정혜원, 김대중, 김하동, 최성희, 안철우, 차봉수, 이현철, 허갑범

Background: The prevalence of obesity is known to be lower in Asian population than that in Europe. But, the health risks associated with obesity occur at a lower body mass index (BMI) in Asian. The aim of this study was to assess the prevalence of the metabolic syndrome and its components in Korean adult population according to the new criteria for obesity proposed in Asia-Pacific Perspective. Methods: From individuls, who participated in medical check-up of Korean Association of Health (KAH), 1,230 individuals were included in the analysis. In patients with type 2 diabetes (n=131), subjects with impaired fasting glucose (IFG) (n=84), or individuals who have insulin-resistance but show normal fasting glucose (NFG) (n=1015), the metabolic syndrome was defined as presence of at least two of the following components; hypertension, dyslipidemia, and obesity. Results: Metabolic syndrome was present in 19% of men and 16% of women. In detail, about 10% in NFG, 50% in IFG, and 70% of patients with type 2 diabetes fulfilled the criteria of metabolic syndrome. In comparison with the lowest tertile of waist circumference and BMI, the prevalence of the metabolic syndrome increased about 13 fold in subjects with the highest tertile. Using a multiple regression analysis, HOMA-IR was associated with an increased risk for the metabolic syndrome (RR=2.23, p=0.001). Conclusion: The metabolic syndrome, according to the new criteria for obesity in Asian-Pacific Perspective in Korean adult population, is seen as much as Western countries. Insulin resistance and hyperinsulinemia can be suggested as the main causes of the metabolic syndrome.ope

Proteinuria is Associated with Carotid Artery Atherosclerosis in Non-Albuminuric Type 2 Diabetes: A Cross-Sectional Study

The association of specific urinary proteins other than albumin with cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) has been shown. In this respect, CV outcomes may differ in non-albuminuric T2D patients who were considered as a low risk group, according to the presence of proteinuria. We investigated the association between proteinuria and atherosclerosis assessed by carotid artery intima-media thickness (CIMT) in non-albuminuric T2D patients. 2047 T2D patients whose urine albumin-to-creatinine ratio was below 30 mg/g were recruited and classified into a non-proteinuria (NP, uPCR < 150 mg/g, n = 1865) group and a non-albuminuric proteinuria (NAP, uPCR ≥ 150 mg/g, n = 182) group. CIMT was compared between the two groups and logistic regression analysis was conducted to verify whether proteinuria could predict deteriorated CIMT status. In this cross-sectional study, mean CIMT of the NAP group were significantly thicker than those of the NP group (0.73 ± 0.16 vs. 0.70 ± 0.14, p = 0.016). The presence of proteinuria is associated with deteriorated CIMT after the adjustment for conventional risk factors (odds ratio, 2.342; 95% confidence interval, 1.082-5.070, p = 0.030) in regression analysis. We postulated that the measurement of urinary protein in conjunction with albumin might be helpful for predicting atherosclerosis, especially for non-albuminuric patients.ope

Reduction in microalbuminuria by calcium channel blockers in patients with type 2 diabetes mellitus and hypertension-A randomized, open-label, active-controlled, superiority, parallel-group clinical trial

