Insulin- and Lipopolysaccharide-Mediated Signaling in Adipose Tissue Macrophages Regulates Postprandial Glycemia through Akt-mTOR Activation.

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.

Different post-pancreatectomy glucagon responses to a meal test between surgical approaches.

Residual pancreatic endocrine function is important for maintaining metabolic status after pancreatectomy and is closely related to patient nutritional status and prognosis. In contrast to insulin secretion, the significance of glucagon secretion following pancreatectomy remains unclear. In this study, we assessed the changes in pancreatic glucagon secretion during pancreatectomy to determine their pathophysiological significance. We evaluated glucagon and insulin secretion using a liquid meal tolerance test before and after pancreatectomy in patients scheduled to undergo pancreaticoduodenectomy (PD) or distal pancreatectomy (DP). After pancreatectomy, fasting plasma glucagon levels were significantly decreased in both the PD (n = 10) and DP (n = 5) groups (PD: from 18.4 to 10.5 pg/mL, p = 0.037; DP: from 21.0 to 12.1 pg/mL, p = 0.043), whereas postprandial plasma glucagon levels were not changed. In the liquid meal tolerance test after pancreatectomy, 60-min plasma glucagon levels and the area under the curve (AUC) for 0-120 min of PD were significantly higher than those for DP (60-min plasma glucagon: PD 49.0 vs. DP 21.7 pg/mL, p = 0.040; AUC0-120min: PD 4,749 vs. DP 3,564 µg min/mL, p = 0.028). Postoperative plasma glucose, serum insulin, and serum C-peptide levels during the liquid meal tolerance test were not significantly different between the two groups. Although fasting plasma glucagon levels decreased, postprandial glucagon responses were maintained after both PD and DP. The difference in residual meal-stimulated glucagon response between PD and DP suggests that a relative excess of postprandial glucagon is involved in the postoperative nutritional status after PD through its impact on systemic metabolic status.

Elevated free thyroxine and free triiodothyronine probably caused by high-dose biotin intake in a patient with Graves' disease: a case report.

Biotin is a water-soluble vitamin that acts as a cofactor for carboxylase, and is often used as a component in several immunoassays. We present a case of a 46-year-old male with Graves' disease (GD) who revealed elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels after high-dose biotin intake. Levels of these hormones had been within the reference range when he was on thiamazole 5 mg/day for 7 years; however, the levels increased from 1.04 to 2.20 ng/dL and from 3.05 to 9.84 pg/mL for FT4 and FT3, respectively, after he started taking biotin 72 mg/day. Despite these high levels, his symptoms and the other laboratory results, including the thyroid-stimulating hormone level, did not suggest GD relapse. His thyroid hormone data was decreased and returned within the reference range immediately after the laboratory assays for FT3 and FT4 had been coincidentally changed from those containing streptavidin-biotin complexes to biotin-free ones. Biotin interference, which is caused by high-dose biotin intake and immunoassays using some form of streptavidin-biotin complex, is sometimes clinically problematic, giving high or low results. To our knowledge, this is the first case report of a patient with GD on high-dose biotin receiving high thyroid hormone level results that were initially misunderstood as an aggravation of the disease; there are some reports of misdiagnosis of hyperthyroidism due to biotin administration. Unexpected fluctuations in thyroid function test results in patients with GD should be checked for biotin intake, immunoassays and the limiting concentration of biotin to avoid misdiagnosis of relapse.

PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells.

Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T (Treg) cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-γ, the 'master regulator' of adipocyte differentiation, as a crucial molecular orchestrator of VAT Treg cell accumulation, phenotype and function. Unexpectedly, PPAR-γ expression by VAT Treg cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of Treg cells with unique functions can be precisely targeted to therapeutic ends.

Circulating TNF receptor levels are associated with estimated glomerular filtration rate even in healthy individuals with normal kidney function.

The association between serum tumor necrosis factor receptor (TNFRs: TNFR1, TNFR2) levels and estimated glomerular filtration rate (eGFR) observed in patients with diabetes has not been comprehensively tested in healthy subjects with normal kidney function. It also remains unclear whether TNFR levels differ by age and sex, and between healthy subjects and diabetics. We measured serum TNFR levels in 413 healthy subjects and 292 patients with type 2 diabetes. In healthy subjects, TNFR levels did not differ between men and women. Additionally, TNFR2, but not TNFR1, levels increased with age. In multivariate analysis, TNFR1 was associated only with cystatin C-based eGFR (eGFR-CysC), whereas TNFR2 was associated with systolic blood pressure in addition to eGFR-CysC. Both TNFRs were associated with lower eGFR (eGFR-Cys < 90 mL/min/1.73 m2) even after adjustment for relevant clinical factors. Upon combining healthy subjects and patients with diabetes, the presence of diabetes and elevated glycated hemoglobin level were significant factors in determining TNFR levels. TNFR levels were associated with eGFR-CysC, but were not affected by age and sex in healthy subjects with normal kidney function. TNFR levels in patients with diabetes appeared to be higher than in healthy subjects.

