Development and Testing of the Foot Care Scale for Older Japanese Diabetic Patients.

We aimed to develop and test the reliability and validity of a foot care self-management assessment tool for older Japanese patients with diabetes. In this cross-sectional observational study, which was carried out according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines, additional items were developed and selected to reflect older Japanese patients' needs a thorough investigation with experts in diabetes and geriatrics. A total of 200 older patients with diabetes in a foot care outpatient clinic were included in the study to finalize the scale items and verify the scale's reliability and validity. A factor analysis yielded a 4-factor, 9-item scale. Factors 1 to 4 were "skin condition" (3 items), "nail clipping" (2 items), "attention to wounds" (2 items), and "relationships with others" (2 items). The Cronbach's α coefficients for the 4 factors were .852, .900, .820, and .571, respectively. The overall scale was 0.797, indicating good internal consistency. Spearman's correlation coefficients for each of the 4 factors with the scale's total score showed good stability; all correlations were significant. In Japan's super-aged society, it is important to focus on foot care practices among older adults and to promote good foot care practices among early older adults so that they can practice self-care at home. Therefore, a scale for comprehensively evaluating foot care in elderly patients with diabetes is needed. The Foot Care Scale for Older Diabetics could be useful as a tool for assessing the ability to self-manage foot care in older Japanese patients with diabetes.

Associations between diabetes-related foot disease, diabetes, and age-related complications in older patients.

PURPOSE: To examine the relationship of diabetes-related foot disease (DFD) with diabetes and age-related complications in older patients with diabetes mellitus (DM). METHODS: We examined 562 outpatients with diabetes, aged ≥ 65 years, for DFD. The variables collected in this study were demographics, DM-related complications, treatment method, and age-related complications. Differences in the complications were compared between patients with and without DFD. Logistic regression analysis was used to determine the associations of DFD with DM and age-related complications. RESULTS: A total of 246 patients (43.8%) had DFD. Logistic regression analysis identified low grip strength [Odds ratio (OR): 1.83, 95% confidence interval (CI) 1.21-2.76), hypertension (OR: 1.81, 95% CI 1.09-3.00), and diabetes-related peripheral neuropathy (DPN) (OR: 1.92, 95% CI 1.24-2.98) to be significantly associated with DFD. Patients with DPN and hypertension had a higher risk of DFD than patients with DPN or hypertension alone. Individuals with DPN and low grip strength (OR: 1.74, 95% CI 1.09-2.81) were at a lower risk than those with low grip strength alone. CONCLUSION: Hypertension, DPN, and low grip strength were significantly associated with DFD in older patients with DM, with the risk of DFD being higher in patients with both DPN and hypertension. When considering DFD in older patients with DM, low grip strength should be considered equally important as a DM-related complication.

Microvascular complications and frailty can predict adverse outcomes in older patients with diabetes.

AIM: We aimed to assess whether frailty and diabetes-related factors could predict the occurrence of adverse events in older patients with diabetes, who constitute a patient population prone to physical decline and reductions in skeletal muscle mass. METHODS: This retrospective cohort study comprised 477 patients who were being managed by outpatient diabetes care, and the reductions in their muscle strength and walking speed were assessed. Patients were evaluated using the Kihon Checklist, Mini Nutritional Assessment and Mini Mental State Examination, and followed up for 1 year, during which adverse events were monitored and confirmed from past medical records and face-to-face interviews. Intergroup comparisons of participants with and without adverse events during the observation period were undertaken by the paired-sample t-, Mann-Whitney U- and chi-square tests. Multiple logistic regression analysis, adjusted for sex and age, was conducted to determine significant predictors of adverse event incidence. RESULTS: Overall, 12.4% (n = 59; age 74.2 ± 6.2 years) of the patients experienced adverse events. We observed significant between-group differences in the Kihon Checklist total score, walking speed, hypoglycemia episodes, nephropathy, retinopathy, and neuropathy. Microvascular complications and frailty were significant predictors of adverse event incidence (respective odds ratio [95% confidence interval]: 1.403 [1.109-1.775] per additional complication; 2.419 [1.331-4.397] for frailty; both P < 0.05). CONCLUSIONS: In this study, we found that frailty, which was assessed using the Kihon Checklist, and the number of microvascular complications predicted adverse events in older patients with diabetes and should to be assessed. Geriatr Gerontol Int 2021; 21: 359-363.

