Adaptive support ventilation as an effective treatment option for central sleep apnea in an older adult with heart failure with preserved ejection fraction: a case report.

BACKGROUND: Adaptive support ventilation (ASV) is a proposed treatment option for central sleep apnea (CSA). Although the effectiveness of ASV remains unclear, some studies have reported promising results regarding the use of ASV in patients with heart failure with preserved ejection fraction (HfpEF). To illustrate the importance of suspecting and diagnosing sleep-disordered breathing (SDB) in older adults unable to recognize symptoms, we discuss a case in which ASV was effective in a patient with CSA and HfpEF, based on changes in the Holter electrocardiogram (ECG). CASE PRESENTATION: An 82-year-old man presented to our hospital with vomiting on April 19, 2021. Approximately 10 years before admission, he was diagnosed with type 1 diabetes mellitus and recently required full support from his wife for daily activities due to cognitive dysfunction. Two days before admission, his wife was unable to administer insulin due to excessively high glucose levels, which were displayed as "high" on the patient's glucose meter; therefore, we diagnosed the patient with diabetic ketoacidosis. After recovery, we initiated intensive insulin therapy for glycemic control. However, the patient exhibited excessive daytime sleepiness, and numerous premature ventricular contractions were observed on his ECG monitor despite the absence of hypoglycemia. As we suspected sleep-disordered breathing (SDB), we performed portable polysomnography (PSG), which revealed CSA. PSG revealed a central type of apnea and hypopnea due to an apnea-hypopnea index of 37.6, which was > 5. Moreover, the patient had daytime sleepiness; thus, we diagnosed him with CSA. We performed ASV and observed its effect using portable PSG and Holter ECG. His episodes of apnea and hypopnea were resolved, and an apparent improvement was confirmed through Holter ECG. CONCLUSION: Medical staff should carefully monitor adult adults for signs of or risk factors for SDB to prevent serious complications. Future studies on ASV should focus on older patients with arrhythmia, as the prevalence of CSA may be underreported in this population and determine the effectiveness of ASV in patients with HfpEF, especially in older adults.

[Switching insulin degludec to insulin glulisine improved nocturnal hypoglycemia and ventricular arrythmia in an elderly type 1 diabetes patient with chronic heart failure: A case report].

The patient was 82-year-old man with type 1 diabetes mellitus. He had been using insulin degludec (IDeg) and insulin glulisine (IGlu) for treatment. He was admitted to our hospital due to diabetic ketoacidosis. As he started eating after recovery, we restarted intensive insulin therapy for glycemic control. Although he had eaten almost whole meals, his fasting blood glucose was extremely low, and the existence of nocturnal hypoglycemia was apparent. We reduced the dose and changed the injection time (evening→morning) of IDeg. We also stopped the evening IGlu injection; however, his nocturnal hypoglycemia did not improve. We decided to switch IDeg to insulin glargine U300 and to attach an intermittently scanned continuous glucose monitor (isCGM). His nocturnal hypoglycemia improved three days later. Since he had chronic heart failure and premature ventricular contractions, we used a Holter electrocardiogram to investigate the difference in arrythmia during hypoglycemia and non-hypoglycemia. As a result, the number of premature ventricular contractions was apparently high during hypoglycemia. In the present case, which involved an elderly patient with type 1 diabetes mellitus, chronic heart failure and nocturnal hypoglycemia, switching IDeg to insulin glargine U300 improved nocturnal hypoglycemia. IDeg differs from insulin glargine U300 in that it has a fatty acid side chain, which leads IDeg to combine with serum albumin. We thought that the increased level of free fatty acid due to hypoglycemia was competing against albumin combined IDeg, which increased free IDeg, and as a result, encouraged hypoglycemia.

Association of higher arterial ketone body ratio (acetoacetate/ß-hydroxybutyrate) with relevant nutritional marker in hemodialysis patients.

