Identification of a homozygous c.1039C>T (p.R347C) variant in CYP17A1 in a 67-year-old female patient with partial 17α-hydroxylase/17,20-lyase deficiency.

17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by pathogenic mutations in CYP17A1. Impaired 17α-hydroxylase and 17,20-lyase activities typically induce hypertension, hypokalemia, sexual infantilism, and amenorrhea. Most patients with 17OHD are diagnosed in adolescence. Here, we report a female (46, XX) patient with 17OHD who was diagnosed at the age of 67 years. Genetic analysis was performed using direct DNA sequencing of polymerase chain reaction (PCR) products and multiplex ligation-dependent probe amplification (MLPA) analysis. Direct DNA sequencing revealed a homozygous c.1039C>T in CYP17A1, corresponding to a p.R347C amino acid change. MLPA probe signals showed that the CYP17A1 mutation was present in the homozygous carrier state. The patient's dehydroepiandrosterone sulfate and androstenedione levels were extremely low, despite elevated adrenocorticotropic hormone (ACTH) and normal cortisol levels. A corticotropin-releasing hormone (CRH) test showed no response of cortisol, despite a normal response of ACTH. Rapid ACTH injection resulted in elevations in the deoxycorticosterone, corticosterone, aldosterone, and 17-hydroxypregnenolone levels, but not in the cortisol level. These results suggested that 17α-hydroxylase/17,20-lyase activities were partially impaired. Computed tomography revealed bilateral adrenal hyperplasia and a hypoplastic uterus. A high basal plasma ACTH level and a discrepancy between ACTH and cortisol responses in a CRH test may provide a definitive diagnostic clue for this disease.

Presence of aberrant adrenocorticotropic hormone precursors in two cases of McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is a rare disorder. MAS is classically defined by the occurrence of fibrous dysplasia, café-au-lait skin macules, and precocious puberty. In addition to precocious puberty, other hyperfunctioning endocrinopathies may occur. We evaluated hypothalamic-pituitary-adrenal function in two cases of typical MAS associated with fibrous dysplasia and growth hormone excess. Pituitary adenoma or hyperplasia was not detected by magnetic resonance imaging. Hormonal data showed normal or low cortisol levels, despite high ACTH levels in the blood. A high ratio of circulating ACTH to cortisol was found in the two cases. Insulin tolerance and CRH tests showed hyper-responses of ACTH and an insufficient increase in cortisol levels. No involvement of 11ß-HSD1 by GH excess was suggested because basal levels of ACTH and cortisol showed no changes, even after therapy for acromegaly by somatostatin analogues. Patients with Cushing's disease cases of pituitary macroadenoma can have high circulating ACTH precursor levels, and elevated ACTH precursors have been observed in ectopic ACTH syndrome. Autonomous cortisol excess was excluded by the level of midnight cortisol and the level of cortisol after a low-dose dexamethasone suppression test in the two cases. Finally, the gel filtration profiles of immunoreactive ACTH contents showed the presence of aberrant ACTH precursors. To the best of our knowledge, there have been no reports of MAS associated with aberrant ACTH precursors. Our findings in these cases emphasize that attention should be to secretion of inactive ACTH precursors in MAS.

Secondary oxalosis induced by xylitol concurrent with lithium-induced nephrogenic diabetes insipidus: a case report.

BACKGROUND: Xylitol is an approved food additive that is widely used as a sweetener in many manufactured products. It is also used in pharmaceuticals. Secondary oxalosis resulting from high dietary oxalate has been reported. However, reported cases of oxalosis following xylitol infusion are rare. CASE PRESENTATION: A 39-year-old man with a 16-year history of organic psychiatric disorder was hospitalized for a laparoscopic cholecystectomy because of cholecystolithiasis. He had been treated with several antipsychotics and mood stabilizers, including lithium. The patient had polyuria (> 4000 mL/day) and his serum sodium levels ranged from 150 to 160 mmol/L. Urine osmolality was 141 mOsm/L, while serum arginine vasopressin level was 6.4 pg/mL. The patient was diagnosed with nephrogenic diabetes insipidus (NDI), and lithium was gradually discontinued. Postoperative urine volumes increased further to a maximum of 10,000 mL/day, and up to 10,000 mL/day of 5% xylitol was administered. The patient's consciousness level declined and serum creatinine increased to 4.74 mg/dL. This was followed by coma and metabolic acidosis. After continuous venous hemodiafiltration, serum sodium improved to the upper 140 mmol/L range and serum creatinine decreased to 1.25 mg/dL at discharge. However, polyuria and polydipsia of approximately 4000 mL/day persisted. Renal biopsy showed oxalate crystals and decreased expression of aquaporin-2 (AQP2) in the renal tubules. Urinary AQP2 was undetected. The patient was discharged on day 82 after admission. CONCLUSIONS: Our patient was diagnosed with lithium-induced NDI and secondary oxalosis induced by excess xylitol infusion. NDI became apparent perioperatively because of fasting, and an overdose of xylitol infusion led to cerebrorenal oxalosis. Our patient received a maximum xylitol dose of 500 g/day and a total dose of 2925 g. Patients receiving lithium therapy must be closely monitored during the perioperative period, and rehydration therapy using xylitol infusion should be avoided in such cases.