Association of Glucose Fluctuations with Sarcopenia in Older Adults with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus accelerates loss of muscle mass and strength. Patients with Alzheimer's disease (AD) also show these conditions, even in the early stages of AD. The mechanism linking glucose management with these muscle changes has not been elucidated but has implications for clarifying these associations and developing preventive strategies to maintain functional capacity. This study included 69 type 2 diabetes patients with a diagnosis of cognitive impairment (n = 32) and patients with normal cognition (n = 37). We investigated the prevalence of sarcopenia in diabetes patients with and without cognitive impairment and examined the association of glucose alterations with sarcopenia. Daily glucose levels were evaluated using self-monitoring of blood glucose, and we focused on the effects of glucose fluctuations, postprandial hyperglycemia, and the frequency of hypoglycemia on sarcopenia. Diabetes patients with cognitive impairment displayed a high prevalence of sarcopenia, and glucose fluctuations were independently associated with sarcopenia, even after adjusting for glycated hemoglobin A1c (HbA1c) levels and associated factors. In particular, glucose fluctuations were significantly associated with a low muscle mass, low grip strength, and slow walking speed. Our observation suggests the importance of glucose management by considering glucose fluctuations to prevent the development of disability.

Postprandial Hyperglycemia Is Associated With White Matter Hyperintensity and Brain Atrophy in Older Patients With Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus is associated with neurodegeneration and cerebrovascular disease. However, the precise mechanism underlying the effects of glucose management on brain abnormalities is not fully understood. The differential impacts of glucose alteration on brain changes in patients with and without cognitive impairment are also unclear. This cross-sectional study included 57 older type 2 diabetes patients with a diagnosis of Alzheimer's disease (AD) or normal cognition (NC). We examined the effects of hypoglycemia, postprandial hyperglycemia and glucose fluctuations on regional white matter hyperintensity (WMH) and brain atrophy among these patients. In a multiple regression analysis, postprandial hyperglycemia was independently associated with frontal WMH in the AD patients. In addition, postprandial hyperglycemia was significantly associated with brain atrophy, regardless of the presence of cognitive decline. Altogether, our findings indicate that postprandial hyperglycemia is associated with WMH in AD patients but not NC patients, which suggests that AD patients are more susceptible to postprandial hyperglycemia associated with WMH.

Release of Phosphorylated HSP27 (HSPB1) from Platelets Is Accompanied with the Acceleration of Aggregation in Diabetic Patients.

We investigated the relationship between HSP27 phosphorylation and collagen-stimulated activation of platelets in patients with diabetes mellitus (DM). Platelet-rich plasma was prepared from blood of type 2 DM patients. The platelet aggregation was analyzed in size of aggregates by an aggregometer using a laser scattering method. The protein phosphorylation was analyzed by Western blotting. Phosphorylated-HSP27 and PDGF-AB released from platelets were measured by ELISA. The phosphorylated-HSP27 levels at Ser-78 and Ser-82 induced by collagen were directly proportional to the platelet aggregation. Total HSP27 levels in platelets were decreased concomitantly with the phosphorylation. The released HSP27 levels were significantly correlated with the phosphorylated levels of HSP27 in the platelets stimulated by 0.3 µg/ml collagen. The low dose collagen-stimulated release of HSP27 was detected but relatively small in healthy donors. The released levels of PDGF-AB were in parallel with the levels of released HSP27. Area under the curve (AUC) of small aggregation (9-25 µm) induced by 0.3 µg/ml collagen was inversely proportional to the levels of released HSP27. AUC of large aggregation (50-70 µm) was directly proportional to the levels of released HSP27. Exogenous recombinant phosphorylated- HSP27 hardly affected the aggregation or the released levels of PDGF-AB induced by collagen. These results strongly suggest that HSP27 is released from human platelets accompanied with its phosphorylation induced by collagen, which is correlated with the acceleration of platelet aggregation in type 2 DM patients.

Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway.

Galectin-9 is a beta-galactoside-binding lectin expressed in various tissues. It binds various glycoconjugates and modulates a variety of biological functions in various cell types. Although galectin-9 is expressed in bone, its function in human osteoblasts remains unclear. We demonstrate that galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway in the absence of bone morphogenetic proteins (BMPs). Galectin-9 increases alkaline phosphatase activities in human osteoblasts and induces the phosphorylation of Smad1/5/8 and translocation of Smad4 to the nucleus in the absence of BMPs. Galectin-9 also induces binding of Smad4 to the Id1 promoter and increases its activity. Anti-CD44 antibody inhibits Smad1/5/8 phosphorylation by galectin-9. Galectin-9 binds to CD44 and induces the formation of a CD44/BMP receptor complex. Because Smad1 is phosphorylated by BMP receptors, we propose that formation of the CD44/BMP receptor complex induced by galectin-9 may provide a trigger for the activation of Smads.

Advanced glycation end products increase endothelial permeability through the RAGE/Rho signaling pathway.

Although increased vascular permeability is known to be a major characteristic of diabetic vasculopathy, the precise mechanisms and relevance of advanced glycation end products (AGE) to hyperpermeability of vessels remains unclear. Here, we studied changes in cytoskeletal configuration and the signaling mechanism induced by AGE in human endothelial cells. AGE-BSA stimulation induced Rho activation, intercellular gap formation, prominent actin stress fiber and cell contraction without changing VE-cadherin, and subsequently transendothelial diffusion of FITC-labeled dextran. These processes induced by AGE-BSA were inhibited by either Rho-kinase inhibitor Y27632 or anti-RAGE antibody. We also showed that RhoA and RAGE spontaneously formed a complex. These findings suggest that activation of RAGE/Rho is involved in AGE-BSA-induced hyperpermeability through gap formation and actin reorganization in diabetes.

Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK.

BACKGROUND: Monckeberg's calcification in diabetes, known as medial artery calcification, is an independent predictor of cardiovascular mortality. However, the mechanism underlying this phenomenon remains to be elucidated. We demonstrate that advanced glycation end products (AGEs) induce calcification of vascular smooth muscle cells through the receptor for AGE (RAGE)/p38 mitogen-activated protein kinase (MAPK) signaling pathway. METHODS: We detected vascular calcification by von Kossa staining. Alkaline phosphatase (ALP) activity was determined by measuring p-nitrophenol. Osteocalcin concentrations were measured using ELISA. Western blotting for protein phosphorylation and real-time RT-PCR for expression of mRNA were used. RESULTS: AGEs induced calcification of vascular smooth muscle cells. AGEs also induced the expression of Runx2 mRNA. In addition, AGEs increased ALP activity and osteocalcin secretion. Furthermore, AGEs induced phosphorylation of p38 MAPK, and this phosphorylation was inhibited by the anti-RAGE blocking antibody. Increased ALP activity was inhibited by the p38 MAPK inhibitor or anti-RAGE blocking antibody. Furthermore, the p38 MAPK inhibitor and anti-RAGE blocking antibody both inhibited AGE-induced calcification of vascular smooth muscle cells. Diabetic serum induced calcification of smooth muscle cells and the calcification was inhibited by RAGE blocking. CONCLUSION: Our findings indicate that AGEs induce calcification of vascular smooth muscle cells by osteoblast-like differentiation of smooth muscle cells through RAGE/p38 MAPK.

Interaction of galectin-9 with lipid rafts induces osteoblast proliferation through the c-Src/ERK signaling pathway.

