Myocardial fat accumulation is associated with cardiac dysfunction in patients with type 2 diabetes, especially in elderly or female patients: a retrospective observational study.

BACKGROUND: Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation. METHODS: We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed. RESULTS: In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m2, the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = - 0.1923, - 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e') (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e' in these subgroups (p < 0.05). CONCLUSIONS: Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients.

Effective waist circumference reduction rate necessary to avoid the development of type 2 diabetes in Japanese men with abdominal obesity.

The aim of this study was to determine the effective waist circumference (WC) reduction rate in avoiding the development of type 2 diabetes mellitus (T2DM) in <55 years and ≥55 years Japanese men with abdominal obesity. The study subjects were 795 men with WC ≥85 cm, fasting plasma glucose <126 mg/dL, 2-hr plasma glucose on 75 g of oral glucose tolerance test <200 mg/dL, and HbA1c 5.6-6.4 % (38-40 mmol/mol) at baseline who underwent general health checkups more than twice between April 2007 and May 2015. They were divided into 5 groups based on the change in WC during the observation period (WC gain group, and four groups stratified according the rate of WC loss). The subjects were also divided into the <55 years and ≥55 years (at baseline) subgroups. The cumulative incidence rate of T2DM was analyzed and compared among the groups. The cumulative incidence rates of the largest WC loss quartile (≥5.45 %) in all age, of the largest WC loss quartile (≥5.60 %) and second largest WC loss quartile (3.44-5.59 %) in the <55 years subgroup, and of the largest WC loss quartile (≥5.37 %) in the ≥55 years subgroup were significantly lower than that of the gain group (p<0.001, p=0.009, 0.012, and 0.012, respectively). WC reduction rate of at least about 3 % in the younger (<55 years) and at least about 5 % in the older (≥55 years) non-diabetic Japanese men with abdominal obesity can effectively reduce the chance of development of T2DM.

Relationship between serum adiponectin levels and age in healthy subjects and patients with type 2 diabetes.

OBJECTIVE: Serum adiponectin levels are affected by gender, body fat mass, several pathological factors or therapeutic interventions and it might be also affected by age. This study aimed to investigate the relationship between serum adiponectin levels and age in several physiological states. DESIGN, PATIENTS AND MEASUREMENTS: The study was carried out in 21 100 healthy subjects (12 363 men and 8737 women) and 1833 patients with type 2 diabetes (1233 men and 600 women). Physical and demographic characteristics were recorded, and blood samples were collected to measure serum adiponectin levels. Using these data, we determined the relationships between serum adiponectin levels and various parameters, including age. RESULTS: Serum adiponectin levels increased with increasing age of healthy subjects and in patients with diabetes, in both men and women. Serum adiponectin levels were positively correlated with age in healthy subjects and patients with diabetes, in both men and women. In stepwise multiple regression analysis with serum adiponectin levels as the dependent variable and physiological characteristics as explanatory variables, age was significantly and independently associated with serum adiponectin levels in each of these groups of subjects. CONCLUSIONS: Serum adiponectin levels are significantly and positively associated with age in healthy subjects and in patients with diabetes. This association is independent of renal function, body fat status, glucose metabolism and lipid profiles.

Association of adiponectin with blood pressure in healthy people.

OBJECTIVE: With the increasing prevalence of diseases related to obesity, metabolic syndrome and its key player adiponectin are now attracting considerable attention. Hypoadiponectinaemia is reported to be a risk factor for hypertension and associated with endothelial dysfunction, which is closely related to complications of obesity such as hypertension. As there is limited information regarding serum adiponectin levels in normotensive people, we undertook the large-scale study to determine the association of adiponectin with blood pressure (BP) in mainly normotensive people. DESIGN, PATIENTS AND MEASUREMENTS: In 21 100 Japanese adults (12 363 men and 8737 women) who had no apparent diseases, we examined the relationship between the serum adiponectin concentration and BP by performing a questionnaire survey, physical measurements and measurement of laboratory parameters including the serum adiponectin level. RESULTS: Subjects with hypoadiponectinaemia had higher systolic and diastolic BPs as already reported. And interestingly, subjects with higher adiponectin had lower systolic and diastolic BP. According to linear regression analysis, adiponectin showed a significant negative correlation with systolic and diastolic BP independently of the other variables. Analysis of covariance according to adiponectin quintiles showed that systolic and diastolic BP in highest adiponectin quintile was significantly lower than in other quintiles. CONCLUSIONS: This study revealed that there were significant trends toward lower systolic and diastolic BP with higher adiponectin not only in hypertensive people but also in normotensive people.