BACKGROUND: An association of higher levels of ß-hydroxybutyrate (ß-HB) in serum with greater mortality in hemodialysis (HD) patients has been reported. This study examined the significance of arterial ketone body ratio (AcAc/ß-HB), a relevant marker of energy state, in HD patients. METHODS: The levels of arterial AcAc and ß-HB, and AcAc/ß-HB ratio were determined in 49 HD patients just before undergoing an HD session. Additionally, changes in those levels during the session were examined to investigate their associations with clinical nutritional markers. RESULTS: Arterial ß-HB, but not AcAc, was significantly higher at the baseline in 25 patients with type 2 diabetes mellitus (T2DM) as compared to 24 non-DM patients, with a significant reduction in arterial AcAc/ß-HB ratio seen in those with DM. Although the arterial AcAc/ß-HB ratio before the HD session was significantly higher in the non-DM group, it did not differ significantly after the session between the groups, indicating a faster rate of ß-HB disappearance from circulation in non-DM HD patients during the interdialytic period. Multiple regression analysis, which included age, gender, presence/absence of DM, log HD duration, log ß-HB, and log AcAc/ß-HB ratio as independent variables, revealed an independent and significant association of log AcAc/ ß-HB ratio, but not log ß-HB, with serum albumin and uric acid. CONCLUSION: We found that a decreased AcAc/ß-HB ratio resulting from increased ß-HB, but not increased ß-HB itself, was a significant factor independently associated with decreased levels of serum albumin and uric acid, known to be related to higher mortality in HD patients. Furthermore, it is possible that higher mortality in DM HD patients can be explained by reduced arterial AcAc/ß-HB ratio.

Comparison of efficacy and safety of insulin degludec/liraglutide and insulin glargine U-100/lixisenatide in individuals with type 2 diabetes mellitus using professional continuous glucose monitoring.

AIM/INTRODUCTION: Insulin glargine U100/lixisenatide and insulin degludec/liraglutide are fixed-ratio combinations containing basal insulin and a glucagon-like peptide-1 receptor agonist capable of reducing both fasting and postprandial blood glucose levels with a single formulation. This study aimed to compare the time in range (TIR) and the time below range (TBR) level 1 using professional continuous glucose monitoring and to establish criteria for the differential use of the fixed-ratio combinations. MATERIALS AND METHODS: Thirty-six outpatients with type 2 diabetes mellitus (24 men and 12 women; average age, 62.1 years) were randomly assigned to the groups. At 0 and 18 weeks, a device was worn to compare the TIR and TBR level 1. The correlation between the C-peptide index at baseline and TIR at 18 weeks was assessed. RESULTS: The TIR and TBR level 1 showed no significant differences between the two groups. Both groups showed significant positive correlations between the C-peptide index and the TIR (P = 0.002, r = 0.679; P = 0.002, r = 0.681, respectively). The changes in glycemic variability, therapeutic indices, and body mass index were not significantly different among the groups (P > 0.05). The receiver operating curve analysis revealed that the cut-off values of the C-peptide index to achieve TIR of >70% at 18 weeks were 1.258 (sensitivity, 77.8%; specificity, 100%) and 1.099 (sensitivity, 57.1%; specificity, 90.9%) in the insulin glargine U100/lixisenatide and insulin degludec/liraglutide groups, respectively. CONCLUSIONS: A TIR of >70% was achieved for both fixed-ratio combinations without significant differences.

Polycythemia with elevated erythropoietin production in a patient with a urinary stone and unilateral hydronephrosis: a case report.