UNLABELLED: Galectin-9 is a beta-galactoside-binding lectin expressed in various tissues, including bone. The role of galectin-9 in human osteoblasts, however, remains unclear. This study showed that galectin-9 interacts with lipid rafts and induces osteoblast proliferation through the c-Src/ERK signaling pathway. INTRODUCTION: Galectin-9 is a beta-galactoside-binding lectin that modulates many biological functions by interacting with particular carbohydrates attached to proteins and lipids. However, the role of galectin-9 in bone metabolism and osteoblast proliferation remains unclear. This study investigated the effects of galectin-9 on osteoblast proliferation and its signaling mechanisms. MATERIALS AND METHODS: The effect of galectin-9 on osteoblast proliferation was tested by measuring the conversion of tetrazolium salt WST-8 to formazan. Protein phosphorylation was assayed by western blotting and confocal microscopy was used to localize lipid rafts. RESULTS: Galectin-9-induced proliferation of the obtained osteoblasts in a dose-dependent manner, whereas galectin-1, -3, and -4 did not. Galectin-9-induced phosphorylation of c-Src and subsequent ERK1/ERK2 in the osteoblasts. The galectin-9-induced phosphorylation and proliferation were inhibited by PP2, a selective inhibitor of c-Src. Galectin-9-induced clustering of lipid rafts detected by cholera toxin B (CTB; binding the raft-resident ganglioside GM1) using confocal microscopy. Cross-linking of the GM1 ganglioside with CTB by anti-CTB antibody-induced phosphorylation of c-Src, whereas disruption of galectin-9-induced lipid rafts by beta-methylcyclodextrin reduced c-Src phosphorylation and proliferation of the cells. CONCLUSIONS: These results suggest that galectin-9, but not other galectins, induced proliferation of human osteoblasts through clustering lipid rafts on membrane and subsequent phosphorylation of the c-Src/ERK signaling pathway.

[Vascular injury by glucocorticoid; involvement of apoptosis of endothelial cells].

Idiopathic osteonecrosis of the femoral head (IONF) is known to be caused by tissue ischemia, which is mainly associated with high-dose glucocorticoid (GC) used for the treatments of systemic autoimmune diseases. However, precise pathological mechanisms of IONF remain unclear. We first found that hypoxia-inducible factor (HIF) -1alpha, a major transcription factor rapidly induced under hypoxic conditions, was highly expressed on endothelial cells of femoral head in patients with IONF. Transfection of HIF-1alpha induced p21-mediated arrest of cell cycle and subsequent apoptosis in endothelial cells. High dose GC also induced cell cycle arrest and apoptosis. Furthermore, there were additional effects between HIF-1alpha and high dose GC for the growth arrests and apoptosis of the cells. However, C-type natriuretic peptide (CNP) inhibited both cell cycle arrest and apoptosis of the endothelial cells in a concentration-dependent manner. There results indicate that hypoxia and high-dose GC play a pivotal role for vascular injury and that CNP could have a potential to protect the vascular injury seen in patients with IONF.

[Diabetic vascular calcification and abnormal bone metabolism: the relation between bone and vascular].

High-frequency severe atherosclerosis/calcinosis is observed in diabetes mellitus and chronic dialysis, which leads to cardiovascular events. However, the effective treatment for suppressing the progression of vascular calcification has not been established. Here we review the mechanism of vascular calcification and present our findings that a first generation of bisphosphonate is useful in prevention of vascular calcification in diabetes and chronic renal failure.

Intravenous cyclophosphamide pulse therapy is effective for refractory Graves' ophthalmopathy.