A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Circulating tumor necrosis factor-related biomarkers predict kidney function decline in Japanese patients with diabetes: An observational cohort study.

AIMS: Tumor necrosis factor (TNF) receptors (TNFRs: TNFR1 and, TNFR2) are reportedly associated with chronic kidney disease (CKD) progression chiefly in Caucasian patients with diabetes. We assessed the prognostic value of TNF-related biomarkers for CKD progression in Japanese patients with diabetes. METHODS: We estimated TNF-related biomarkers using an enzyme-linked immunosorbent assay in 640 patients with diabetes. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) per one standard deviation (SD) increase in a log-transformed biomarker. The kidney and the composite outcome were defined as a 30% reduction in estimated glomerular filtration rate (eGFR) from baseline, and kidney outcome plus death before kidney outcome, respectively. RESULTS: During the median follow-up of 5.4 years, 75 (11.7%) patients reached the kidney outcome and 37 (5.8%) died before reaching the kidney outcome. Each SD increase in baseline circulating TNFR1, TNFR2, and ephrin type-A receptor 2 (EphA2) was associated with a higher risk of the kidney outcome independently from baseline eGFR and urine albumin-to-creatinine ratio. However, circulating osteoprotegerin was associated with the composite outcome only. CONCLUSIONS: Elevated TNFR1, TNFR2, and EphA2 were associated with both kidney and composite outcomes in Japanese patients with diabetes.

Treatment Burden on Once-Weekly Omarigliptin Versus Daily Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes: Randomized Controlled Trial (ONWARD-DPP4 Study).

INTRODUCTION: Preference for quality of life is important in deciding the treatment strategy for patients with type 2 diabetes mellitus. This study aimed to assess the effect of omarigliptin on patients' psychological attitudes and responses compared with daily dipeptidyl peptidase-4 inhibitors (DPP4is) by measuring the burden of pharmacotherapy using the Diabetic Treatment Burden Questionnaire (DTBQ). METHODS: Patients with type 2 diabetes mellitus who were taking daily DPP-4is were enrolled and randomized to a group that switched to omarigliptin or a group that continued daily DPP4is and were monitored for 12 weeks. The primary endpoint was the change in the DTBQ score from baseline to week 12. The secondary endpoints included changes in blood test results, medication preferences and medication adherence. RESULTS: The DTBQ total score significantly decreased from baseline to week 12 in both groups; however, no significant intergroup differences were observed. The DTBQ subscale, implementation and flexibility burden scores significantly decreased in the group that switched to omarigliptin, although no significant intergroup difference in the change was observed. DTBQ scores and medication preferences were associated with improvements in the DTBQ scores. CONCLUSION: Although this study failed to demonstrate the improvement of DTBQ total score by switching from daily DPP4is to omarigliptin compared with continuing the daily DPP4is, the DTBQ subscale score implementation and flexibility burden score were significantly improved only in the group that switched to omarigliptin, suggesting the possibility of switching from daily DPP4is to omarigliptin to decrease the patients' medication burden. TRIAL REGISTRATION: jRCTs031200437.

Progranulin and Its Receptor Predict Kidney Function Decline in Patients With Type 2 Diabetes.

Progranulin (PGRN), a growth factor, is abundantly expressed in a broad range of tissues and cell types with pleiotropic functions including inflammation, neurodegeneration, and facilitating lysosome acidification. PGRN binds to TNF receptors (TNFR) and inhibits downstream inflammatory signaling pathways. TNFR is a well-known predictor of glomerular filtration rate (GFR) decline in a variety of diseases. Therefore, we measured circulating PGRN in addition to TNFR using an enzyme-linked immunosorbent assay and explored whether it predicted renal prognosis in 201 Japanese patients with type 2 diabetes. During a median follow-up of 7.6 years, 21 participants reached primary renal endpoint, which involves a decline of at least 57% in eGFR from baseline, or the onset of end-stage renal disease. Univariate Cox regression analysis revealed that classical renal measures (GFR and albuminuria), two TNF-related biomarkers (PGRN and TNFR), and BMI were associated with this outcome. Multivariate analysis demonstrated that high levels of PGRN [HR 2.50 (95%CI 2.47-2.52)] or TNFR1 [HR 5.38 (95%CI 5.26-5.50)] were associated with this outcome after adjusting for relevant covariates. The high levels of PGRN as well as TNFR1 were associated with a risk of primary renal outcome in patients with type 2 diabetes after adjusting for established risk factors.

