA-S level 1,462 ng/mL. The tumor is considered to be a cortisol-producing adenoma with modestly excessive DHEA-S production rather than isolated DHEA-S-producing adenoma. Immunohistochemical study of steroidogenic enzymes is a valuable addition to blood hormone measurement to clarify steroid production profile.

Previous reports indicated the therapeutic effect of chronic continuous positive airway pressure (CPAP) therapy on cardiac hypertrophy due to sleep apnea syndrome. However, little is known for cases involving diabetic complications. This retrospective observational study examined the effects of CPAP therapy on left ventricular hypertrophy (LVH) in patients with obstructive sleep apnea syndrome (OSAS) and type 2 diabetes mellitus (T2DM). For all cases, the observation period was 3 years from the time when the patient was introduced to CPAP therapy. Overall, 123 patients were divided into a good CPAP group (CPAP ≥4 h/day, n = 63) and non-adherence group (CPAP <4 h/day, n = 60). The mean CPAP usage times were 5.58 ± 1.23 and 1.03 ± 1.17 h/day in the good CPAP and non-adherence groups, respectively. Regression tendencies of the thickness of the left ventricular posterior (–0.30 ± 1.19 mm) and interventricular septal walls (–0.48 ± 1.22 mm) were observed in the good CPAP group. Hypertrophic tendencies of the left ventricular posterior wall (+0.59 ± 1.44 mm) and interventricular septal wall thickness (+0.59 ± 1.43) were observed in the non-adherence group. Left ventricular posterior wall thickness (coefficient: –0.254, p = 0.0376) and interventricular septal wall thickness (coefficient: –0.426, p = 0.0006) were more likely to be greater in the non-adherence group than in the good CPAP group. Patients in the non-adherence group with an apnea hypopnea index ≥30 had increased left ventricular posterior wall thickness (coefficient: –0.263, p = 0.0673) and interventricular septal wall thickness (coefficient: –0.450, p = 0.0011). In conclusion, appropriate CPAP therapy is an effective treatment for LVH in patients with T2DM and OSAS, especially for severe cases.

5α-reductase type 2 (5αRD2) deficiency is a 46,XY disorder of sex development caused by impaired conversion of testosterone (T) to dihydrotestosterone (DHT). Penile enlargement therapy is important for male patients with 46,XY 5αRD2 deficiency who have undermasculinized external genitalia, such as severe micropenis. High-dose T and percutaneous DHT replacement are reportedly efficacious for penile enlargement in patients with this disorder. We presented herein the longitudinal course of four patients with 46,XY 5αRD2 deficiency who received T and DHT. T replacement therapy during infancy increased the stretched penile length (SPL) in three of the patients but was ineffective in one patient. DHT was administered to the three patients after T replacement therapy and further increased the SPL. During and after puberty, two patients asked for and received T replacement therapy, which contributed to increasing their SPL. A semen test in one patient with T replacement therapy at age 27 years revealed cryptozoospermia despite normal testicular volume. The clinical course of our patients during infancy indicated that DHT therapy may be preferrable to T replacement therapy for penile enlargement in patients with 5αRD2 deficiency. During and after puberty, T replacement therapy promoted penile enlargement possibly because of increased conversion of T to DHT via increased 5α-reductase type 1 activity even in patients in whom it was ineffective during infancy. In conclusion, DHT is effective for penile enlargement during infancy in patients with 5αRD2 deficiency while T replacement therapy is a viable option during puberty.

