Yuko Chiba

Remarkable increase in lumbar spine bone mineral density and amelioration in biochemical markers of bone turnover after parathyroidectomy in elderly patients with primary hyperparathyroidism: a 5-year follow-up study.

We evaluated the efficacy of parathyroidectomy (PTX) on bone mineral density (BMD) and hormonal and biochemical markers of bone metabolism in elderly primary hyperparathyroidism (PHPT) patients, and followed these patients for 5 years after PTX. Eleven PHPT patients were enrolled and were followed for 5 years by measuring lumbar spine BMD (LSBMD), femoral BMD (FBMD), radial BMD (RBMD), parathyroid hormone (PTH), 1,25-dihydroxyvitamin D [1,25(OH)2D], serum calcium (SCa), inorganic phosphate (iP), bone-specific alkaline phosphatase (BAP), intact osteocalcin (IOC), urinary excretion of type I collagen cross-linked N-telopeptide (NTx), and urinary deoxypyridinoline (DPD). PTX produced significant increases in LSBMD of 12%, 19%, and 29% as compared with pretreatment levels after 1, 3, and 5 years, respectively (P < 0.01, compared to baseline), whereas there was no significant increase in FBMD and a slight decrease in RBMD. SCa and iP levels remained normal over the five years. PTX also resulted in significant decreases in PTH, 1,25(OH)2D, BAP, IOC, NTx, and DPD that continued for at least 3 years after PTX. In conclusion, PTX seemed effective to normalize various markers of bone metabolism in elderly PHPT patients and is recommended to patients with low LSBMD to prevent future fractures. On the other hand, the use of PTX for low FBMD or RBMD patients requires further discussion.

β-Cell Telomere Attrition in Diabetes: Inverse Correlation Between HbA1c and Telomere Length

CONTEXT Although accelerated β-cell telomere shortening may be associated with diabetes that shows a dramatically increased incidence with aging, β-cell telomere length in diabetes has never been explored. OBJECTIVE The objective of the present study was to examine telomere length in the β-cells of patients with diabetes. DESIGN AND PATIENTS We determined telomere length in β- and α-cells of pancreases obtained at autopsy from 47 patients with type 2 diabetes and 51 controls, all older than 60 years. MAIN OUTCOME MEASURE The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined for β- (NTCRβ) and α- (NTCRα) cells by quantitative fluorescence in situ hybridization. RESULTS The NTCRβ was reduced by 27% ± 25% and NTCRα by 15% ± 27% in the patients with diabetes relative to the controls (P < .01 for both). Importantly, the degree of shortening was significantly (P < .01) greater in β-cells than in α-cells. The histogram of NTCR distribution was significantly skewed to the left in the patients with diabetes relative to the controls for both β- and α-cells, indicating preferential depletion of longer-telomere islet cells. Glycated hemoglobin was negatively correlated with β-cell telomere length, and the telomeres were significantly shorter in patients who had used hypoglycemic agents than in those who had not. CONCLUSION The telomeres of β-cells are shortened in patients with type 2 diabetes. There may be a vicious cycle involving β-cell telomere attrition and sustained hyperglycemia.

NO donor induces Nec-1-inhibitable, but RIP1-independent, necrotic cell death in pancreatic β-cells

Nitric oxide (NO) has been implicated in pancreatic β‐cell death in the development of diabetes. The mechanisms underlying NO‐induced β‐cell death have not been clearly defined. Recently, receptor‐interacting protein‐1 (RIP1)‐dependent necrosis, which is inhibited by necrostatin‐1, an inhibitor of RIP1, has emerged as a form of regulated necrosis. Here, we show that NO donor‐induced β‐cell death was inhibited by necrostatin‐1. Unexpectedly, however, RIP1 knockdown neither inhibited cell death nor altered the protective effects of necrostatin‐1 in NO donor‐treated β‐cells. These results indicate that NO donor induces necrostatin‐1‐inhibitable necrotic β‐cell death independent of RIP1. Our findings raise the possibility that NO‐mediated β‐cell necrosis may be a novel form of signal‐regulated necrosis, which play a role in the progression of diabetes.

