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.

Effect on Hemoglobin A1c (HbA1c) and Body Weight After Discontinuation of Tirzepatide, a Novel Glucose-Dependent Insulinotropic Peptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist: A Single-Center Case Series Study.

Introduction The purpose of this study was to examine changes in blood glucose levels and body weight after discontinuation of tirzepatide, a novel long-acting dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). Methods Nine subjects (five males, four females, age 54.3±5.4 years, body mass index 33.5±3.3 kg/m2) participating with type 2 diabetes in the SURPASS J-mono study were included. Subjects were randomized to tirzepatide 5 mg, 10 mg, 15 mg, or a dulaglutide 0.75 mg group. Fifty-two weeks after randomization, study drug administration was discontinued. To investigate progress after the end of administration, changes in hemoglobin A1c (HbA1c) and body weight were further examined two, four, and six months after discontinuation of the study drug. Results After fifty-two weeks, all tirzepatide groups had improved HbA1c and body weight compared with the dulaglutide group. At two, four, and six months after the end of study drug administration, re-elevation of HbA1c was observed in all groups. Furthermore, in the tirzepatide groups, dose-dependent weight regain was observed from an early stage. Conclusions Compared to dulaglutide, tirzepatide exhibited excellent blood-glucose-improving and weight-reducing effects. However, exacerbation of blood glucose and rebound of weight gain occurred relatively early after administration was ended. For type 2 diabetes patients who need weight loss and are prescribed tirzepatide, these findings suggest a necessity for continuous prescription or careful follow-up when stopping.

Long-Term Follow-Up Over 16 Years for Pituitary Hyperplasia Due to Primary Hypothyroidism With Positive Thyroid Stimulation Blocking Antibody: A Case Report.

Primary hypothyroidism is a known risk factor for pituitary hyperplasia, which develops symptoms due to compression of the optic chiasma and increased intracranial pressure. As pituitary hyperplasia is known to improve after levothyroxine replacement therapy, there are no reports of a long clinical course of pituitary hyperplasia due to primary hypothyroidism. We describe a case of follow-up over 16 years for pathologically diagnosed pituitary hyperplasia due to primary hypothyroidism with positive thyroid stimulation blocking antibody. Repeated enlargement and shrinkage were confirmed, but observations also suggested that the pituitary gland did not always return to normal size.

Antithyroid arthritis syndrome caused by methimazole in a patient with Graves' disease.

Summary: This is a report on antithyroid arthritis syndrome (AAS) which is a rare adverse effect of antithyroid agents. AAS presents with severe symptoms including myalgia, arthralgia, arthritis, fever, and skin eruption due to the use of antithyroid agents. We encountered a 55-year-old woman with severe pain in the hand and forearm and arthralgia in multiple joints, including the knee, ankle, hand, and wrist on day 23 after initiation of methimazole (MMI) for Graves' disease. Blood tests revealed elevated inflammation markers such as C-reactive protein and interleukin-6, and magnetic resonance imaging of the hands confirmed inflammation findings. After withdrawing MMI on day 25, symptoms showed a tendency toward improvement. Afterwards, inflammation markers also dropped to an almost normal range. In addition to the above findings, the absence of anti-neutrophil cytoplasmic antibodies and most vasculitis symptoms such as nephritis, skin, or pulmonary lesions led to the diagnosis of AAS. A resolution of symptoms, except for mild arthralgia in the second to fourth fingers of the right hand, was observed 61 days after discontinuation of MMI. Although the pathogenesis is unclear, the positive drug lymphocyte stimulation test for MMI and the several weeks before the onset of AAS suggested involvement of a type IV allergic reaction. Based on a discussion of definitive treatment for Graves' disease, radioactive iodine ablation with 131I, which was selected by the patient, was performed and improved her thyroid function. Our case demonstrates the importance of awareness regarding AAS, which is a rare and under-recognized, but life-threatening adverse effect of antithyroid agents. Learning points: Clinicians should be aware of the possibility of developing antithyroid arthritis syndrome (AAS) in patients treated with antithyroid medications, which can lead to severe migratory polyarthritis. Prompt cessation of the antithyroid agent is essential for the resolution of AAS. Anti-neutrophil cytoplasmic antibody (ANCA) negativity is needed to differentiate from antithyroid agent-induced ANCA-associated vasculitis, which shows arthritis similar to AAS.

Association of Serum Zinc Level with severity of chronic kidney disease in diabetic patients: a cross-sectional study.