Graves' ophthalmopathy is the most frequent extrathyroidal manifestation of Graves' disease. Although glucocorticoids and orbital radiotherapy have been used and are effective for the disease, we often experience cases refractory to either therapy. We report here a case that did not respond satisfactorily to either therapy and was later successfully treated by intravenous cyclophosphamide (IV-CY) pulse therapy. A 31 year old woman presented with typical Graves' disease and ophthalmopathy. After establishing a euthyroid state, she received intravenous glucocorticoid pulse therapy and orbital radiotherapy. Although this induced the resolution of the ophthalmopathy, it was temporary and thyroid-stimulating antibody (TSAb) increased to high titers, associated with relapse of ophthalmopathy 2 months after the treatment. Four courses of IV-CY pulse therapy were administered, which resulted in complete improvement of the symptoms and normalization of the TSAb titers. We suggest that IV-CY pulse therapy might be useful for Graves' ophthalmopathy, especially for patients refractory to glucocorticoid pulse therapy.

Increased expression levels of monocyte CCR2 and monocyte chemoattractant protein-1 in patients with diabetes mellitus.

Increased monocyte recruitment into subendothelial space in atherosclerotic lesions is one of the hallmarks of diabetic angiopathy. The aim of this study was to determine the state of peripheral blood monocytes in diabetes associated with atherosclerosis. Diabetic patients treated with/without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n=106). We also included 24 non-diabetic control subjects. We measured serum levels of monocyte chemoattractant protein (MCP)-1, fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, body mass index (BMI), high sensitivity CRP (hs-CRP) and evaluated CCR2, CD36, CD68 expression on the surface of monocytes. Serum MCP-1 levels were significantly (p<0.05) higher in diabetic patients than in normal subjects. In diabetic patients, serum MCP-1 levels correlated significantly with FPG, HbA1c, triglyceride, BMI, and hs-CRP. The expression levels of CCR2, CD36, and CD68 on monocytes were significantly increased in diabetic patients and were more upregulated by MCP-1 stimulation. Our data suggest that elevated serum MCP-1 levels and increased monocyte CCR2, CD36, CD68 expression correlate with poor blood glucose control and potentially contribute to increased recruitment of monocytes to the vessel wall in diabetes mellitus.

[Marked weight loss in two female patients with prader-willi syndrome by behavioral modification and improvement of the environment].

Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability, and is considered to be mainly the result of a hypothalamic defect. PWS is characterized by hyperphagia, obesity, mental retardation and hypogonadism from a young age. Hyperphagia is one of the most serious problems, which is organic in origin, inducing morbid obesity and leading to respiratory failure. Most studies attempting to control obesity in children with PWS by dietary management reported limited success due to difficulty in controlling foraging and food stealing. Here we report 16- and 20-year-old female patients with PWS who showed marked weight loss and improvement of respiratory failure by behavior modification and improvement of the environment.

Successful treatment of insulinoma by a single daily dose of octreotide in two elderly female patients.

We report two cases of insulinoma in advanced age patients considered unsuitable for surgery, in whom single daily doses of octreotide successfully improved hypoglycemia and hyperinsulinemia. The biological half-life of octreotide is about 100 min, hence it is customary to use two or three administrations per day to prevent hypoglycemia in insulinoma patients. The first case was a 76-year-old woman who presented with hyperinsulinemic hypoglycemia. Computed tomography (CT) and magnetic resonance imaging did not identify a tumor in the pancreas but a 1.5-cm tumor was found in the pancreatic body on abdominal angiography and selective arterial calcium stimulation and hepatic venous sampling (ASVS) were compatible with insulinoma. The patient refused surgery, but was successfully treated with octreotide at 50 microg subcutaneous injection once daily. Since the treatment was started (1 year), she has not suffered hypoglycemia. Case 2 was an 85-year-old woman who presented with hyperinsulinemic hypoglycemia. CT identified a 1.5-cm tumor in the pancreatic uncus, but she was considered unsuitable for surgery due to advanced age, obesity and cardiopulmonary dysfunction. Octreotide at 100 microg subcutaneous injection once daily prevented further hypoglycemic attacks, but two months later, postprandial plasma glucose was elevated. Octreotide was gradually reduced to 50 microg once daily. Three years have passed since the treatment without any hypoglycemic attack. Successful treatment with octreotide once daily could be due to old-age-related slow metabolism and could be potentially considered as the treatment of choice for elderly patients with insulinoma especially those considered unsuitable for surgery.