Relationship between serum cystatin C and serum adiponectin level in type 2 diabetic patients.

BACKGROUND: To investigate the relationship between serum levels of cystatin C and adiponectin in patients with type 2 diabetes. METHODS: We examined serum cystatin C and adiponectin levels in 234 patients with type 2 diabetes who visited our hospital. RESULTS: The serum level of cystatin C was positively correlated with age (P < 0.001), duration of diabetes (P = 0.013), serum creatinine (P < 0.001), uric acid (P < 0.001), and adiponectin (p = 0.001), while it was inversely correlated with estimated glomerular filtration rate (P < 0.001). Serum adiponectin was significantly higher in patients with high serum cystatin C levels than in those with normal cystatin C levels (8.3 ± 4.7 and 6.2 ± 3.2 µg/mL, respectively; P < 0.001). Adiponectin was also significantly higher in male patients with high cystatin C levels, but not in females. In multiple regression analysis, serum adiponectin was also independently and significantly correlated to age, diastolic blood pressure, high-density lipoprotein cholesterol, triglyceride and serum cystatin C. CONCLUSIONS: Serum adiponectin level was correlated with serum cystatin C level on simple and multiple regression analyses in patients with type 2 diabetes. Although circulating adiponectin is increased in advanced kidney disease, it might be biologically inactive due to binding to cystatin C and thus not display an anti-arteriosclerotic effect.

Expression of chemokines, CXC chemokine ligand 10 (CXCL10) and CXCR3 in the inflamed islets of patients with recent-onset autoimmune type 1 diabetes.

The aim of this study is to present direct evidence for the involvement of CXC chemokine ligand 10 (CXCL10) and CXCR3 in human autoimmune type 1 diabetes. We examined five patients with recent-onset type 1 diabetes and five control subjects without diabetes. Islet cell antibodies or GAD antibodies or both were detected in all five patients. We used double-immunofluorescence to detect the expression of CXCL10 and CXCR3 (the receptor of CXCL10). CXCL10 was detected in the islets of all five patients. Almost all (84.2 ± 10.3 %, mean ± SD) CXCL10-positive cells were insulin-positive in the islet area. CXCL10-positive cells with glucagons, somatostatins or pancreatic polypeptides were not detected at all. CXCL10 expression was not seen in any islet without beta cells. CXCR3 was detected in the islet areas of all five patients. Almost all (80.3 ± 13.4 %, mean ± SD) CXCR3-positive cells were CD3-positive T cells. Our study showed that CXCL10 was expressed in the remaining beta cells, and the infiltrating T cells expressed CXCR3, in pancreatic islets of patients with recent-onset type 1 diabetes. The interaction of CXCL10 and CXCR3 would contribute to the selective destruction of beta cells in the development of type 1 diabetes.

Glucose enhances collectrin protein expression in insulin-producing MIN6 beta cells.

Collectrin is a novel target gene of hepatocyte nuclear factor-1alpha in pancreatic beta-cells and controls insulin exocytosis. Although glucose is known to stimulate the expression of genes of the insulin secretory pathway, there is no information on how glucose regulates collectrin expression. We investigated the effects of glucose on the expression of collectrin in MIN6 beta-cell line. Glucose, in a dose-dependent manner, increased collectrin protein levels without changing collectrin mRNA levels and protein stability, indicating that glucose stimulation of collectrin protein expression is primarily mediated at a translational level. Although mannose and pyruvate also increased collectrin protein expression level, neither 2-deoxyglucose, mitochondrial fuels leucine and glutamate, sulphonylurea nor Ca(2+) channel blockers, mimicked the effects of glucose. These data indicate the involvement of mitochondrial TCA cycle intermediates, distal to pyruvate, in the regulation of collectrin protein expression in beta-cells.

Increase in Adiponectin Level Prevents the Development of Type 2 Diabetes in Japanese Men With Low Adiponectin Levels.