BACKGROUND: In recent years, it has been reported that diabetic patients tend to have a lower zinc intake due to unbalanced diet accompanying changes in lifestyle habits. We investigated serum zinc concentration in diabetic patients according to the stage of nephropathy. METHODS: We enrolled 227 diabetic patients (119 men, 108 women, average age 65.7 ± 14.7 [mean ± standard deviation]) who were hospitalized for diabetes treatment due to poor blood glucose control. We investigated the relationship between fasting serum zinc concentration and estimated glomerular filtration rate (eGFR) and albuminuria (urinary albumin-to-creatinine ratio, UACR), as well as serum zinc concentration by stage of diabetic kidney disease and chronic kidney disease. RESULTS: The mean HbA1c value was 10.5 ± 2.1%. Serum zinc concentration was 75.5 ± 16.0 µg/dL in males and 75.7 ± 12.2 µg/dL in females, showing no gender difference and no significant relationship with diabetes type. The serum zinc concentration was negatively correlated with age (r = - 0.309, P < 0.001) and positively correlated with eGFR (r = 0.144, P = 0.030). A tendency was observed of serum zinc concentration to decrease after overt nephropathy, with values of 76.4 ± 14.1 µg/dL in pre-nephropathy (stage 1, n = 131), 78.5 ± 13.2 µg/dL in incipient nephropathy (stage 2, n = 65), 66.4 ± 14.3 µg/dL in overt nephropathy (stage 3, n = 25), and 65.7 ± 11.9 µg/dL in kidney failure (stage 4, n = 6). Serum zinc showed a negative trend with estimated GFR (P = 0.004) and significant reduction in albuminuria, with stage A3 (n = 29, 65.7 ± 13.9 µg/dL) having lower levels than A1 (n = 131, 76.4 ± 14.1 µg/dL, P = 0.001) and A2 (n = 67, 78.4 ± 13.1 µg/dL, P < 0.001). CONCLUSIONS: In diabetic patients, serum zinc concentration tended to decrease as age increased and also as renal function deteriorated. This study suggests that consideration of zinc deficiency is necessary in patients with overt albuminuria.

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.

Westernization of Lifestyle and Atherosclerosis in the Japanese: Lessons from the Hawaii - Los Angeles - Hiroshima Study.

Japanese Americans include Japanese individuals migrating from Japan to the United States (first-generation Japanese Americans [JA-1]) and their offspring (second- or later-generation Japanese Americans [JA-2]). Although Japanese Americans share their genetic predisposition with the Japanese, their lifestyles have been westernized rapidly and extensively. We conducted a medical survey for atherosclerosis among Japanese Americans living in Hawaii and Los Angeles and native Japanese living in Hiroshima for 50 years since 1970 (the Hawaii-Los Angeles-Hiroshima Study) and obtained the following results:(1) In the 1990s, a westernized lifestyle induced hyperlipidemia among Japanese Americans, and based on the evaluation of the carotid artery intima-media wall thickness (IMT), atherosclerosis was apparently more advanced in Japanese Americans than in native Japanese. In addition, the advancement of atherosclerosis corresponded to the degree of westernization of lifestyles in JA-1 and JA-2.(2) In the 2010s, the serum total cholesterol and low-density lipoprotein cholesterol levels in native Japanese were significantly higher than those in Japanese Americans, and the difference in the progression of carotid artery IMT was smaller between native Japanese and Japanese Americans.(3) Maintaining a healthy Japanese lifestyle since childhood may suppress future worsening of risk factors for atherosclerosis (such as obesity and diabetes mellitus) and contribute to atherosclerosis prevention in the Japanese.

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 .

Fulminant Type 1 Diabetes Mellitus Presenting 15 Days after Delivery Diagnosed in Cooperation with Obstetricians.

The patient was a 32-year-old Japanese woman who was given a 75-g oral glucose tolerance test at the 35th week of pregnancy and was normoglycemic. She had excessive thirst and polyuria from 15 days after delivery. When she visited for the 1-month postpartum checkup, her plasma glucose level was 479 mg/dL, HbA1c was 7.4%, and urinary C-peptide was 1.1 µg/mL; she was therefore diagnosed with fulminant type 1 diabetes mellitus associated with pregnancy. All physicians should be aware of this disease so as to provide a prompt diagnosis and emergency treatment and consequently improve the maternal prognosis.

Westernization of lifestyle affects quantitative and qualitative changes in adiponectin.

BACKGROUND: Although Japanese-Americans and native Japanese share the same genetic predispositions, they live different lifestyles, resulting in insulin resistance in Japanese-Americans. We investigated whether the quantitative and qualitative changes in adiponectin (APN) due to differences in lifestyle contribute to the development of insulin resistance. METHODS: We evaluated 325 native Japanese in Hiroshima, Japan and 304 Japanese-Americans in Los Angeles, the United States, who were aged between 30 and 70 years and underwent medical examinations between 2009 and 2010. All participants underwent a 75-g oral glucose tolerance test (OGTT) to assess their glucose tolerance. The insulin response to oral glucose load, the Matsuda index, total APN levels, and C1q-APN/total-APN ratios were compared between native Japanese and Japanese-Americans. RESULTS: Compared with the native Japanese, the Japanese-Americans had significantly lower Matsuda index and higher area under the curve values for serum insulin concentration during OGTT in the normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) groups, but not in the diabetes mellitus (DM) group. Furthermore, the Japanese-Americans had significantly lower total APN levels and higher C1q-APN/total-APN ratios than the native Japanese in the NGT and IGT groups, but not in the DM group. CONCLUSIONS: This study suggested that, in Japanese people, the westernization of their lifestyle might affect quantitative and qualitative changes in APN and induce insulin resistance.

Progression of Carotid Atherosclerosis in Two Japanese Populations with Different Lifestyles.

