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.

Hyperinsulinemic hypoglycemia syndrome associated with mutations in the human insulin receptor gene: report of two cases.

Insulinoma and insulin or insulin receptor (IR) autoantibodies are the main causes of hyperinsulinemic hypoglycemia in adults, but the exact cause in other cases remains obscure. This study is to determine the genetic basis of hyperinsulinemic hypoglycemia in two cases without the above abnormalities. Sequence analysis of IR gene in two patients with adult-onset hyperinsulinemic hypoglycemia and their relatives were performed, and the mutant gene observed in one case was analyzed. Both cases had normal levels of fasting plasma glucose (FPG), fasting hyperinsulinemia, low insulin sensitivity, and hypoglycemia with excessive insulin secretion during oral glucose tolerance test (OGTT). Both reported adult-onset postprandial hypoglycemic symptoms. In one patient, a missense mutation (Arg256Cys) was detected in both alleles of the IR gene, and his parents had the same mutation in only one allele but no hypoglycemia. The other had a novel nonsense mutation (Trp1273X) followed by a mutation (Gln1274Lys) in one allele, and his 9-year old son had the same mutation in one allele, together with hyperinsulinemic hypoglycemia during OGTT. Overexpression experiments of the mutant gene found in Case 1 in mammalian cells showed abnormal processing of the IR protein and demonstrated reduced function of Akt/Erk phosphorylation by insulin in the cells. In two cases of hyperinsulinemic hypoglycemia in adults, we found novel mutations in IR gene considered to be linked to hypoglycemia. We propose a disease entity of adult-onset hyperinsulinemic hypoglycemia syndrome associated with mutations in IR gene.

Choroidal thickness changes after diabetes type 2 and blood pressure control in a hospitalized situation.

PURPOSE: To investigate the effect of acute diabetic control on choroidal thickness in patients with Type 2 diabetes. METHODS: Seventeen eyes of 17 patients with Type 2 diabetes were included in this prospective observational study. The patients with Type 2 diabetes who were scheduled to undergo a program of intensive diabetic control underwent prototype high-penetration optical coherence tomography before and 2 weeks after the start of treatment. The choroidal thickness changes 2 weeks after the protocol of intensive diabetic control were assessed, and associated ophthalmologic and general parameters were explored. Seventeen eyes of 17 healthy volunteers were included to compare diabetic patients. The choroidal thickness also was measured in this group at baseline and after 2 weeks. And the intraobserver and interobserver reproducibility were verified using this control group. RESULTS: The intraobserver (intraclass coefficient, 0.992) and interobserver reproducibility (0.982) in our subfoveal choroidal thickness measurement were high. The mean subfoveal choroidal thickness after 2 weeks (226 ± 56 µm) was significantly greater than at baseline (215 ± 52 µm, P < 0.05); there was no difference between the baseline and 2-week values in the control group (baseline, 312 ± 113 vs. 2-week value, 307 ± 103 µm; P = 0.17). The changes in refractive error (P < 0.001), axial length (P < 0.01), and diastolic blood pressure (P < 0.01) were associated significantly with changes in choroidal thickness 2 weeks after the intensive control. The pretreatment body mass index (P < 0.05) and hemoglobin A1c (P < 0.005) also were associated significantly with increased choroidal thickness. CONCLUSION: Diabetic patients showed a significant increase of choroidal thickness after the intensive control. Various ophthalmologic and systemic parameters seem to affect the choroidal thickness changes. This may be related to the progression of retinopathy after acute glycemic control.

Increase in glycemic set point, alongside a decrease in waist circumference, in the non-diabetic population during the Japanese National Intervention Program for metabolic syndrome: A single-center, large-scale, matched-pair analysis.

BACKGROUND: In 2008, the Japanese government implemented a National Intervention Program for metabolic syndrome. Low-risk individuals were not direct targets of this intervention. Nevertheless, they were indirectly enlightened by this massive campaign. Documentation of the metabolic shifts in low-risk individuals following the program launch may inform public health policy regarding approaches to metabolic risks in the general population. METHODS: We conducted a cross-sectional analysis of data from non-diabetic participants who underwent general health check-ups at the Physical Check-up Center of Sumitomo Hospital. Participants during 2007-2008 were pair-matched with those during 2015-2016 with respect to sex, age, smoking status, hemoglobin level, and red blood cell (RBC) count. Each participant was included only once in the study. RESULTS: Totals of 3,140 men and 2,048 women were pair-matched. The non-diabetic participants showed lower waist circumference, blood pressure, heart rate, and serum lipid concentrations during the second study period. In contrast, the entire distributions of fasting plasma glucose (FPG) concentration in both sexes and glycated hemoglobin (HbA1c) in women were shifted upwards. In men, Δ FPG was +1.6 mg/dL (P < 0.001) and Δ HbA1c was ±0% (P = 0.6). In women, Δ FPG was +3.0 mg/dL (P < 0.001), and Δ HbA1c was +0.1% (P < 0.001). Δ Homeostasis model assessment of ß-cell function was -6.6 in men (P < 0.001) and -10.3 in women (P < 0.001). The homeostasis model assessment of insulin resistance did not change significantly. CONCLUSIONS: The "glycemic set point" has increased in non-diabetic people in Japan during recent years. Lifestyle or environmental changes may have caused this metabolic shift through obesity-independent pathways, possibly through effects on pancreatic ß-cell function. The underlying mechanism awaits further investigation.