Comparison of Patient-Led and Physician-Led Insulin Titration in Japanese Type 2 Diabetes Mellitus Patients Based on Treatment Distress, Satisfaction, and Self-Efficacy: The COMMIT-Patient Study.

INTRODUCTION: In Japan, patient-led insulin titration is rare in type 2 diabetes mellitus (T2DM) patients. Few studies have compared the effects of patient-led versus physician-led insulin titration on patient-reported outcomes in Japanese T2DM patients. This study aimed to compare the effects of patient-led and physician-led insulin titration in Japanese insulin-naïve T2DM patients on safety, glycemic control, and patient-reported outcomes (emotional distress, treatment satisfaction, and self-efficacy). METHODS: Ultimately, 125 insulin-naïve Japanese T2DM patients were randomly assigned to either a patient-led insulin self-titration group or a physician-led insulin titration group and monitored for 24 weeks. The primary endpoint was a change in emotional distress as measured using the Problem Areas in Diabetes scale (PAID). Secondary endpoints included treatment satisfaction, as measured with the Diabetes Treatment Satisfaction Questionnaire (DTSQ), self-efficacy as measured using the Insulin Therapy Self-Efficacy Scale (ITSS), glycated hemoglobin (HbA1c) levels, fasting plasma glucose levels, body weight, insulin daily dose, and frequency of hypoglycemia. RESULTS: There was no significant difference between the groups in PAID and DTSQ scores. The results for the primary endpoint should be interpreted taking account that the sample size for the power calculation was not reached. ITSS scores were significantly higher in the patient-led self-titration group. HbA1c and fasting plasma glucose levels were significantly decreased in both groups, but the decrease was significantly larger in the patient-led self-titration group. Although the insulin daily dose was significantly higher in the patient-led self-titration group, severe hypoglycemia did not occur in either group, and the frequency of hypoglycemia was similar in both groups. CONCLUSION: Self-measurement of blood glucose and self-titration of insulin enhanced the patients' self-efficacy without compromising their emotional distress or treatment satisfaction. Also, insulin self-titration was found to be safe and effective; it resulted in better glycemic control without severe hypoglycemia. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (registration number: UMIN000020316).

Fractional excretion of tumor necrosis factor receptor 1 and 2 in patients with type 2 diabetes and normal renal function.

AIMS/INTRODUCTION: Increased concentrations of serum tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2) are positively associated with the urinary albumin-to-creatinine ratio (ACR), and negatively associated with the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. However, the mechanism underlying this increase and the relationship between TNFRs in serum, and urine and kidney measures (ACR and eGFR) are unclear. MATERIALS AND METHODS: This was a cross-sectional study that included 499 patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2 . The concentrations of TNFRs in serum and urine, and their respective fractional excretion, were measured. RESULTS: Serum and urinary TNFR levels were positively associated with the ACR, and negatively associated with the eGFR. The fractional excretion of TNFRs did not differ between patients with an eGFR ≥90 and those with an eGFR 60-89 mL/min/1.73 m2 , and also did not correlate with eGFR. After adjustment for relevant covariates, the serum TNFRs were associated with a lower eGFR (60-89 mL/min/1.73 m2 ) and an increased ACR (≥30 mg/gCr), but urinary TNFRs were associated with an increased ACR (≥30 mg/gCr) alone, in the multivariate logistic model. CONCLUSIONS: The pattern of fractional excretion TNFRs showed that an increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline. Kidney measures appear to be strongly associated with serum TNFRs rather than urinary TNFRs in patients with type 2 diabetes and normal renal function.

Comprehensive efficacy of ipragliflozin on various conditioned type 2 diabetes compared with dipeptidyl peptidase-4 inhibitors and with both agents, based on a real-world multicenter trial.