Evaluation of growth hormone-releasing peptide-2 for diagnosis of thyrotropin-producing pituitary adenomas.

Thyrotropin (TSH)-producing adenomas are a rare cause of hyperthyroidism and are a type of functional pituitary adenoma. The diagnosis of TSH-producing adenoma is a challenging problem in clinical endocrinology. Since growth hormone-releasing peptide-2 (GHRP-2) fails to induce TSH secretion in normal subjects, the effect of GHRP-2 on TSH levels was therefore examined in patients with TSH-producing adenomas. A total of 5 patients (4 women and 1 man) referred to our departments for further evaluation of pituitary hormones were followed-up using the GHRP-2, TSH-releasing hormone (TRH), octreotide, and bromocriptine tests to examine and evaluate TSH secretory dynamics in TSH-producing adenomas. Of 5 patients, 2 (40%) showed such a significant response, defined as a >50% increase in serum TSH level above baseline in the GHRP-2 test. Additionally, 1 patient showed a 48% increase in serum TSH level. In 1 patient whose adenoma was completely removed, basal serum concentrations of TSH were sufficiently suppressed after the operation, and serum TSH levels failed to increase in response to GHRP-2 administration. In 4 patients (80%), a poor response of serum TSH levels was observed in the TRH test. In 2 out of 5 patients (40%), serum TSH levels were significantly decreased following octreotide administration. No patient demonstrated a significant response to the bromocriptine test. In addition to TRH test, the GHRP-2 test as a potential diagnostic tool for TSH-producing pituitary adenomas.

Lower aldosterone-renin ratio is a risk factor for total and cancer death in Japanese individuals: the Takahata study.

OBJECTIVE: A higher plasma aldosterone-renin ratio (ARR) is an established marker for screening for primary aldosteronism (PA). The association between higher ARR and mortality in a general population has not been fully explored. We here examined whether higher ARR is a risk factor for total and cause-specific mortality in a Japanese population. SUBJECTS AND METHODS: A population-based, longitudinal study of 1,310 Japanese individuals (age: 63·9 ± 9·8 years) enrolled in the Takahata study between 2004 and 2006 and followed for up to 8 years. The incidence and causes of death were monitored annually until 10 January 2012 (median follow-up: 2691 days). RESULTS: During the follow-up period, 64 subjects died. Kaplan-Meier analysis showed a significantly increased risk for total and cancer mortality in subjects with lower ARR (log-rank P < 0·001). Cox's proportional hazard model analyses with adjustment for age and gender showed that lower ARR was associated with increased total and cancer mortality in subjects with low (≦72) vs high (>72) ARR (hazard ratios and 95% confidential intervals: 2·56, 1·44-4·56 and 2·78, 1·16-6·65, respectively). CONCLUSIONS: Lower ARR was a significant and independent risk factor for increased total and cancer mortality in this Japanese population. Subjects with higher ARR were not-at-risk for total death in general. These findings increase the necessity for identifying people with PA from those with higher ARR. People with higher ARR without PA may be at very low risk for total and cancer death.

Evaluation of the diagnostic criteria for Cushing's disease in Japan.

Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome is caused by an ACTH-producing tumor, as is the case with Cushing's disease and ectopic ACTH syndrome (EAS). Diagnosis and differential diagnosis of Cushing's disease from EAS in ACTH-dependent Cushing's syndrome are thus challenging problems in clinical endocrinology. The diagnostic criteria for Cushing's disease in Japan, established by the working group of the Japan Ministry of Health, Labour and Welfare, were originally reported in 2003 and revised in 2007 and 2010. In addition, criteria for subclinical Cushing's disease were established in Japan in 2010. In this review, we evaluate the usefulness and accuracy of the most recent diagnostic criteria. Previous data suggest that as an initial test of Cushing's syndrome, 0.5 mg dexamethasone is more sensitive than 1 mg in the overnight dexamethasone suppression test (DST). Here, we recommend 0.5 mg plus a plasma cortisol cut-off level of 3 µg/dL as a suitable low-dose overnight DST for screening of all cases of ACTH-dependent Cushing's syndrome in Japan. Recently, standardization of cortisol measurements by the ID-LC/MS/MS method using seven assay kits with standard plasma material containing synthetic hydrocortisone-d4 was carried out in Japan. The resulting relative standard deviation was within 10%. The cut-off value remains valid even after standardization of plasma cortisol measurements. Although the recent diagnostic criteria achieve higher diagnostic specificity, care should be taken since data for Cushing's disease partially overlaps with some cases of EAS. Overall, therefore, this review suggests that the accuracy of each diagnostic test should be considered.

Renal Injuries in Primary Aldosteronism: Quantitative Histopathological Analysis of 19 Patients With Primary Adosteronism.

[Figure: see text].

Evaluation of plasma, salivary, and urinary cortisol levels for diagnosis of Cushing's syndrome.

As a screening test for Cushing's syndrome, the evaluation of late-night cortisol levels is indispensable. We evaluated the usefulness and accuracy of plasma, urinary, and salivary cortisol levels measured late at night for the diagnosis of Cushing's syndrome. High cortisol levels (> 5 microg/dL) during the night are indicative of Cushing's syndrome, although night plasma cortisol levels are not readily reproducible because of the stressful situation. There was no correlation between plasma and urinary cortisol levels late at night, and late-night urinary cortisol levels provided weak information for the diagnosis of Cushing's syndrome. By contrast, late-night plasma and salivary cortisol levels showed a positive correlation, and salivary cortisol sampling was found to be useful for the diagnosis of Cushing's syndrome, because more than 0.4 microg/dL of late-night salivary cortisol levels gave a sensitivity of 86% and a specificity of 100% in our hospital. This method is also useful for the diagnosis of early or mild stage Cushing's syndrome, so-called subclinical Cushing's syndrome. Inherent differences between assays make it difficult to define optimal diagnostic criteria. However, the relative levels of salivary cortisol ratio, which is presented as a relative level, compared with the mean levels of healthy subjects in each institute, is useful for the screening of Cushing's syndrome as the cut-off level of 1.5 shows both high sensitivity and specificity in subclinical and overt Cushing's syndrome. Late-night salivary cortisol measurement is therefore a primary method of choice in the screening of patients suspected of having Cushing's syndrome.

Two Cases of Hypopituitarism Caused by Intrasellar Aneurysm.

Giant internal carotid artery aneurysms sometimes extend into the sellar region, which rarely but occasionally results in hypopituitarism due to the compression of the normal pituitary gland or hypothalamus. Hyponatremia is a known complication of hypopituitarism. We herein report two cases of hypopituitarism caused by intrasellar aneurysm of different origins, resulting in hyponatremia. Untreated hypopituitarism may lead to lethargy, coma, cardiac arrhythmia, and death. Therefore, we must be alert for the occurrence of giant intrasellar aneurysm, as it causes hypopituitarism. The prompt diagnosis and treatment of hypopituitarism are necessary to prevent this fatal outcome.

Association between higher urinary normetanephrine and insulin resistance in a Japanese population.

Since activation of the sympathetic nervous system is associated with both impaired insulin secretion and insulin resistance, or namely with diabetes, evaluation of such activation in ordinary clinical settings may be important. Therefore, we evaluated the relationships between urinary concentrations of the catecholamine metabolites, urinary normetanephrine (U-NM) and urinary metanephrine (U-M), and glucose metabolism in a general population. From 1,148 participants in the 2016 population-based Iwaki study of Japanese, enrolled were 733 individuals (gender (M/F): 320/413; age: 52.1±15.1), who were not on medication affecting serum catecholamines, not diabetic, and had complete data-set and blood glucose levels appropriate for the evaluation of insulin secretion and resistance, using homeostasis model assessment (HOMA-ß and HOMA-R, respectively). Univariate linear regression analyses revealed significant correlations between both U-NM and U-M, and HOMA-ß, but adjustment for multiple factors correlated with HOMA indices abolished these (ß = -0.031, p = 0.499, and ß = -0.055, p = 0.135, respectively). However, the correlation between U-NM and HOMA-R observed using univariate linear regression analysis (ß = 0.132, p<0.001) remained significant even after these adjustments (ß = 0.107, p = 0.007), whereas U-M did not correlate with HOMA-R. Furthermore, use of the optimal cut-off value of U-NM for the prediction of insulin resistance (HOMA-R >1.6) determined by ROC analysis (0.2577 mg/gCr) showed that individuals at risk had an odds ratio of 2.65 (confidence interval: 1.42-4.97) after adjustment for the same factors used above. Higher U-NM concentrations within the physiologic range are a significant risk factor for increased insulin resistance in a general Japanese population.