BACKGROUND: Absolute polycythemia can be primary or secondary. Erythropoietin-producing diseases (for example, hypoxia) are the major cause of secondary polycythemia. There are reports of polycythemia secondary to hydronephrosis. However, to our knowledge, there is no report on polycythemia secondary to hydronephrosis due to a urinary stone. Herein, we present a case of polycythemia with an elevated erythropoietin level in a patient with a urinary stone and unilateral hydronephrosis. CASE PRESENTATION: A 57-year-old Japanese man presented with polycythemia and an elevated erythropoietin level. Erythropoietin accumulation was not due to erythropoietin secretion by a tumor as no obvious lesions were detected on contrast-enhanced computed tomography. Abdominal ultrasonography revealed a stone in the left urinary tract and renal hydronephrosis, and 2 weeks later, the patient underwent transurethral ureterolithotripsy without complications. Blood tests 2 weeks after transurethral ureterolithotripsy showed that the erythropoietin level had declined. Hemoglobin concentration decreased from 20.8 mg/dL before and immediately after transurethral ureterolithotripsy to 15.8 mg/dL 3 months after transurethral ureterolithotripsy. This case was diagnosed as erythropoietin elevation due to unilateral hydronephrosis with a urinary stone, resulting in polycythemia. CONCLUSIONS: Hydronephrosis is a common disease but is not often associated with polycythemia. Further studies are required to elucidate the mechanism and implications of elevated erythropoietin production in hydronephrosis.

Beneficial effects of luseogliflozin on lipid profile and liver function in patients with type 2 diabetes mellitus (BLUE trial): a single-center, single-arm, open-label prospective study.

BACKGROUND: Arteriosclerosis and non-alcoholic fatty liver disease are major complications of diabetes mellitus. Hyperglycemia, insulin resistance, obesity, and metabolic syndrome are associated with the progression of these complications. Sodium-glucose transporter 2 inhibitors such as luseogliflozin are oral hypoglycemic agents that reduce glucose levels, induce loss of weight or body fat, and improve liver function. However, the effects of these agents on lipid profiles are unclear. Therefore, this study aimed to investigate these effects and their relationship with arteriosclerosis and non-alcoholic fatty liver disease. METHODS: This single-center, single-arm, open-labeled prospective study enrolled 25 outpatients with type 2 diabetes mellitus who visited Minami Osaka Hospital. Laboratory tests and body measurements were performed at weeks 0 and 24. Luseogliflozin was started at 2.5 mg/day after breakfast, and data from weeks 0 and 24 were evaluated. There were no changes in the doses of other antidiabetic and dyslipidemia drugs a month prior to or during the study. RESULTS: The patients showed significant reductions in the levels of triglycerides, remnant-like particle cholesterol, and triglyceride/high-density lipoprotein cholesterol ratio, along with significant increases in the levels of high-density lipoprotein cholesterol and apolipoprotein A-1. Alanine aminotransferase, γ-glutamyl transpeptidase, and the fatty liver index were significantly reduced. CONCLUSIONS: Luseogliflozin-induced changes in the lipid profile were related to the suppression or improvement of arteriosclerosis and liver function, respectively. Patients who received this drug also showed improvements in the levels of liver enzymes and reductions in the fatty liver index. Earlier use of luseogliflozin might prevent diabetic complications. Trial registration This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN 000043595) on April 6th, 2021.

Comparisons of efficacy and safety in insulin glargine and lixisenatide plus glulisine combination therapy with multiple daily injection therapy in Japanese patients with type 2 diabetes.

AIMS/INTRODUCTION: Multiple daily injection therapy for early glycemic control in patients with type 2 diabetes mellitus is associated with hypoglycemia and weight gain. This study aimed to compare the efficacy (time in range of glucose level 70-180 mg/dL), safety (time below range level 1 of glucose <70 mg/dL), glycemic variability changes, therapeutic indices, body mass index and titration periods between multiple daily injection and insulin glargine U100 and lixisenatide (iGlarLixi) combination (iGlarLixi + insulin glulisine; injected once daily [evenings]) therapies using intermittent continuous glucose monitoring. MATERIALS AND METHODS: A total of 40 hospitalized patients with type 2 diabetes were randomly assigned to the iGlarLixi + insulin glulisine group or the multiple daily injection group. An intermittent continuous glucose monitoring system was attached, and each injection was adjusted to achieve the target glucose level according to the respective titration algorithm. Times in and below the range were analyzed using data collected on days 11-13 of the intermittent continuous glucose monitoring. RESULTS: The time in range did not significantly differ between the groups. However, the time below range level 1 was lower in the iGlarLixi + insulin glulisine group (P = 0.047). The changes in glycemic variability, therapeutic indices and body mass index were not significantly different between the groups, although the titration period was significantly shorter in the iGlarLixi + insulin glulisine group (P = 0.033). CONCLUSIONS: iGlarLixi + insulin glulisine combination therapy is safe and equally efficacious as multiple daily injection therapy for glycemic control, while avoiding hypoglycemia risk and reducing the number of injections are required.