Familial partial lipodystrophy (FPLD) 3 is a rare genetic disorder caused by peroxisome proliferator-activated receptor γ gene (PPARG) mutations. Most cases have been reported in Western patients. Here, we describe a first pedigree of FPLD 3 in Japanese. The proband was a 51-year-old woman. She was diagnosed with fatty liver at age 32 years, dyslipidemia at age 37 years, and diabetes mellitus at age 41 years. Her body mass index was 18.5 kg/m², and body fat percentage was 19.2%. On physical examination, she had less subcutaneous fat in the upper limbs than in other sites. On magnetic resonance imaging, atrophy of subcutaneous adipose tissue was seen in the upper limbs and lower legs. Fasting serum C-peptide immunoreactivity was high (3.4 ng/mL), and the plasma glucose disappearance rate was low (2.07%/min) on an insulin tolerance test, both suggesting apparent insulin resistance. The serum total adiponectin level was low (2.3 μg/mL). Mild fatty liver was seen on abdominal computed tomography. On genetic analysis, a P495L mutation in PPARG was identified. The same mutation was also seen in her father, who had non-obese diabetes mellitus, and FPLD 3 was diagnosed. Modest increases in body fat and serum total adiponectin were seen with pioglitazone treatment. Attention should be paid to avoid overlooking lipodystrophy syndromes even in non-obese diabetic patients if they show features of insulin resistance.

Acromegaly is characterized by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), accompanied by a compromise in the perception of wellness. The Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) is relevant to assessing signs and symptoms but is mainly used to evaluate the efficacy of a pharmacological intervention. To explore the perioperative variation in symptom severity, the divergence between subgroups stratified according to clinical outcomes or treatment modalities, and the interaction between symptom scores and clinical indices, we prospectively recruited 106 patients with acromegaly from 2016 to 2018. Oral glucose tolerance and GH tests were performed, and PASQ was administered before treatment and 6 months postoperatively. Patients were divided into active (n = 49) and remission (n = 57) groups according to postoperative GH and IGF-1 levels. PASQ scores and GH and IGF-1 levels decreased significantly postoperatively in both groups. A significantly higher preoperative headache score and greater extent of decrease in arthralgia were seen in the active and remission groups, respectively. No significant variation in PASQ scores was found between patients receiving surgery alone and those receiving preoperative somatostatin analogs. Preoperative fasting GH (GH0) levels were positively correlated with preoperative excessive perspiration. Further regression analyses validated the variation in GH0 as a noteworthy determinant of the extent of change in soft-tissue swelling, excessive perspiration, fatigue, and total PASQ scores. Patient-reported symptoms were substantially alleviated after surgery, independent of endocrine remission or use of preoperative somatostatin. A GH level decrease was a notable coefficient for PASQ scores.

There is uncertainty regarding the need for COVID-19 peri-vaccination glucocorticoid coverage in patients with adrenal insufficiency. In this survey conducted in a single tertiary medical institution, 167 consecutive outpatients taking physiological glucocorticoids because of adrenal insufficiency were included. The patients declared if they developed an adrenal crisis after vaccination, and the amount and duration of an increase in their glucocorticoid dosage, if any. None of the patients without preventive glucocorticoid increase suffered an adrenal crisis after COVID-19 vaccination. Only 8.3% (14 cases) and 27.5% (46 cases) of the patients needed to escalate the dose of glucocorticoids when systemic symptoms appeared after the first and second injections, respectively. Glucocorticoids were increased in patients <60 years of age more than in patients ≥60 years of age at the time of both the first (p = 0.026) and second injections (p = 0.005). Sex and the causes of adrenal insufficiency were not associated with the frequency of the patients who needed glucocorticoid dose escalation. In the cases with increased glucocorticoids, the median dosage for escalation was 10 mg (hydrocortisone equivalent). In conclusion, even without prophylactic glucocorticoid administration, adrenal crisis did not occur during the peri-COVID-19 vaccination period. The dose escalation of steroid was more frequent in younger patients following the second vaccination. Careful monitoring of adverse effects and the appropriate management of glucocorticoids when necessary are essential following COVID-19 vaccinations.