AIMS: The effects of ipragliflozin, the first sodium-glucose co-transporter 2 inhibitors (SGLT2i) launched in Japan in 2014, and with dipeptidyl peptidase-4 inhibitors (DPP-4i) on glycemic control and metabolic changes were investigated comprehensively on various conditioned type 2 diabetes (T2DM) by evaluating various clinical parameters in a real-world setting. MATERIALS AND METHODS: A total of 101 patients with T2DM aged 20-80 years with 7.0% ≤ HbA1c < 10.0% were followed in this 52-week, open-label, prospective, real-world, multicenter study. RESULTS: HbA1c decreased significantly in all groups. In ipragliflozin using groups, body weight, waist circumference, blood pressure, HOMA-IR, AST, ALT, γ-GTP, uric acid and leptin levels decreased, in contrast, HDL-cholesterol, total ketone bodies, blood urea nitrogen, creatinine, RBC, hemoglobin and hematocrit levels increased, however, in DPP-4i sole group, no significant trends were observed in these parameters. Change in leptin positively correlated with insulin, while change in total ketone bodies inversely correlated with ALT in ipragliflozin using groups. Fasting active gastric inhibitory polypeptide levels decreased in ipragliflozin sole group. Glucagon showed no changes. No significant safety concerns were observed in this study. CONCLUSIONS: Ipragliflozin is useful and safe, showing some contrastive effects on several clinical parameters which are not shown with DPP-4i, resulting several clinical benefits. The co-administration of ipragliflozin and a DPP-4i has a better clinical outcome than either single-agent therapy.

Quality-of-Life Comparison of Dapagliflozin Versus Dipeptidyl Peptidase 4 Inhibitors in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial (J-BOND Study).

INTRODUCTION: No study has compared the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) on patients' quality-of-life (QOL). METHODS: We enrolled 253 drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM), randomly assigned them into a dapagliflozin (SGLT2i) group or DPP4i group in approximately 1:1 ratio, and monitored them for 24 weeks. The primary endpoint was the proportion of subjects indicating improvement in the "overall quality of life" domain of SHIELD-WQ-9 at week 24. Secondary endpoints included other domains of SHIELD-WQ-9, DTR-QOL, EQ-5D-5L, medication preference, medication adherence, diet therapy adherence, body weight, body mass index (BMI), abdominal circumference, HbA1c, and frequency of adverse events. RESULTS: The proportion of subjects indicating improvement in the "overall quality of life" domain of SHIELD-WQ-9 at week 24 was higher in the dapagliflozin group (28.4%) than in the DPP4i group (18.6%) (p = 0.08). The proportion of subjects indicating improvement in the "physical health" domain of SHIELD-WQ-9 at week 24 was significantly higher in the dapagliflozin group (42.2%) than in the DPP4i group (23.7%) (p = 0.004). Total scores and domain 1 scores of DTR-QOL showed greater improvement in the dapagliflozin group (14.3 ± 15.6 and 15.5 ± 20.8, respectively) than in the DPP4i group (10.2 ± 15.6 and 10.3 ± 19.5, respectively) (both p = 0.05). EQ-5D-5L scores had significantly improved in the DPP4i group (0.023 ± 0.088) (p = 0.005); the intergroup difference was not significant (p = 0.14). Body weight (p < 0.001), BMI (p < 0.001), and abdominal circumference (p = 0.019) had significantly decreased in the dapagliflozin group compared with the corresponding values in the DPP4i group. CONCLUSION: Dapagliflozin showed a comparable or more favorable benefit on Japanese patients' QOL compared with DPP4is. Dapagliflozin was well tolerated. It significantly reduced body weight, which was significantly correlated with improvement in the patients' QOL. This study demonstrates that dapagliflozin can be used as a first-line drug for T2DM in Japan with a beneficial impact on patients' QOL. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN000030514); Japan Registry of Clinical Trials (jRCTs051180165).

Circulating kidney injury molecule-1 as a biomarker of renal parameters in diabetic kidney disease.