Progression of Hypopituitarism and Hypothyroidism after Treatment with Pembrolizumab in a Patient with Adrenal Metastasis from Non-small-cell Lung Cancer.

Pembrolizumab, or anti-programmed death receptor 1 antibody, is an immune checkpoint inhibitor that can cause immune-related adverse events. We herein report for the first time the progression of hypopituitarism and hypothyroidism after treatment with pembrolizumab in a patient with adrenal metastasis of non-small-cell lung cancer. Severe primary hypothyroidism occurred three weeks after the first administration of pembrolizumab. Four months after the discontinuation of pembrolizumab, isolated adrenocorticotropic hormone (ACTH) deficiency was noted. Corticotropin-releasing hormone and rapid ACTH tests performed repeatedly showed that the patient's pituitary and adrenal function had been gradually deteriorating. It is important to diagnose adrenal insufficiency without delay in order to prevent adrenal crisis.

Diagnostic usefulness of the growth hormone-releasing peptide-2 test as a substitute for the insulin tolerance test in hypopituitarism.

Adrenal insufficiency can result from primary disorder of the adrenal gland or occurs secondarily due to deficiency in adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH). To prevent adrenal crisis, it is thus important to test the remaining function of the adrenal gland. Tests for the function of the hypothalamic-pituitary-adrenal (HPA) axis are also useful for examining localization of disease causing adrenal insufficiency. Generally, the insulin tolerance test (ITT) is useful for examining the HPA axis in both hypothalamic and pituitary diseases; however, ITT has a number of disadvantages. The growth hormone-releasing peptide (GHRP)-2 test may be a useful tool for diagnosing secondary adrenal insufficiency such as hypothalamic disorder and pituitary damage. In the present study, we examined the diagnostic usefulness of the GHRP-2 test as a substitute for ITT in hypopituitarism. We showed that patients with significant ACTH response to ITT also had significant response to the GHRP-2 test, while patients with no significant ACTH response to ITT also had no significant response to the GHRP-2 test. These data suggest that the GHRP-2 test may be a useful diagnostic tool for secondary adrenal insufficiency such as hypothalamic disorder and pituitary damage.

Inhibitory effects of glucocorticoids on urocortin-mediated increases in interleukin-6 gene expression in rat aortic smooth muscle cells.

Urocortin (Ucn) 1, Ucn2, and Ucn3 have potent effects on appetite and the cardiovascular system. Endogenous Ucns in combination with CRF receptor type 2beta may have a physiological role in the cardiovascular system. We previously demonstrated that both Ucn1 and Ucn2 increased IL-6 output levels in A7r5 aortic smooth muscle cells. In the present study, we extended observations on stress or hormone-induced changes in IL-6 gene expression in the cardiovascular system, and determined the effects of glucocorticoids on Ucn-mediated increases in IL-6 mRNA levels, protein levels, and gene transcription activity in A7r5 cells. Ucn1, Ucn2, and Ucn3 all increased IL-6 mRNA levels via CRF receptor type 2. Dexamethasone blocked the ability of Ucn1 to increase IL-6 mRNA and protein levels, while it failed to attenuate the Ucns-mediated changes in cyclic AMP (cAMP)-response element binding protein or extracellular signal-related kinases phosphorylation. Dexamethasone also suppressed Ucn1- or cAMP-stimulated IL-6 gene transcription via a glucocorticoid receptor. Together, these findings demonstrate that glucocorticoids suppress IL-6 gene transcription via Ucn-induced cAMP-dependent pathways in A7r5 cells.

Acute mesenteric ischemia and hepatic infarction after treatment of ectopic Cushing's syndrome.