Efficacy of IDegLira Versus IDegAsp Therapy in Patients with Type 2 Diabetes: A Randomized Crossover Study by isCGM.

INTRODUCTION: We aimed to compare the efficacy of insulin degludec/insulin aspart (IDegAsp) and insulin degludec/liraglutide (IDegLira) in controlling glucose fluctuation and suppressing postprandial glucose levels using intermittently scanned continuous glucose monitoring. METHODS: Twenty-four patients with type 2 diabetes mellitus were randomly allocated to receive either IDegLira or IDegAsp followed by IDegAsp or IDegLira, respectively. A crossover study was conducted with intermittently scanned continuous glucose monitoring. We compared the postprandial blood glucose level, time in range, and time below range from a 3-day intermittently scanned continuous glucose monitoring period for each treatment group. RESULTS: The time in range was significantly higher in IDegLira than in IDegAsp. Postprandial glucose levels 90 and 120 min after breakfast and 60, 90, and 120 min after lunch were significantly lower for IDegLira than for IDegAsp. However, postprandial glucose levels 90 and 120 min after supper were significantly lower for IDegAsp than for IDegLira. There was no significant difference in the time below range between IDegLira and IDegAsp. CONCLUSION: IDegLira was more effective in treating type 2 diabetes mellitus than IDegAsp, as indicated by a higher time in range and lower postprandial glucose level at breakfast and lunch. This study was registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN 000039221).

Comparative Effects of Etelcalcetide and Maxacalcitol on Serum Calcification Propensity in Secondary Hyperparathyroidism: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T50 value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T50 value than a vitamin D receptor activator maxacalcitol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 µg thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T50 value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively. RESULTS: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T50 value was changed from 116 minutes (interquartile range, 90-151) to 131 minutes (interquartile range, 102-176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98-174) to 166 minutes (interquartile range, 127-218) in the etelcalcetide group. The increase in T50 value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score. CONCLUSIONS: Etelcalcetide was more effective in increasing T50 value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VICTORY; UMIN000030636 and jRCTs051180156.

Efficacy and Safety of Tofogliflozin and Ipragliflozin for Patients with Type-2 Diabetes: A Randomized Crossover Study by Flash Glucose Monitoring.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors promote urinary glucose excretion. However, the differences in the effects of various SGLT2 inhibitors are unknown. We used flash glucose monitoring (FGM) to identify the differences between tofogliflozin and ipragliflozin in terms of efficacy in reducing glycemic variability and mitigate hypoglycemia risk. METHODS: In this crossover study, 24 patients with type-2 diabetes mellitus (T2DM) receiving insulin glargine U300 therapy were randomly allocated to tofogliflozin and ipragliflozin or ipragliflozin and tofogliflozin group. Glycemic variability and hypoglycemia were compared using to the 3-day FGM data per treatment period. RESULTS: Glucose level 2 h after each meal was significantly lower with tofogliflozin administration than with ipragliflozin administration. Time below the target glucose range after tofogliflozin administration was significantly lower than that after ipragliflozin administration (2.1% ± 4.4% vs. 8.7% ± 11.7%). The 24-h standard deviation of glucose level, mean amplitude of glycemic excursion, and mean percent time with nocturnal hypoglycemia after tofogliflozin administration were significantly lower than those after ipragliflozin administration. CONCLUSIONS: Tofogliflozin was more effective and safer than ipragliflozin in reducing glycemic variability and mitigating hypoglycemia risk in patients with T2DM treated with insulin glargine U300. TRIAL REGISTRATION: This trial was registered at the University Hospital Medical Information Network Clinical Trial Registry (no. UMIN000037158).