Although metabolic syndrome, including visceral fat accumulation, causes kidney and cardiovascular diseases, the impact of visceral fat accumulation on mild decreased renal function remains unclear. This study examines the association between visceral fat area (VFA) measured by bioimpedance methods and the estimated glomerular filtration rate based on serum cystatin C (eGFRcys) in the Japanese urban population. This community-based cross-sectional study enrolled 952 individuals (287 men, 665 women) who participated in the second follow-up survey of the Kobe Orthopedic and Biomedical Epidemiological (KOBE) study. We compared the multivariate-adjusted means of eGFRcys among VFA quartile groups by gender using the analysis of covariance. Models were adjusted for age, high blood pressure, hypercholesterolemia, glucose intolerance, smoking, and alcohol use, and further adjusted for body mass index (BMI). The highest VFA quartile group had lower eGFRcys than the lowest VFA quartile group after adjusted for cardiometabolic risk factors, except for BMI (93.1 [95% confidence interval (CI), 90.1–96.2] vs. 82.1 [95% CI, 79.1–85.0] in men and 95.8 [95% CI, 94.1–97.5] vs. 89.4 [95% CI, 87.8–90.9] in women). Moreover, further adjustment for BMI revealed a similar result in men (93.5 [95% CI, 89.8–97.2] vs. 81.6 [95% CI, 77.9–85.3]), while no significant association was found in women. This study suggests a significant association between increased VFA levels and lower eGFRcys levels independent of cardiometabolic risk factors, such as glucose intolerance and hypercholesterolemia in men and women, as well as independent of BMI in men.

We aimed to identify the association between obstructive sleep apnea (OSA), insulin resistance (IR), and metabolic syndrome (MetS) in a nationwide population-based sample. A total of 7,900 adults with information on the STOP-Bang score and MetS (3,341 men and 4,469 women) were identified from the dataset of the Korea National Health and Nutrition Examination Survey 2019–2020. The association between OSA, IR, MetS, and its components was estimated using complex sample logistic regression analysis with adjustments for age, body mass index, residence, smoking status, alcohol consumption, household income, education, and the presence of diabetes. Participants with a high OSA score were more likely to have IR (odds ratio [OR] 2.78, 95% confidence interval [CI] 1.96–3.95 in men and OR 2.64, 95% CI 0.55–12.80 in women), MetS (OR 6.05, 95% CI 4.23–8.69 in men and OR 4.20, 95% CI 1.23–15.70 in women), and components of MetS, compared to individuals with a low OSA score. Compared to premenopausal women, postmenopausal women had a more intense association between OSA and IR (OR 1.78, 95% CI 0.13–24.43 for premenopausal women and OR 3.64, 95% CI 0.60–22.28 for postmenopausal women) and MetS (OR 2.58, 95% CI 0.23–29.55 for premenopausal women and OR 5.36, 95% CI 1.42–20.21 for postmenopausal women). OSA was associated with abdominal obesity and hypertension in premenopausal women, while all components of MetS were associated with OSA in postmenopausal women. Further studies are necessary to elucidate the underlying mechanisms of these findings.

Metformin monotherapy as first-line treatment for patients with type 2 diabetes (T2D) has been shown to effectively improve blood glucose levels and motivation to undergo treatment and prevent complications. However, no studies have reported its effect when combined with other drugs or compared the effect based on administration time. This study aimed to investigate the effect of metformin administration in Japanese patients with T2D, examine how the introduction line impacts the effect of metformin, and examine the characteristics of patients demonstrating improved blood glucose levels. Data on characteristics of patients who were newly prescribed metformin with no shifting of hypoglycemic agents in the subsequent 24-week observation period, and their age [mean, 56.8 years], body mass index [mean, 27.5 kg/m²], glycated hemoglobin [HbA1c] [mean, 8.1%], and duration of diabetes [mean, 3.0 years] were obtained from the medical records of 201 patients. The changes in HbA1c by introduction line after 24 weeks were –1.59%, –0.91%, –0.89%, and –0.65% in the first, second, third, and fourth induction lines, respectively; earlier introduction more significantly improved blood glucose. The factors significantly associated with HbA1c changes were early introduction, high baseline HbA1c, high estimated glomerular filtration rate, decreased insulin secretion, short estimated duration of diabetes, and increased metformin dose. Furthermore, factors contributing to the largest HbA1c improvement by metformin were high baseline HbA1c and early administration. Metformin is expected to lower blood glucose levels in Japanese patients with T2D, even in those with decreased insulin secretion, due to its early introduction as a first-line drug.