CONTEXT: Low serum adiponectin (Ad) level is an important risk factor for the development of type 2 diabetes mellitus (T2DM). OBJECTIVE: To determine whether the changes in Ad in subjects with low baseline serum Ad levels can reduce the rate of development of T2DM. DESIGN/SETTING/PARTICIPANTS: We performed a large-scale longitudinal study of 7052 healthy Japanese men who underwent general health checkups more than twice between April 2007 and May 2015 at the Physical Check up Center, Sumitomo Hospital. The participants were divided into quartile groups according to baseline Ad level. Subjects of the lowest baseline Ad group (≤5.2 µg/mL) were subdivided into quartile subgroups according to the percent change in Ad (%ΔAd) and into two subgroups according to endpoint Ad (>5.2 and ≤5.2 µg/mL). MAIN OUTCOME MEASURES: The cumulative incidence rate of T2DM. RESULTS: The cumulative incidence rate of T2DM of the lowest baseline Ad group (≤5.2 µg/mL) was significantly higher than the other quartile groups. The cumulative incidence rates of T2DM were significantly lower in the largest (≥21.5%) and the second largest (9.3% to 21.4%) %ΔAd-increased subgroups compared with the %ΔAd-decreased subgroup (P < 0.001 and P = 0.005, respectively). The cumulative incidence rates of T2DM were significantly lower in the endpoint Ad >5.2 µg/mL subgroup than in the ≤5.2 µg/mL subgroup (P < 0.001). CONCLUSIONS: Increases in serum Ad levels of at least ~10% or >5.2 µg/mL can potentially reduce the risk of development of T2DM in Japanese men with low baseline Ad levels who are at a high risk of developing T2DM.

A Novel Mutation in the type Iα Regulatory Subunit of Protein Kinase A (PRKAR1A) in a Cushing's Syndrome Patient with Primary Pigmented Nodular Adrenocortical Disease.

A 40-year-old man presented with Cushing's syndrome due to bilateral adrenal hyperplasia with multiple nodules. Computed tomography scan results were atypical demonstrating an enlargement of the bilateral adrenal glands harboring multiple small nodules, but the lesion was clinically diagnosed to be primary pigmented nodular adrenocortical disease (PPNAD) based on both endocrinological test results and his family history. We performed bilateral adrenalectomy and confirmed the diagnosis histologically. An analysis of the patient and his mother's genomic DNA identified a novel mutation in the type Iα regulatory subunit of protein kinase A (PRKAR1A) gene; p.E17X (c.49G>T). This confirmed the diagnosis of PPNAD which is associated with Carney Complex.

Serum adiponectin levels predict the risk of coronary heart disease in Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: An inverse association between adiponectin and coronary heart disease (CHD) has been found in Caucasians, but it is uncertain whether this association can be extrapolated to the East Asian population. The present study aimed to investigate whether serum adiponectin levels can predict CHD in Japanese patients with type 2 diabetes as observed in Caucasians. MATERIALS AND METHODS: This longitudinal study included 504 patients with type 2 diabetes (342 men and 162 women) who were admitted to Sumitomo Hospital between July 2005 and December 2006. We used Cox proportional hazard analysis to estimate the hazard ratio (HR) of CHD associated with serum adiponectin levels at baseline. RESULTS: During a median follow up of 5.7 years (2177 person-years), 40 participants had new CHD and 10 had recurrent CHD. After multivariate adjustment, the highest compared with the lowest quartile of serum adiponectin levels had a significantly reduced risk of CHD (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.13-0.94; P = 0.017). The multivariate adjusted HR for the risk of CHD according to a doubling of adiponectin at baseline was 0.61 (95% CI 0.39-0.97; P = 0.037). CONCLUSIONS: High serum adiponectin levels are significantly associated with a lower risk of CHD in Japanese patients with type 2 diabetes. This association is independent of other well-known CHD risk factors.

Resolution of gelatinous bone marrow transformation following hormone replacement therapy in a patient with primary insufficiency of the adrenal and thyroid glands.

A 59-year-old man with recurrent oral cancer presented with severe pancytopenia, hyponatremia and hypoglycemia. Endocrine testing showed a partial primary adrenal insufficiency and primary hypothyroidism. The bone marrow biopsy showed a gelatinous transformation with hypocellularity and fat atrophy. His pancytopenia, hyponatremia and hypoglycemia resolved following treatment with corticosteroids and thyroid hormone replacement therapy. The follow-up bone marrow biopsy demonstrated a resolution of the gelatinous transformation. This case is a rare example of a patient with a primary insufficiency of the adrenal and thyroid glands that is associated with gelatinous bone marrow transformation (GMT). The GMT was resolved through the administration of corticosteroids and thyroid hormone replacement therapy.

Long-term efficacy of trilostane for Cushing's syndrome due to adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia.

A 66-year-old man with Cushing's syndrome due to adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) was treated for 7 years with trilostane, a 3ß-hydroxysteroid dehydrogenase inhibitor. Administration of trilostane reduced the serum cortisol level to around the upper limit of normal for 7 years, and symptoms of excessive glucocorticoid production (such as moon face and obesity) were gradually improved. On the other hand, the size of both adrenal glands gradually increased despite treatment with trilostane. Though trilostane therapy could not prevent adrenal growth, it did suppress cortisol secretion over the long term, so it might be a reasonable option for AIMAH in addition to adrenalectomy.