SUMMARY: Patients with Cushing's syndrome and excess exogenous glucocorticoids have an increased risk for venous thromboembolism, as well as arterial thrombi. The patients are at high risk of thromboembolic events, especially during active disease and even in cases of remission and after surgery in Cushing's syndrome and withdrawal state in glucocorticoid users. We present a case of Cushing's syndrome caused by adrenocorticotropic hormone-secreting lung carcinoid tumor. Our patient developed acute mesenteric ischemia after video-assisted thoracoscopic surgery despite administration of sufficient glucocorticoid and thromboprophylaxis in the perioperative period. In addition, our patient developed hepatic infarction after surgical resection of the intestine. Then, the patient was supported by total parenteral nutrition. Our case report highlights the risk of microthrombi, which occurred in our patient after treatment of ectopic Cushing's syndrome. Guidelines on thromboprophylaxis and/or antiplatelet therapy for Cushing's syndrome are acutely needed. LEARNING POINTS: The present case showed acute mesenteric thromboembolism and hepatic infarction after treatment of ectopic Cushing's syndrome.Patients with Cushing's syndrome are at increased risk for thromboembolic events and increased morbidity and mortality.An increase in thromboembolic risk has been observed during active disease, even in cases of remission and postoperatively in Cushing's syndrome.Thromboprophylaxis and antiplatelet therapy should be considered in treatment of glucocorticoid excess or glucocorticoid withdrawal.

Association between serum prolactin levels and insulin resistance in non-diabetic men.

Prolactin (PRL) has roles in various physiological functions. Although experimental studies showed that PRL has both beneficial and adverse effects on type 2 diabetes mellitus, clinical findings in subjects with hyperprolactinemia indicate adverse effects on glucose metabolism. However, effects of PRL within the physiological range in human are controversial. A population-based study of 370 Japanese men enrolled in the 2014 Iwaki study (aged 52.0 ± 14.8 years). In this cross-sectional study, associations between serum PRL levels and homeostatic model assessment (HOMA) indices representing glucose metabolism in a physiological setting were examined using multivariable regression analysis. Although univariate linear regression analyses showed significant associations between serum PRL levels and HOMA indices, adjustment with multiple factors made the association with HOMA-ß (insulin secretion) insignificant, while those with HOMA-R (insulin resistance) remained significant (ß = 0.084, p = 0.035). Non-linear regression analyses showed a regression curve with a peak at serum PRL level, 12.4 ng/mL and a positive association of serum PRL level with HOMA-R below the peak (ß = 0.119, p = 0.004). Higher serum PRL levels within the physiological range seem to be associated with insulin resistance in men.

Dominance of the hypothalamus-pituitary-adrenal axis over the renin-angiotensin-aldosterone system is a risk factor for decreased insulin secretion.

How the association between the hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin-aldosterone system (RAAS) affects glucose metabolism were not well examined in a general population. Participants of the population-based 2015 Iwaki study were enrolled (n: 1,016; age: 54.4 ± 15.1 years). Principal component (PC) analysis identified two PCs: PC1 represented levels of the HPA axis (serum cortisol) and the RAAS (plasma aldosterone) as a whole, and PC2 represented the HPA axis relative to the RAAS (HPA axis dominance). We examined the association between these PCs and glucose metabolism using homeostasis model assessment indices of reduced insulin sensitivity (HOMA-R) and secretion (HOMA-ß). Univariate linear regression analyses showed a correlation between PC2 and HOMA-ß (ß = -0.248, p < 0.0001), but not between PC1 and HOMA-ß (ß = -0.004, p = 0.9048). The correration between PC2 and HOMA-ß persisted after adjustment for multiple factors (ß = -0.101, p = 0.0003). No correlations were found between the PCs and HOMA-R. When subjects were tertiled based on PC2, the highest tertile was at greater risk of decreased insulin secretion (defined as the lower one third of HOMA-ß (≤68.9)) than the lowest tertile after adjustment for multiple factors (odds ratio, 2.00; 95% confidence interval, 1.35-2.97). The HPA axis dominance is associated with decreased insulin secretion in a Japanese population.

Urocortin induces interleukin-6 gene expression via cyclooxygenase-2 activity in aortic smooth muscle cells.