AIM: We have conducted medical surveys on two Japanese populations (Japanese Americans living in the US and native Japanese living in Japan) to investigate the impact of westernization of lifestyles on diseases in Japanese people. A 1998 survey revealed that the progression of carotid intima-media wall thickness (IMT) was faster by approximately 20 years in Japanese Americans than in native Japanese. In this study, we compared the progression of atherosclerosis in native Japanese versus that in Japanese Americans using carotid IMT data from medical examinations conducted in the 2010s. METHODS: This study included 115 native Japanese living in Hiroshima who underwent a medical examination in 2014 and 112 Japanese Americans living in Hawaii who underwent a medical examination in 2012, excluding those receiving medication for diabetes mellitus (DM) or dyslipidemia. Carotid IMT was compared between the two Japanese populations. RESULTS: Serum total and low-density lipoprotein cholesterol levels were significantly higher in native Japanese than in Japanese Americans. The median carotid IMT was significantly greater in Japanese Americans than in native Japanese [median (25th-75th percentile): 1.27 (0.86-2.02) mm vs. 1.00 (0.80-1.30) mm, P =0.001]. Regression curves showed that the age at which IMT exceeded 1.1 mm was estimated at ＞50 years in Japanese Americans and at approximately 60 years in native Japanese. CONCLUSIONS: According to surveys conducted in 2012 and 2014, carotid IMT was still greater in Japanese Americans than in native Japanese. However, a comparison with data from the 1998 survey showed that current native Japanese had higher serum lipid levels and more advanced atherosclerosis.

Low high-density lipoprotein cholesterol level is a significant risk factor for development of type 2 diabetes: Data from the Hawaii-Los Angeles-Hiroshima study.

AIMS/INTRODUCTION: A low level of high-density lipoprotein cholesterol (HDLC) is a common feature of metabolic syndrome. We have reported that Japanese-Americans who share a virtually identical genetic makeup with native Japanese, but who have lived Westernized lifestyles for decades, have lower HDLC levels and a high prevalence of type 2 diabetes compared with native Japanese. However, the impact of low HDLC level on type 2 diabetes is unclear. The aims of the present study were to evaluate whether serum HDLC level was associated with development of type 2 diabetes and if the effect might be modified by lifestyle. MATERIALS AND METHODS: We examined 1,133 non-diabetic Japanese-Americans and 1,072 non-diabetic Japanese, who underwent the 75-g oral glucose tolerance test (OGTT) and were followed for an average of 8.8 and 7.0 years, respectively. We analyzed whether serum HDLC level is a risk factor for development of type 2 diabetes based on the Cox proportional hazards model. RESULTS: After adjustment for age and sex, hazard ratios for development of type 2 diabetes per unit of serum HDLC level (mmol/L) were 0.292 (95% confidence interval [CI] 0.186-0.458, P < 0.0001) among Japanese-Americans and 0.551 (95% CI 0.375-0.88, P = 0.0023) among native Japanese. Comparable hazard ratios after further adjustment for category of OGTT and body mass index were 0.981 (95% CI 0.970-0.993, P = 0.0018) and 0.991 (95% CI 0.980-1.002, P = 0.112), respectively. CONCLUSIONS: HDLC level was associated with development of type 2 diabetes in both Japanese-Americans and native Japanese. However, these results suggest that the impact of high-density lipoprotein on glucose metabolism might be affected by lifestyle.

Relationship between serum cholesterol efflux capacity and glucose intolerance in Japanese-Americans.

AIM: Serum cholesterol efflux has been suggested to be a key anti-atherogenic function of reverse cholesterol transport. Meanwhile, the quantitative and qualitative alteration of the levels of lipoproteins in the serum has been reported in patients with diabetes, although it remains unclear whether the serum cholesterol efflux capacity is impaired in cases of newly diagnosed glucose intolerance. We thus assessed the relationship between the serum cholesterol efflux capacity and glucose intolerance as detected using oral glucose tolerance tests (OGTTs). METHODS: We measured the capacity of whole serum to mediate cholesterol efflux from human THP-1 macrophages in a cohort of 439 Japanese-Americans who underwent 75-g OGTTs. A multiple regression analysis was performed to examine the relationship between the serum cholesterol efflux capacity and glucose intolerance. RESULTS: The serum cholesterol efflux capacity was found to be negatively correlated with the area under the curve for the serum glucose concentration during the 75-g OGTTs in all subjects. In addition, the serum cholesterol efflux capacity was found to be modestly but significantly lower in the glucose intolerance group (31.4 ± 6.2%) than in the normal glucose tolerance group (33.2 ± 6.1%). There was also a negative association between the serum cholesterol efflux capacity and glucose intolerance after adjusting for age and sex. Moreover, this association remained significant even after further adjustments for serum total cholesterol, high-density lipoprotein cholesterol, apolipoprotein AI and C-reactive protein. CONCLUSIONS: The serum cholesterol efflux capacity is impaired in Japanese-Americans newly diagnosed with glucose intolerance. This impairment may contribute in some manner to increasing the risk of atherosclerotic disease in subjects with glucose intolerance.