Comparison of the efficacy and safety of insulin degludec/aspart (twice-daily injections), insulin glargine 300 U/mL, and insulin glulisine (basal-bolus therapy).

AIMS/INTRODUCTION: We compared the efficacy and safety of insulin degludec/aspart (IDegAsp) twice-daily injections with insulin glargine 300 U/mL and insulin glulisine basal-bolus therapy (Gla300/Glu) using insulin glargine 300 U/mL (Gla300) and insulin glulisine (Glu). MATERIALS AND METHODS: A total of 20 patients with type 2 diabetes mellitus were treated with IDegAsp twice-daily injections; achievement of target preprandial glucose concentration of 100-130 mg/dL at breakfast and supper was determined using a wearable flash glucose monitoring system. Patients were later switched to Gla300/Glu basal-bolus therapy before breakfast and before supper. Data were collected on days 2-4 and days 12-14 for each treatment period. The study's primary efficacy end-point was the mean percentage of time with a target glucose range of 70-180 mg/dL, and safety end-points were the mean percentage of time with hypoglycemia having glucose levels <70 mg/dL, clinically important hypoglycemia with glucose levels <54 mg/dL and nocturnal (00.00-06.00) hypoglycemia. RESULTS: Considering efficacy, the mean percentage of time for the target glucose range of IDegAsp was significantly lower than that of Gla300/Glu (73.1 [69.4-81.1] vs 84.2 [80.2-93.1], P = 0.001). Considering safety, the mean percentages of hypoglycemia (<70 mg/dL; 2.1 [0.0-9.4] vs 14.4 [4.4-22.3]), clinically important hypoglycemia (<54 mg/dL; 0.0 [0.0-0.2] vs 1.9 [0.0-5.6]) and nocturnal (00.00-06.00 hours) hypoglycemia (0.5 [0.0-5.9] vs 8.9 [3.1-11.8]) of Gla300/Glu were significantly lower than those of IDegAsp (P = 0.012, 0.036 and 0.007, respectively). CONCLUSIONS: When compared with the IDegAsp twice-daily injections, Gla300/Glu basal-bolus therapy might achieve more effective glycemic control without hypoglycemic risk.

Efficacy and safety of insulin glargine 300 U/mL vs insulin degludec in patients with type 2 diabetes: A randomized, open-label, cross-over study using continuous glucose monitoring profiles.

AIMS/INTRODUCTION: Compared with glargine 100 U/mL (Gla100), glargine 300 U/mL (Gla300) and degludec (Deg) - the ultralong-acting insulins - reportedly have more stable effects and reduce the risk of hypoglycemia. Currently, they are considered to be the most useful basal insulins. The present study aimed to compare the efficacy and safety of Gla300 and Deg on glycemic control using continuous glucose monitoring. MATERIALS AND METHODS: In this single-center, open-label, parallel-group, two-period, cross-over study, 30 patients with type 2 diabetes were randomized to once-daily Gla300 followed by Deg with the same units (n = 15) or vice versa (n = 15). The primary end-points of this study were the mean percentage of time within the target glucose range of 70-180 mg/dL as efficacy and hypoglycemia of <70 mg/dL as safety indicators, as measured using continuous glucose monitoring during each treatment period. RESULTS: The mean percentage of time within the target glucose range was not different between Gla300 and Deg (77.8 ± 19.2 vs 76.9 ± 18.3%, P = 0.848). However, the mean percentage of time of hypoglycemia with Gla300 was significantly lower than that of Deg (1.3 ± 2.7 vs 5.5 ± 6.4%, P = 0.002). In the secondary safety end-points, the mean percentage of time of severe hypoglycemia (<54 mg/dL) or nocturnal hypoglycemia with Gla300 was also significantly lower than that of Deg. CONCLUSIONS: The present study showed the comparable efficacy of Gla300 and Deg on glycemic control; however, the risk of hypoglycemia was markedly lower for Gla300 than for Deg.