Background: It has been suggested that renoprotection with calcium channel blockers (CCBs) may differ. This study aimed to compare the anti-proteinuric effect of different CCBs in patients with type 2 diabetes (T2D). Methods: A multicentre, randomized, open-label, active-controlled study was performed in seven centres in Korea. A total of 74 patients with T2D and microalbuminuria treated with renin-angiotensin system (RAS) blockers were randomized to a cilnidipine 10 mg treatment (n=38) or amlodipine 5 mg treatment (n=36). Results: Urine albumin to creatinine ratio (ACR) reduction was similar between the two groups at 12 weeks (-53.0±123.2 mg/g in cilnidipine group and -35.7±83.6 mg/g in amlodipine group, P=.29) or 24 weeks (-57.3±106.9 mg/g in cilnidipine group and -20.0±110.4 mg/g in amlodipine group, P=.24). In a subgroup analysis, cilnidipine treatment showed a larger ACR reduction than amlodipine treatment at 12 weeks (-84.7±106.8 mg/g in cilnidipine group and -9.5±79.2 mg/g in amlodipine group, P=.01) and 24 weeks (-84.0±111.7 mg/g in cilnidipine group and 14.6±119.4 mg/g in amlodipine group, P=.008), particularly in patients with a longer duration of diabetes more than 10 years. Conclusions: Cilnidipine did not show any additional anti-albuminuric effect compared with amlodipine in patients with T2D and microalbuminuria treated with an RAS blocker. However, the anti-albuminuric effect of cilnidipine might differ according to the duration of diabetes.ope

Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARγ agonists

The impact of type 2 diabetes on the ability of muscle to accumulate and dispose of fatty acids and triglycerides was evaluated in cultured muscle cells from nondiabetic (ND) and type 2 diabetic (T2D) subjects. In the presence of 5 μM palmitate, T2D muscle cells accumulated less lipid than ND cells (11.5 ± 1.2 vs. 15.1 ± 1.4 nmol/mg protein, P < 0.05). Chronic treatment (4 days) with the peroxisome proliferator-activated receptor-γ (PPARγ) agonist troglitazone increased palmitate accumulation, normalizing uptake in T2D cells. There were no significant differences between groups with regard to the relative incorporation of palmitate into neutral lipid species. This distribution was also unaffected by troglitazone treatment. β-Oxidation of both long-chain (palmitate) and medium-chain (octanoate) fatty acids in T2D muscle cells was reduced by ∼40% compared with ND cells. Palmitate oxidation occurred primarily in mitochondrial (∼40–50% of total) and peroxisomal (20–30%) compartments. The diabetes-related defect in palmitate oxidation was localized to the mitochondrial component. Both palmitate and octanoate oxidation were stimulated by a series of thiazolidinediones. Oxidation in T2D muscle cells was normalized after treatment. Troglitazone increased the mitochondrial component of palmitate oxidation. Skeletal muscle cells from T2D subjects express defects in free fatty acid metabolism that are retained in vitro, most importantly defects in β-oxidation. These defects can be corrected by treatment with PPARγ agonists. Augmentation of fatty acid disposal in skeletal muscle, potentially reducing intramyocellular triglyceride content, may represent one mechanism for the lipid-lowering and insulin-sensitizing effects of thiazolidinediones.ope

Neonatal Tetany Caused by Hyperparathyroidism Undetected During Pregnancy

Primary hyperparathyroidism is rarely encountered during pregnancy but its prompt diagnosis and treatment if encountered during pregnancy is important because it can carry considerable morbidity not only for the mother but also for the fetus. It tends to remain undiagnosed because 50~80% of the patients are asymptomatic. Even if they do demonstrate symptoms, those are often nonspecific. The other reason for non-diagnosis is masking of hypercalcemia due to the change of calcium homeostasis during pregnancy. Neonatal tetany can be a clue for the presence and diagnosis maternal hyperparathyroidism. The asymptomatic patient who is diagnosed postpartum when her newborn is symptomatic should undergo elective parathyroidectomy to avoid future complication. We experienced a woman with undiagnosed primary hyperparathyroidism during pregnancy whose two children suffered neonatal tetany. We report this case along with a review of literature on primary hyperparathyroidism in pregnancy and calcium homeostasis during pregnancy.ope

Efficacy and safety of ipragliflozin as an add-on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

AIM: To evaluate the efficacy and safety of ipragliflozin vs placebo as add-on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM). METHODS: This double-blind, placebo-controlled, multi-centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT). RESULTS: In total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add-on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were -0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference -0.83% [95% CI -1.07 to -0.59]; P < .0001). More ipragliflozin-treated patients than placebo-treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (P < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference -1.64 mmol/L, -1.50 μU/mL, -1.72 kg, and -0.99, respectively; P < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted. CONCLUSIONS: Ipragliflozin as add-on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.ope