Corticotropin-releasing factor (CRF) plays a central role in controlling stress-related activity of the hypothalamic-pituitary-adrenal axis. Four CRF-related peptides have been found in mammals: CRF and urocortins (Ucns) 1-3. Ucns bound to CRF(2beta) receptors have a physiological role in the cardiovascular system. We previously found that both Ucn1 and -2 induced accumulation of intracellular cAMP via CRF(2beta) receptor binding and significantly increased IL-6 secretion by A7r5 aortic smooth muscle cells. In the present study, we investigated Ucn effects on IL-6 gene expression and IL-6 synthesis in A7r5 aortic smooth muscle cells. Ucn1 and -2 stimulated IL-6 gene transcription and IL-6 secretion via CRF(2) receptors. Indomethacin, a cyclooxygenase (COX) inhibitor, suppressed IL-6 gene transcription and IL-6 secretion by Ucn1 or -2. NS-398, a COX-2 inhibitor, suppressed IL-6 induction to the same extent as indomethacin. These results suggest that the COX-2 pathway is involved downstream in regulation of Ucn-increased IL-6 gene expression and IL-6 secretion. In addition, COX-2 expression levels were increased at 6 h with the combination of Ucn1 and IL-1, compared with single peptide activation. Ucn1 showed a potent stimulatory effect on IL-6 output, whereas IL-1 alone had no significant effects. However, when Ucn1 was simultaneously used with IL-1, it markedly potentiated the increments in IL-6 output and promoter activity produced by Ucn1. Taken together, these findings indicate that the COX-2 pathway plays a major role in increasing IL-6 levels stimulated by Ucn and IL-1 in A7r5 cells.

Association Between Pituitary-Adrenal Axis Dominance Over the Renin-Angiotensin-Aldosterone System and Hypertension.

CONTEXT: The hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin aldosterone system (RAAS) are well known to be associated with hypertension. However, the extent of the effects is not yet well elucidated in general conditions. OBJECTIVE: To separately determine the effect of the HPA axis and the RAAS on hypertension in a general population. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 859 Japanese individuals enrolled in the 2014 Iwaki study and without hypertension or steroid treatment (age, 50.2 ± 14.7 years). MAIN OUTCOME MEASURES: Hypertension prevalence, plasma concentration of aldosterone, ACTH, cortisol, and plasma renin activity. RESULTS: Principal component (PC) analysis using these four hormones identified two PCs (PC1 and PC2), which represent levels of these hormones as a whole, and dominance between the HPA axis (ACTH and cortisol) and the RAAS (plasma renin activity and plasma concentration of aldosterone), respectively. Association between these PCs and hypertension was significant (PC1, high vs low, odds ratio [OR], 1.48; 95% confidence interval [CI], 1.09-2.02; and PC2, HPA axis vs RAAS dominancy, OR, 2.08; and 95% CI, 1.51-2.85). However, association between the hormone levels as a whole and hypertension became insignificant after adjustment for multiple factors including these PCs together. However, association between the HPA axis dominance and hypertension remained significant even after the adjustment (the HPA axis vs the RAAS, OR, 1.73; 95% CI, 1.20-2.48). CONCLUSIONS: The HPA axis dominance over the RAAS is significantly associated with hypertension in a Japanese population.

Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population.

Glucocorticoids (GCs) are well known to induce insulin resistance. However, the effect of GCs on insulin secretion has not been well characterized under physiological conditions in human. We here evaluated the effect of GCs on insulin secretion/ß-cell function precisely in a physiological condition. A population-based study of 1,071 Japanese individuals enrolled in the 2014 Iwaki study (390 men, 681 women; aged 54.1 ± 15.1 years), those excluded individuals taking medication for diabetes or steroid treatment, were enrolled in the present study. Association between serum cortisol levels and insulin resistance/secretion assessed by homeostasis model assessment using fasting blood glucose and insulin levels (HOMA-R and HOMA-ß, respectively) were examined. Univariate linear regression analyses showed correlation of serum cortisol levels with HOMA-ß (ß = -0.134, p <0.001) but not with HOMA-R (ß = 0.042, p = 0.172). Adjustments for age, gender, and the multiple clinical characteristics correlated with HOMA indices showed similar results (HOMA-ß: ß = -0.062, p = 0.025; HOMA-R: ß = -0.023, p = 0.394). The correlation between serum cortisol levels and HOMA-ß remained significant after adjustment for HOMA- R (ß = -0.057, p = 0.034). When subjects were tertiled based on serum cortisol levels, the highest tertile was at greater risk of decreased insulin secretion (defined as lower one third of HOMA-ß (≤70)) than the lowest tertile, after adjustment for multiple factors including HOMA- R (odds ratio 1.26, 95% confidence interval 1.03-1.54). In conclusion, higher serum cortisol levels are significantly associated with decreased insulin secretion in the physiological cortisol range in a Japanese population.