Differential Effect of Hypoalbuminemia on Hypoglycemia on Type 2 Diabetes Patients Treated with Insulin Glargine 300 U/ml and Insulin Degludec.

INTRODUCTION: Hypoglycemia resulting from insulin therapy for treatment of diabetes increases the risk of adverse cardiovascular events. Determining biomarkers that provide accurate estimation of hypoglycemia risk may allow for more accurate patient management and care. The purpose of this study was to determine the cutoff value of serum albumin (s-alb) that increases the risk of hypoglycemia in patients treated with insulin degludec. METHODS: This study used a crossover design and randomized 30 patients admitted for glycemic control to compare differences between insulin glargine 300 U/ml (Gla300) and degludec treatments. RESULTS: The cutoff value of s-alb associated with 24-h hypoglycemia and nocturnal hypoglycemia in patients treated with degludec was 3.8 g/dl. In patients with s-alb levels < 3.8 g/dl, mean percentages of time with hypoglycemia, clinically important hypoglycemia, and nocturnal hypoglycemia were significantly lower in those treated with Gla300 compared with patients treated with degludec. CONCLUSION: This study identified a cutoff value for s-alb levels that indicates risk of hypoglycemia in patients treated with degludec. Monitoring s-alb levels in patients treated with degludec will help to mitigate the risk of hypoglycemia. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN 000031044).

Significant correlation of glycated albumin, but not glycated haemoglobin, with arterial stiffening in haemodialysis patients with type 2 diabetes.

OBJECTIVE: We recently reported that glycated albumin (GA) is a better indicator of glycaemic control compared with glycated haemoglobin (HbA1c) in haemodialysis (HD) patients with type 2 diabetes. As poor glycaemic control is considered an independent risk factor for atherosclerosis in diabetes, the relationship between GA, HbA1c and arterial stiffening was examined in HD patients with type 2 diabetes. PATIENTS AND METHODS: The present study comprised 134 HD patients with type 2 diabetes, and 158 patients without diabetes. Brachial-ankle pulse wave velocity (baPWV) was measured in all patients using a waveform analyser. RESULTS: The mean plasma glucose (PG), GA and HbA1c levels were 7.49 +/- 2.28 mmol/l, 20.8 +/- 5.57% and 5.62 +/- 1.26%, respectively, in HD patients with diabetes (n = 134), which were significantly greater than the respective values of 5.77 +/- 1.89 mmol/l, 15.6 +/- 2.34% and 4.98 +/- 0.80% in those without diabetes (n = 158) (P < 0.0001). BaPWV was 21.69 +/- 6.90 m/s in HD patients with diabetes, which was significantly greater than the value of 18.74 +/- 4.89 m/s in those without diabetes (P < 0.0001). When the analysis was performed in a combined population of those patients with and without diabetes, the mean PG (r = 0.155, P < 0.05) and GA (r = 0.117, P < 0.05), but not HbA1c (r = 0.092, P = 0.125), exhibited significant correlations with baPWV. Multivariate regression analysis, which included age, gender, mean blood pressure, and serum levels of albumin, creatinine and LDL cholesterol, to evaluate the independent association of each marker for glycaemic control with baPWV values in HD patients demonstrated that GA, but not HbA1c or PG, was an independent factor that was significantly associated in a positive manner with baPWV in HD patients. CONCLUSION: It was suggested that poor glycaemic control, as reflected by increased GA values, might be associated with increased arterial stiffening in HD patients.

[Osteoporosis in diabetes].