A rare case of primary hyperparathyroidism with clear cell adenoma.

We report a 52-year-old woman who was noted to have elevated alkaline phosphatase (ALP), hypercalcemia (Ca: 11.7 mg/dL), and intact parathyroid hormone (intact PTH: 643.1 pg/mL), and then referred to our hospital with suspected hyperparathyroidism. Ultrasound examination of the neck and magnetic resonance imaging showed a mass region in the posterior aspect of the left lobe of the thyroid, and Tl-Tc subtraction scintigraphy showed Tl uptake at the same location. Based on laboratory and imaging studies, she was diagnosed with primary hyperparathyroidism. The excised parathyroid was a large mass measuring 6.8 x 2.8 x 1.9 cm in diameter and weighing 15.4 g. It was soft, covered with a thin capsule, did not infiltrate the thyroid parenchyma, and showed no evidence of malignant process. Histopathological examination showed that it was clear cell adenoma. There was no evidence of metastasis from the parathyroid tumor in other organs. The post-operative course was excellent, and serum PTH, Ca, and ALP levels returned to normal. Among parathyroid tumors, large adenomas are commonly considered to be more likely malignant, but in this case it was benign despite measuring more than 6 cm in diameter. The histopathological type of the adenoma was clear cell adenoma, a very rare type. We report a clear cell adenoma of the parathyroid gland, which has not been described previously in Japan.

Cardiac autonomic balance and QT dispersion during head-up tilt testing in diabetics with and without sensory neuropathy.

BACKGROUND: Cardiovascular autonomic dysfunction is associated with higher mortality in diabetics. However, detection methods of early cardiac diabetic dysautonomia, and its correlation with severity of sensory neuropathy, have not been described. METHODS: We analyzed the heart rate variability (HRV) by spectral analysis and QT dispersion in 23 diabetics with and without sensory neuropathy, and in 5 age-matched controls, in the supine position and during head-up tilt testing (HUT). Diabetics were divided into 3 groups according to the degree of sensory neuropathy. RESULTS: In the spectral analysis of HRV, the high frequency components in the supine position decreased as a function of severity of the neuropathy. High frequency in diabetics was significantly decreased in the supine position, even in absence of sensory neuropathy. The low/high frequency ratio (L/H) in the supine position was similar among controls and the 3 patient groups. L/H in diabetics with moderate or severe neuropathy did not increase from the supine to the upright position. Baseline QT dispersion increased proportionally to the severity of sensory neuropathy and, in patients without apparent sensory neuropathy, QT dispersion increased significantly during HUT. CONCLUSIONS: The spectral analysis of HRV and measurements of QT dispersion, before and during HUT, were reliable detection methods of early abnormalities in autonomic balance and may predict a risk of sudden cardiac death in diabetics.

Adult-onset idiopathic progressive acro-osteolysis with proximal symphalangism.

We experienced a 57-year-old female with adult-onset non-congenital idiopathic acro-osteolysis combined with proximal symphalangism. At the age of 36, she developed severe pain and swelling of the toe base of both feet and underwent Clayton surgery. However, the size of her toes diminished progressively over the 5-year period after surgery. At the age of 41, she suffered pain and swelling of the proximal interphalangeal (PIP) joints of fingers of both hands. These PIP joints became rigid and inflexible. Subsequently, she noticed shortening of the little finger of both hands, followed later by shortening of the index, middle, and ring fingers. At the age of 57, the thumbs began to shorten. Laboratory and endocrinological examinations were not abnormal. Finally, we diagnosed her with acro-osteolysis combined with proximal symphalangism by radiological examination. In this case, previously unreported mutations of the Noggin gene were identified. This is the first case report of adult-onset, non-congenital idiopathic acro-osteolysis combined with proximal symphalangism.