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.

Hyperinsulinemia and Insulin Receptor Gene Mutation in Nonobese Healthy Subjects in Japan.

CONTEXT: Hyperinsulinemia is often observed in obese people, owing to their insulin resistance accompanied by visceral fat accumulation, but the frequency of hyperinsulinemia in nonobese people is not well known. Mutations in the insulin receptor gene are known to cause insulin resistance and hyperinsulinemia in type A insulin resistance syndrome, Rabson-Mendenhall syndrome, and Donohue syndrome. However, insulin receptor gene abnormalities have not been investigated in asymptomatic hyperinsulinemic subjects. PURPOSE: The aim of the current study was to investigate the prevalence of hyperinsulinemia in nonobese Japanese subjects and to examine the involvement of insulin receptor gene mutations. METHODS: We enrolled 11,046 subjects who received health checkups. From these, we extracted nonobese subjects (body mass index <25 kg/m2) who exhibited hyperinsulinemia (serum fasting immunoreactive insulin ≥15 µU/mL). Genetic analysis was performed for the insulin receptor gene in 11 nonobese subjects with hyperinsulinemia. RESULTS: The prevalence of hyperinsulinemia without apparent diabetes in nonobese subjects was 0.4% (33/8630). In the 11 analyzed subjects, two novel heterozygous nonsense mutations were detected [c.2106 T>G (p.Y702X) and c.2779-2780 GC>A]. The prevalence of insulin receptor gene mutations was 18.2% (2/11). CONCLUSIONS: To our knowledge, this is the first report of the prevalence of hyperinsulinemia in nonobese healthy subjects. We identified two novel mutations in the insulin receptor gene. These findings indicate that mutations in the insulin receptor gene may be related to fasting hyperinsulinemia, and insulin receptor gene screening may be useful for determining the cause of unexplained hyperinsulinemia.

Liraglutide is effective in type 2 diabetic patients with sustained endogenous insulin-secreting capacity.

UNLABELLED: Aims/Introduction: Recently, glucagon-like peptide-1 (GLP-1) receptor agonists of liraglutide have become available in Japan. It has not yet been clarified what clinical parameters could discriminate liraglutide-effective patients from liraglutide-ineffective patients. MATERIALS AND METHODS: We reviewed 23 consecutive patients with type 2 diabetes admitted to Osaka University Hospital for glycemic control. All of the patients were treated with diet plus insulin (or plus oral antidiabetic drugs) to improve fasting plasma glucose (FPG) and postprandial glucose below 150 and 200 mg/dL, respectively. After insulin secretion and insulin resistance were evaluated, insulin was replaced by liraglutide. The efficacy of liraglutide was determined according to whether glycemic control was maintained at the target levels. RESULTS: Liraglutide was effective in 13 of 23 patients. There were significant differences in the parameters of insulin secretion, including fasting C-peptide (F-CPR), C-peptide index (CPI), insulinogenic index (I.I.) and urine C-peptide (U-CPR), between liraglutide-effective and -ineffective patients. The duration of diabetes was significantly shorter in liraglutide-effective patients than in liraglutide-ineffective patients. In receiver operating characteristic analyses, the cut-off value for predicting the efficacy of liraglutide was 0.14 for I.I., 1.1 for CPI, 1.5 ng/mL for F-CPR, 33.3 µg/day for U-CPR and 19.5 years for duration of type 2 diabetes. CONCLUSIONS: Insulin secretion evaluated by F-CPR, CPI, I.I., U-CPR and the duration of type 2 diabetes were useful parameters for predicting the efficacy of liraglutide in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00168.x, 2011).

Long-term suppressive effect of octreotide on progression of metastatic gastrinoma with multiple endocrine neoplasia type 1: seven-year follow up.

A 30-year-old woman had a history of prolactinoma and primary hyperparathyroidism. She was diagnosed as having multiple endocrine neoplasia type 1 with gastrinoma and liver metastases. Octreotide therapy was started and the serum gastrin level decreased immediately. Octreotide continued to suppress gastrin secretion over the next 7 years. The Ki67/MIB1 proliferation index of this tumor was only 0.5 % and somatostatin receptor (SSTR) 2 expression was very strong in both 2002 and 2009. This case suggests the importance of investigating the Ki67/MIB1 index and SSTR expression in patients with metastatic gastrinoma.

Thyroid follicular adenoma producing parathyroid hormone-related protein with a normal serum calcium level.

A 64-year-old woman had normal serum calcium and plasma parathyroid hormone levels, despite an extremely high plasma parathyroid hormone-related protein (PTHrP) level. She underwent medical screening at our hospital and several neck tumors were detected by ultrasonography. After surgical resection of these tumors, her plasma PTHrP level was normalized. Histological examination showed that the resected tumors were thyroid follicular adenomas, while immunohistochemistry revealed positive staining with a monoclonal antibody for PTHrP. This is a rare case of thyroid follicular adenoma producing PTHrP in a patient with a normal serum calcium level despite elevation of plasma PTHrP.