A Case of panhypopituitarism Due to Craniopharyngioma with Slipped Capitalis Femoral Epiphysis

Craniopharyngioma accounts for 3% to 5% of intracranial tumors and is the second most common neoplasm in the sellar region. Panhypopituitarism associated with craniopharyngioma has been reported in 7% of all patients with craniopharyngioma. Slipped capital femoral epiphysis is the condition in which the femoral head slips downward and backward on the femoral neck at the epiphyseal plate due to growth disturbance of capital physis, the actual cause of which is unknown. It is a disease of adolescence, during which many physiologic hormonal changes occur. The clinical association between slipped capital femoral epiphysis and endocrine disease is well known. There have been four cases of slipped capital femoral epiphysis associated with endocrine disorders in Korea. This is the first Korean case report of slipped capital femoral epiphysis combined with craniopharyngioma caused by hypopituitarism.ope

Efficacy and Safety of Mitiglinide in Korean Type 2 Diabetic Patients: Prospective Randomised Multicenter Comparative Phase 3 Study

Background Mitiglinide, one of the meglitinides, is expected to prevent postprandial hyperglycemia of type 2 diabetes by enhancing early phase insulin secretion. The aim of this study was to verify the efficacy and safety of mitiglinide compared to nateglinide. Methods One hundred eleven of diabetic patients were randomised and administered of mitiglinide (n = 56) and nateglinide (n = 55) before a meal time for 12 weeks. The changes of HbA1c, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) were analyzed. The safety of this drug was investigated as well. Results The change of HbA1c was not significantly different between two groups (-0.77 ± 1.08% in mitiglinide vs. -0.66 ± 0.79% in nateglinide, P = 0.57). The reduction of FPG (-12.2 ± 25.0 mg/dL vs. -6.1 ± 22.3 mg/dL, P = 0.218), PPG 1 hr (-48.0 ± 47.1 mg/dL, vs. -29.4 ± 43.2 mg/dL, P = 0.051), and PPG 2 hr (-59.2 ± 58.0 mg/dL vs. -43.3 ± 59.0 mg/dL, P = 0.194) were not significantly different between the mitiglinide and the nateglinide, respectively. Drug-related adverse effects were not different between two groups (16.1% in mitiglinide vs. 27.8% in nateglinide, P = 0.137). The frequency of hypoglycemic events were not different between two groups (8.9% in mitiglinide vs. 14.8% in nateglinide, P = 0.339). There were two patients who had complained shoulder pain in the mitiglinide or deterioration of visual acuity in the nateglinide, but those were found to be unrelated with medications. Conclusion This study showed that mitiglinide had reduced HbA1c as similar to nateglinide and that significantly improved HbA1c, FPG and PPG during 12 weeks of treatment. The safety of mitiglinide was also comparable to nateglinide. Mitiglinide could be used as an effective glucose-lowering agent by enhancing early insulin secretion and reducing postprandial glucose excursion, and thereby might contribute long-term cardioprotective effect in Korean type 2 diabetic patients.ope

Randomized, Open Label, Multicenter Clinical Trial about the Effect of Cilazapril on Vascular Endothelial Function in Patients with Type 2 Diabetes Combined with Hypertension