The diabetes is at great risk of the osteoporosis, and the bone fragility unrelated to bone density forms the pathological conditions peculiar to diabetes. The factor participating in diabetic osteoporosis has a state of insulin action deficiency, a hyperglycemic state, diabetic complications, and so on. An osteoblastic cell function is deteriorated and the number of that is decreased by the absolute and relative insulin deficiency, and sustained hyperglycemia also decreases an osteoblastic cell function still more. Furthermore, the osteoclast-related bone resorption is also promoted through sorbitol accumulation in the cell by the hyperglycemia state. The expression of transcription factors regulating osteoblastic cell differentiation is restrained, and the apoptosis of those cells is promoted. As a result, osteoplasty is obstructed. In the bone, AGEs (advanced glycation endproducts) is produced in excess, and bone fragility is promoted by the ratio of the AGEs bridging with the collagen rising. The complications of diabetes, such as visual disorder and the neuropathy, raise the risk of the fall in the diabetic osteoporosis patient, therefore, they will have more chance of fractures.

Changes in brachial-ankle pulse wave velocity in subclinical hypothyroidism during normalization of thyroid function.

OBJECTIVE: Subclinical hypothyroidism affects 5-15% of the population and is associated with increased cardiovascular morbidity, although this is controversial. We recently reported a significant increase in brachial-ankle pulse wave velocity (baPWV), a parameter of arterial stiffening and an independent predictor for cardiovascular events, in subclinical hypothyroidism. The current study was performed to assess changes in enhanced baPWV in subclinical hypothyroidism during normalization of thyroid function. METHODS: Forty-two subclinical hypothyroid patients (male/female ratio 8/34) were monitored for changes in baPWV before and after levothyroxine (L-T(4)) replacement therapy. RESULTS: After attaining euthyroidism, 59.5% and 40.5% of the patients showed reduction and increase of baPWV, respectively. Baseline baPWV and pulse pressure were significantly higher in patients with reduced baPWV (1940.3+/-126.4 vs. 1726.4+/-110.4 cm/s, P=0.046; 62.1+/-3.1 vs. 50.7+/-3.7 mmHg, P=0.026, respectively). Baseline baPWV was significantly correlated with baseline pulse pressure in both groups, but the change in baPWV was significantly correlated with baseline pulse pressure only in patients with reduced baPWV (rho=-0.522, P=0.046). The male/female ratio was significantly lower in patients with reduced baPWV (4/21 vs. 7/10), and systolic, diastolic and pulse pressures and pulse rate decreased significantly only in patients with reduced baPWV. CONCLUSIONS: Our results suggest that L-T(4) replacement therapy may be especially beneficial in female subclinical hypothyroid patients with high baseline baPWV and pulse pressure. The beneficial effects of L-T(4) replacement therapy in decreasing arterial stiffening and thus preventing cardiovascular disease might be limited to this sub-population.

Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with Graves' disease.

OBJECTIVE: The peak systolic velocity (PSV) of the inferior thyroid artery (ITA) is increased in untreated hyperthyroid patients with Graves' disease (GD). We investigated the clinical significance of the ITA-PSV and its determinants in hyperthyroid GD patients. PATIENTS AND METHODS: ITA-PSV, together with thyroid volume, was measured by ultrasonography in untreated hyperthyroid GD patients (n=49) and healthy subjects (n=22). Established markers of GD activity such as TSH receptor antibody (TRAb), thyroid stimulating antibody (TSAb), vascular endothelial growth factor (VEGF) and immunoglobulin E (IgE) were simultaneously determined. RESULTS: ITA-PSV, thyroid volume, VEGF and IgE were significantly higher in hyperthyroid GD patients than in normal subjects. ITA-PSV in hyperthyroid GD patients was correlated positively with serum levels of FT(3), FT(4) and IgE, smoking index and thyroid volume, and negatively with total, HDL- and LDL-cholesterols, but did not correlate significantly with age, triglyceride, TRAb, TSAb or VEGF. In stepwise regression analysis, ITA-PSV showed significant positive and negative associations with IgE and LDL-cholesterol, respectively, in hyperthyroid GD patients. In the pre-treatment hyperthyroid state, FT(4) and ITA-PSV, but not IgE, were found to be significantly and positively associated with the maintenance dose of methimazole (MMI) required to keep serum TSH within normal range for at least 12 months. CONCLUSION: These results suggest that ITA-PSV in untreated hyperthyroid GD patients may reflect GD activity and thus MMI sensitivity.