Implications of Measuring Soluble Receptor Activators of Nuclear Factor-κB Ligand and Osteoprotegerin in Bone Metabolism of Elderly Women

Background/Aim: The discovery of a signaling system consisting of a soluble receptor activator of the NF-κB ligand (sRANKL) and its decoy receptor osteoprotegerin (OPG) has provided a valuable key to understanding the pathophysiology of the bone microenvironment. We conducted a cross-sectional study of the role of sRANKL and OPG levels as they relate to bone metabolism in elderly postmenopausal women with and without osteoporosis. Subjects and Methods: Fifty-one elderly women with or without osteoporosis were enrolled in the study. Bone alkaline phosphatase, osteocalcin, urinary deoxypyridinoline and urinary type I collagen N-terminal telopeptide (NTx) were measured as bone metabolic markers. Serum levels of OPG and sRANKL were measured by sandwich enzyme-linked immunosorbent assay and the lumbar spine bone mineral density (LSBMD) with dual-energy X-ray absorptiometry. Furthermore, we compared the sRANKL and OPG levels in elderly women with and without vertebral fractures (VFs). Results: In elderly postmenopausal women, there was a significant positive association between OPG levels and the T score and Z score of LSBMD (r = 0.345 and p = 0.014 for T score; r = 0.438 and p = 0.001 for Z score). sRANKL levels were not significantly correlated with T score, Z score of LSBMD, or any of the four bone metabolic markers. There were no significant differences in the sRANKL levels among the three groups (normal bone mineral density, osteopenia, and osteoporosis), but a trend toward a higher value in the osteoporosis group. The sRANKL/OPG ratio was negatively correlated with the T score and Z score of LSBMD (r = –0.336, p = 0.017; r = –0.384, p = 0.006, respectively), but not with any of the four bone metabolic markers. OPG levels in elderly women with VFs were lower than in those without VFs (p = 0.05). Multiple regression analysis showed that OPG and NTx are contributing factors to bone loss in elderly women (p = 0.014 and 0.012, respectively). Conclusion: The OPG level provides a good predictor of osteoporosis as well as NTx in elderly women; additionally, the findings suggest that OPG might protect elderly women from bone loss or fractures.

Protective effects of a nicotinamide derivative, isonicotinamide, against streptozotocin-induced β-cell damage and diabetes in mice

OBJECTIVE Nicotinamide rescues β-cell damage and diabetes in rodents, but a large-scale clinical trial failed to show the benefit of nicotinamide in the prevention of type 1 diabetes. Recent studies have shown that Sirt1 deacetylase, a putative protector of β-cells, is inhibited by nicotinamide. We investigated the effects of isonicotinamide, which is a derivative of nicotinamide and does not inhibit Sirt1, on streptozotocin (STZ)-induced diabetes in mice. RESEARCH DESIGN AND METHODS Male C57BL/6 mice were administered with three different doses of STZ (65, 75, and 100 mg/kg BW) alone or in combination with subsequent high-fat feeding. The mice were treated with isonicotinamide (250 mg/kg BW/day) or phosphate-buffered saline for 10 days. The effects of isonicotinamide on STZ-induced diabetes were assessed by blood glucose levels, glucose tolerance test, and immunohistochemistry. RESULTS Isonicotinamide effectively prevented hyperglycemia induced by higher doses of STZ (75 and 100mg/kg BW) alone and low-dose STZ (65 mg/kg BW) followed by 6-week high-fat diet in mice. The protective effects of isonicotinamide were associated with decreased apoptosis of β-cells and reductions in both insulin content and insulin-positive area in the pancreas of STZ-administered mice. In addition, isonicotinamide inhibited STZ-induced apoptosis in cultured isolated islets. CONCLUSIONS These data clearly demonstrate that isonicotinamide exerts anti-diabetogenic effects by preventing β-cell damage after STZ administration. These findings warrant further investigations on the protective effects of isonicotinamide and related compounds against β-cell damage in diabetes.

White Matter Hyperintensity in Elderly Patients with Diabetes Mellitus Is Associated with Cognitive Impairment, Functional Disability, and a High Glycoalbumin/Glycohemoglobin Ratio

Aims: Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus (DM) is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients. Methods: This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research. Results: We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001). Conclusion: GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with DM.

A case of insulin antibody-induced glucose instability in an elderly woman with type 2 diabetes on hemodialysis, successfully ameliorated with liraglutide

We encountered a 68-year-old woman with type 2 diabetes who had frequent insulin-induced hypoglycemia in the morning. She had renal failure, and was on hemodialysis. The hypoglycemia in the morning was severe, induced by the small dosage of insulin, whilst she showed severe postprandial hyperglycemia. A blood test revealed high serum insulin and C-peptide levels, and a high binding rate of insulin antibody. Switching human insulin to an insulin analogue, glulisine, failed to avoid hypoglycemia. Scatchard plot analysis indicated that the high affinity site of the patient’s insulin antibody had a low affinity constant (K1) and a high binding capacity (R1) against all tested insulin, almost equivalent values reported in insulin autoimmune syndrome cases. Treatment with the glucagon-like peptide-1 analogue liraglutide ameliorated the postprandial hyperglycemia without hypoglycemia, resulting in improved glycemic stability. Furthermore, the continued use of liraglutide reduced both serum insulin level and binding rate of insulin antibody. This is the first case of using liraglutide in an insulin-antibody positive patient with renal failure on hemodialysis. Liraglutide could be an effective and safe remedy for patients with insulin antibody-related glucose instability, regardless of their renal function.