Background: The angiotensin converting enzyme inhibitor (ACEi) improves the vascular endothelial cell function and has a better clinical outcome by decreasing the LDL cholesterol oxidation, hypercoagulability, oxidative stress and improving the level of endothelial nitric oxide synthesis in patients with type 2 diabetes and hypertension. However, the correlations between the ACEi and the serum markers for the vascular endothelial function in previous studies were not consistent. Subjects and Methods: Between July 2003 and April 2005, 104 type 2 diabetes patients with hypertension, who had been admitted to 9 major university hospitals in Korea, were examined. The subjects were randomly allocated to the cilazapril (2.5~5 mg/day) and atenolol (50~100 mg/day) treatment group and given a combination of hydrochlorothiazide and amlodipine. The lipid profile and the markers for endothelial function, such as vWF, VCAM, E-selectin, tPA, fibrinogen, adiponectin, hsCRP, nitrotyrosine were evaluated and the differences in the variables were compared with those obtained 6 months later. Results: A total 56 subjects completed the 6-months follow up period. Regarding the baseline characteristics, there were no significant differences in the variables observed in the two groups except for HbA1c (P = 0.037), vWF (P = 0.048), and hsCRP (P = 0.038). After 6 months, both groups showed a significant and identical decrease in the systolic and diastolic blood pressure compared with the baseline (P < 0.002). However, there were no significant differences in the endothelial markers between each group. On the other hand, there was some deterioration in the triglyceride (P = 0.009) and HbA1c (P = 0.017) levels in the atenolol treatment groups. Conclusions: There were no significant differences in the endothelial function markers observed between the cilazapril and atenolol groups. However, cilazapril had an identical effect on the blood pressure reduction compared with atenolol but had fewer adverse effects on the glucose and lipid metabolism.ope

Effect of weight loss on cerebrospinal Fluid and Plasma Concentrations of NPY, α-MSH and leptin in Obese Women

Background: Although leptin and its principal mediators, neuroptide Y (NPY) and α-melanocyte stimulating hormone (MSH) are postulated to play a pivotal role in the energy balance in experimental animals, the physiologic roles of leptin and its molecular targets are not fully identified in cases of human obesity. Methods: The subjects consisted of 16 obese women (mean BMI 35.6 ㎏/㎡) before and after weight loss that was induced by a 2 week-very low caloric diet (800 ㎉/day) and 14 normal weight women (who had a mean BIM of 20.4 ㎏/㎡). We evaluated the plasma and cerebrospinal fluid (CSF) leptin, changes of these peptides during a negative energy balance (800 ㎉/day) were assessed in causes of human obesity. Results: Obese subjects exhibited a 6.3-fold higher plasma leptin level (21.9±1.2 vs 3.5±0.4 ng/㎖, p<0.05) and a 2.8-fold higher CSF leptin level (0.29±0.02 vs 0.10±0.01 ng/㎖, p<0.05) compared to control subjects. The CSF/plasma leptin ration in normal weight subjects was 2.3-fold higher than that in obese subjects. After a weight loss in obese subjects, the plasma leptin level decreased by 40% and the CSF level decreased by 51%. The CSF/plasma leptin ration was slightly lower than the baseline level. There was a positive linear correlation between CSF and plasma leptin level at the baseline in obese subjects (r=0.74, p<0.05) and a positive logarithmic correlation in normal weight subjects and in obese subjects after a weight loss (r=0.66, p<0.05). The BMI negatively correlated with the CSF/plasma leptin ratio (r=-0.86, p<0.05) in any subjects. Neither the baseline plasma levels nor the baseline CSF levels of NPT were different between the normal weight subjects and obese subjects. After a weight loss the CSF NPY level decreased significantly compared to the baseline values in obese subjecs. The α-MSH levels in plasma and CSF did not differ significantly from controls in obese subjects at the baseline or after a weight loss. The baseline CSF leptin level neither correlated with the baseline CSF NPY level nor the baseline CSF α-MSH level. Conclusion: These results demonstrated that the efficiency of leptin delivery to the CNS is reduced in human obesity and that the CNS leptin uptake involves the combinatino of saturable and unsaturable mechanisms. A marked reduction in the CSF leptin levels compared to the plasma level after a weight loss in obese subjecs can be a potent stimulus for the body to regain weight. In contast to the results that were observed in experimental animals, the CSF NPY and α-MSH did not differ from the controls in human obesity and there was no significant correlation between the CSF leptin and CSF of these neuropeptides. This could have resulted from leptin resistance in cases of human obesity although the mechanisms for this resistance remain to be determined.ope