Influence of nutritional status on serum large N-truncated PTH, but not PTH(1-84) in hemodialysis patients.

BACKGROUND: Serum level of parathyroid hormone (PTH), measured by second-generation intact PTH (I-PTH), is known to be associated with nutritional status in hemodialysis (HD) patients. We investigated whether PTH(7-84) and larger N-truncated PTH or PTH(1-84) might be affected by nutritional status in HD patients. METHODS: Serum PTH was determined in 170 male HD patients by either a Bio-intact PTH (Bio-PTH) or I-PTH assay. Lean body mass in the trunk region was measured as a nutritional marker by dual X-ray absorptiometry. RESULTS: The serum PTH(7-84) level was theoretically obtained from the difference between serum I-PTH and Bio-PTH because I-PTH assay cross-reacted with PTH(7-84) with the same degree as PTH(1-84), although N-truncated PTH fragment larger than PTH(7-84) might affect theoretical serum PTH(7-84) level, although slightly. Serum PTH(1-84) was directly obtained from the serum Bio-PTH value because of its exclusive reaction with PTH(1-84). Serum PTH(7-84) correlated significantly with nutritional markers such as body weight, albumin, protein catabolic rate (PCR), TACBUN, BUN, phosphate, and lean body mass in the trunk, whereas PTH(1-84) correlated only with phosphate. Multiple regression analysis revealed that PCR, body weight, and lean body mass in the trunk region are significant factors independently associated with PTH(7-84), but not with PTH(1-84). CONCLUSIONS: The results suggest that serum levels of PTH(7-84) and larger N-truncated PTH fragments, but not PTH(1-84), might be affected by the nutritional state in HD patients, which might explain the reported correlation of serum I-PTH levels with nutritional markers.

Increased levels of C-reactive protein in hypothyroid patients and its correlation with arterial stiffness in the common carotid artery.

OBJECTIVE: Hypothyroidism is associated with increased morbidity from cardiovascular disease. The arterial stiffness index beta (stiffness beta) in the common carotid artery (CCA), which is a parameter of arterial stiffening, is known to increase in hypothyroid patients, while normalization of thyroid function for 1 year by levothyroxine (L-T(4)) replacement therapy significantly decreases CCA stiffness beta. Since serum C-reactive protein (CRP) has recently emerged as an independent factor for cardiovascular risk, the present study was designed to examine whether hypothyroidism causes an increase in CRP and whether the serum CRP level is correlated with CCA stiffness beta in hypothyroid patients. PATIENTS AND METHODS: Serum CRP levels and CCA stiffness beta were determined in 46 patients with hypothyroidism and in 46 age- and sex-matched normal control subjects. Thirty-five patients were further monitored for change in CCA stiffness beta during 1 year in the euthyroid state induced by L-T(4) therapy. RESULTS: Baseline CRP and CCA stiffness beta were both significantly higher in hypothyroid patients than in normal controls [1064.6+/-224.3 vs. 602.1+/-43.3 ng/ml (mean+/-SE), p<0.0001; and 9.25+/-0.84 vs. 8.21+/-0.85, p<0.05, respectively]. Baseline CRP was significantly correlated in a positive manner with baseline values of CCA stiffness beta (r=0.683, p<0.0001). In multivariate analysis, baseline CCA stiffness beta was significantly associated with baseline levels of serum CRP (r=0.740, p<0.0001). During 1 year of L-T(4) replacement therapy, significant decrease in stiffness beta (from 9.25+/-0.84 to 8.57+/-0.58, p<0.0001) to the normal levels was found. Moreover, the change in CCA stiffness beta during L-T(4) replacement therapy was significantly and independently associated in a negative fashion with baseline levels of serum CRP (r=-0.696, p=0.0002). CONCLUSIONS: This study suggests that increased serum CRP might have an important independent role in increased arterial stiffening and the measurement of serum CRP is a useful predictor for the degree of improvement of arterial stiffening in hypothyroid patients.