AIMS/INTRODUCTION: Urinary kidney injury molecule-1 (KIM-1) has been associated with proximal tubular damage in human and animal studies. Although it has been recognized as a biomarker of acute kidney injury and chronic kidney disease, its significance in the serum remains unclear. Therefore, we examined the relationship of serum and urinary KIM-1 levels with renal parameters in patients with type 2 diabetes. MATERIALS AND METHODS: Serum and urinary KIM-1 levels, together with urinary liver-type fatty acid-binding protein, were measured in 602 patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 . These were then compared with the urinary albumin-to-creatinine ratio and eGFR. RESULTS: The serum and urinary KIM-1 levels were significantly different among the three (eGFR ≥60, 45-59, <45 mL/min/1.73 m2 ) groups. These levels were positively associated with the albumin-to-creatinine ratio and negatively associated with eGFR. In a multivariate logistic model, both serum and urinary KIM-1 were associated with an increased albumin-to-creatinine ratio (>30 mg/g Cr), but only the serum KIM-1 was associated with a lower eGFR (<60 mL/min/1.73 m2 ), after adjustment for covariates. CONCLUSIONS: Renal parameters appear to be strongly associated with serum KIM-1, and not urinary KIM-1, in patients with type 2 diabetes and an eGFR ≥30 mL/min/1.73 m2 .

The single nucleotide polymorphism upstream of insulin-induced gene 2 ( INSIG2) is associated with the prevalence of hypercholesterolaemia, but not with obesity, in Japanese American women.

Insulin-induced gene 2 (insig-2) protein is known to play important roles in cholesterol and TAG metabolism both in vivo and in vitro. One particularly interesting single nucleotide polymorphism (SNP), rs7566605, located 10 kb upstream of INSIG2 was reported to have the strongest association with obesity among 86 604 SNP, while the relationship with dyslipidaemia is uncertain. Eight hundred and eighty-five Japanese Americans (347 men and 538 women) and 378 Japanese (182 men and 196 women) were enrolled, and the rs7566605 SNP, which is consistent with either G or C, was determined. We investigated the association between the rs7566605 SNP and the prevalence of hypercholesterolaemia or hypertriacylglycerolaemia, or obesity parameters, as assessed by BMI, waist girth and percentage body fat. There were no significant differences in BMI, waist girth and percentage body fat according to the genotype in each of the four groups, which was divided by population and sex. The prevalence of hypercholesterolaemia was significantly different between the genotypes in Japanese American female subjects (GG, 62.2 %; GC, 57.1 %; CC, 42.1 %; P = 0.021), but not in the other subjects. In Japanese American women, the subjects with the CC genotype had a 0.43-fold decreased risk (95 % CI 0.24, 0.80) for hypercholesterolaemia compared with the GG genotype after adjustment for age, percentage body fat, smoking status and hormone replacement therapy. The CC genotype of the rs7566605 SNP is suggested to be a protective genetic factor against the progression of hypercholesterolaemia on a high-fat diet, especially in Japanese female subjects.

Combined acromegaly and subclinical Cushing disease related to high-molecular-weight adrenocorticotropic hormone.

A 36-year-old man with a 1-year history of diabetes mellitus was referred to the authors' hospital for further endocrinological evaluation of acromegaly. On physical examination, typical acromegalic features but no typical cushingoid features were observed. The clinical diagnosis of growth hormone (GH)-producing pituitary adenoma was confirmed by MR imaging findings, nonsuppression of serum GH levels during a 75-g oral glucose tolerance test (trough GH 6.33 ng/ml), and elevated serum insulin-like growth factor-I levels (1361.3 ng/ml). Moreover, autonomic adrenocorticotropic hormone (ACTH) secretion was suspected, based on inadequate suppression of ACTH or cortisol levels by an 0.5-mg overnight dexamethasone suppression test. Analysis of the patient's plasma by using the gel filtration method revealed the presence of a high-molecular-weight (HMW) form of ACTH known to exhibit low biological activity. Transsphenoidal adenomectomy was performed for the pituitary tumor. Immunohistochemical investigation of the resected specimen showed strong and diffuse immunoreactivity to GH and focal immunoreactivity to ACTH. Although there have been a few cases of pituitary adenoma that produced GH and ACTH concomitantly, this is the first report of the detection of HMW ACTH in patients with GH- and ACTH-producing adenomas. Furthermore, the previous cases also did not exhibit typical cushingoid features. It is suggested that the secretion of ACTH in patients with concurrent GH- and ACTH-secreting adenomas might consist of the HMW form and that the HMW ACTH is consequently associated with a subclinical Cushing state.

Effects of azilsartan compared with telmisartan on insulin resistance in patients with essential hypertension and type 2 diabetes mellitus: An open-label, randomized clinical trial.

BACKGROUND: Based on non-clinical data, it is expected that azilsartan, an angiotensin II receptor blocker, will help improve insulin resistance in addition to its hypotensive action. The present study is aimed to explore the effect of azilsartan compared to telmisartan on insulin sensitivity in hypertensive patients in the clinical setting. METHODS: This multicenter, randomized, open-label, parallel-group exploratory study was conducted in Japan. We randomized adult patients (≥20 years old) with grade I or II essential hypertension and coexisting type 2 diabetes (1:1) to receive either oral azilsartan (20 mg/day;17 patients) or telmisartan (40 mg/day;16 patients) for 12 weeks. The primary endpoint was the change in the homeostasis model assessment ratio of insulin resistance (HOMA-R) from the baseline at the end of the treatment period. We also evaluated its safety and efficacy on other diabetes-related variables and blood pressure. FINDINGS: The mean changes in HOMA-R at the end of treatment were 0.22 (95% CI, -1.09-1.52) in the azilsartan group and -0.23 (95% CI, -0.72-0.27) in the telmisartan group. We found no clinically remarkable changes between the groups in diabetes-related variables such as fasting blood glucose, fasting insulin, HbA1c (NGSP), HOMA-ß, or 1,5-anhydroglucitol. Reductions in clinic systolic and diastolic blood pressure were observed at week 4 and the reduced levels were maintained throughout the treatment period in both groups. No serious treatment-emergent adverse events (TEAEs) were observed. Only one drug-related TEAE (mild decrease in blood pressure) was reported in one patient in the azilsartan group. CONCLUSION: Neither azilsartan nor telmisartan had any clinically remarkable effects on insulin resistance parameters when administered for 12 weeks to patients with grade I or II essential hypertension and coexisting type 2 diabetes mellitus. Azilsartan (20 mg/day) and telmisartan (40 mg/day) exerted comparable antihypertensive effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT02079805.

Association between circulating tumor necrosis factor-related biomarkers and estimated glomerular filtration rate in type 2 diabetes.

Chronic inflammation plays a crucial role in the development/progression of diabetic kidney disease. The involvement of tumor necrosis factor (TNF)-related biomarkers [TNFα, progranulin (PGRN), TNF receptors (TNFR1 and TNFR2)] and uric acid (UA) in renal function decline was investigated in patients with type 2 diabetes (T2D). Serum TNF-related biomarkers and UA levels were measured in 594 Japanese patients with T2D and an eGFR ≥30 mL/min/1.73 m2. Four TNF-related biomarkers and UA were negatively associated with estimated glomerular filtration rate (eGFR). In a logistic multivariate model, each TNF-related biomarker and UA was associated with lower eGFR (eGFR <60mL /min/1.73 m2) after adjustment for relevant covariates (basic model). Furthermore, UA and TNF-related biomarkers other than PGRN added a significant benefit for the risk factors of lower eGFR when measured together with a basic model (UA, ΔAUC, 0.049, p < 0.001; TNFα, ΔAUC, 0.022, p = 0.007; TNFR1, ΔAUC, 0.064, p < 0.001; TNFR2, ΔAUC, 0.052, p < 0.001) in receiver operating characteristic curve analysis. TNFR ligands were associated with lower eGFR, but the associations were not as strong as those with TNFRs or UA in patients with T2D and an eGFR ≥30 mL/min/1.73 m2.

Clinical predictive biomarkers for normoalbuminuric diabetic kidney disease.

AIMS: A portion of patients with diabetes mellitus follow the progression of a non-albuminuria-based pathway; i.e., normoalbuminuric diabetic kidney disease (NA-DKD). However, the risk factors which determine NA-DKD are not yet fully understood. This cross-sectional study was therefore aimed to investigate the association between various biomarker levels and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus and normoalbuminuria (T2D-NA). METHODS: We measured cardiovascular disease (CVD) [serum osteoprotegerin (OPG), plasma brain natriuretic peptide (BNP), cardio-ankle vascular index (CAVI)], tubular damage [urinary L-type fatty acid binding protein (L-FABP)], and inflammatory [serum tumornecrosis factor (TNF) α and its receptors (TNFRs)] biomarkers in 314 patients with T2D-NA. RESULTS: The biomarkers of CVD and inflammation showed a significant negative correlation with eGFR. In a logistic multivariate model, none of the biomarkers, except TNFα and TNFRs, were associated with reduced renal function (eGFR < 60 mL/min/1.73 m2) after adjustment for possible biological and clinical covariates. However, the association observed in TNFα was lost after adjusting for TNFR and other covariates. CONCLUSIONS: In patients with T2D-NA, elevated levels of circulating TNFRs, but not of TNFα, were strongly associated with reduced renal function, independently of all relevant covariates.