Factors Influencing Glycemic Control Response of Sitagliptin / 임상당뇨병

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to reduce blood glucose in type 2 diabetes by prolonging the activity of circulating incretins. However, the factors that affect the efficacy of sitagliptin have not yet been demonstrated. Therefore, we studied them in a Korean population. METHODS: We performed a retrospective analysis in patients taking sitagliptin in Wonju Christian Hospital. One hundred-fifty patients whose serum HbA1c ranged from 6.5% to 11% participated in this study. These patients were divided into two groups: responder and non-responder. The responder group consisted of subjects with glucose lowering greater than 5% of baseline HbA1c. The others were in non-responder group. We analyzed anthropometric data and biochemical markers in all groups, then compared responder group and non-responder group by logistic regression. RESULTS: The change in HbA1c level across all groups was 8.25 +/- 0.82% to 7.64 +/- 1.03% (P value = 0.000). There were 93 and 57 patients in responder and non-responder group, respectively. The responder group had lower BMI, body fat (kg), body fat (%) than the non-responder group (P value = 0.024, P value = 0.029, P value = 0.025), and the HbA1c lowering effect of sitagliptin was greater in male than female (P value = 0.000). CONCLUSION: In this study, HbA1c was effectively lowered in 62% of the patients. The factors that affect the efficacy of sitagliptin were BMI, body fat (kg) body fat (%), and sex. Based on these results, we conclude that sitagliptin lowers glucose more effectively in non-obese male patients.

Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism

Although peroxisome proliferator receptor (PPAR)-alpha and PPAR-gamma agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-delta has not been fully investigated. In this study, we examined the effects of the PPAR-delta agonist GW0742 on fatty liver changes and inflammatory markers. We investigated the effects of PPAR-delta agonist GW0742 on fatty liver changes in OLETF rats. Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemo-attractant protein-1 (MCP-1) and also, PPAR-gamma coactivator (PGC)-1alpha gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. The level of TNF-alpha and MCP-1 was also examined in supernatant of Raw264. 7 cell culture. To address the effects of GW0742 on insulin signaling, we performed in vitro study with AML12 mouse hepatocytes. Rats treated with GW0742 (10 mg/kg/day) from 26 to 36 weeks showed improvement in fatty infiltration of the liver. In liver tissues, mRNA expressions of TNF-alpha, MCP-1, and PGC-1alpha were significantly decreased in diabetic rats treated with GW0742 compared to diabetic control rats. We also observed that GW0742 had inhibitory effects on palmitic acid-induced fatty accumulation and inflammatory markers in HepG2 and Raw264.7 cells. The expression level of Akt and IRS-1 was significantly increased by treatment with GW0742. The PPAR-delta agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1alpha gene expression, and improvement of insulin signaling.

Role of HbA1c in the Screening of Diabetes Mellitus in a Korean Rural Community

BACKGROUND: Recently, the measurement of glycated hemoglobin (HbA1c) was recommended as an alternative to fasting plasma glucose or oral glucose tolerance tests for diagnosing diabetes mellitus (DM). In this study, we analyzed HbA1c levels for diabetes mellitus screening in a Korean rural population. METHODS: We analyzed data from 10,111 subjects from a Korean Rural Genomic Cohort study and generated a receiver operating characteristic curve to determine an appropriate HbA1c cutoff value for diabetes. RESULTS: The mean age of the subjects was 56.3+/-8.1 years. Fasting plasma glucose and 2-hour plasma glucose after 75 g oral glucose tolerance tests were 97.5+/-25.6 and 138.3+/-67.1 mg/dL, respectively. The mean HbA1c level of the subjects was 5.7+/-0.9%. There were 8,809 non-DM patients (87.1%) and 1,302 DM patients (12.9%). A positive relationship between HbA1c and plasma glucose levels and between HbA1c and 2-hour plasma glucose levels after oral glucose tolerance tests was found in a scatter plot of the data. Using Youden's index, the proper cutoff level of HbA1c for diabetes mellitus screening was 5.95% (sensitivity, 77%; specificity, 89.4%). CONCLUSION: Our results suggest that the optimal HbA1c level for DM screening is 5.95%.

A Case of Trophoblastic Tumor Associated with Papillary Thyroid Cancer / 대한내과학회지

Thyroid cancer is one of the most common endocrine malignancies. It is known that thyroid cancer can develop during reproductive periods, possibly due to the effects of sex hormones and growth factors such human chorionic gonadotrophin (HCG). Some data suggest that elevated HCG levels during pregnancy or gestational trophoblastic disease can stimulate thyroid cellular proliferation and promote cancer formation; however, a case of papillary thyroid cancer accompanied by a gestational trophoblastic tumor has not been reported. Here, we report the case of a 44-year-old woman with papillary thyroid cancer during treatment for a gestational trophoblastic tumor.

An Adrenal Cortical Adenoma with Adrenal Medullary Hyperplasia / 대한내과학회지

The relationship between the adrenal cortex and medulla has been studied since the 1960s. Rarely, a patient with an adrenal cortical adenoma presents with the findings of pheochromocytoma. However, there has been no report of a case with the clinical features of pheochromocytoma showing the pathological features of an adrenal cortical adenoma with medullary hyperplasia on histological examination. We report a 59-year-old-man who was shown to have an adrenal cortical adenoma, with medullary hyperplasia, during a diagnostic work up for pheochromocytoma.

Effects of Spironolactone and Losartan on Diabetic Nephropathy in a Type 2 Diabetic Rat Model

BACKGROUND: While there is an evidence that the anti-inflammatory properties of spironolactone can attenuate proteinuria in type 2 diabetes, its effects on vascular endothelial growth factor (VEGF) expression in diabetic nephropathy have not been clearly defined. In this study, we examined the effects of spironolactone, losartan, and a combination of these two drugs on albuminuria, renal VEGF expression, and inflammatory and oxidative stress markers in a type 2 diabetic rat model. METHODS: Thirty-three Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats were divided into four groups and treated with different medication regimens from weeks 25 to 50; OLETF diabetic controls (n=5), spironolactone-treated (n=10), losartan-treated (n=9), and combination of spironolactone- and losartan-treated (n=9). RESULTS: At week 50, the albumin-to-creatinine ratio was significantly decreased in the losartan and combination groups compared to the control OLETF group. No decrease was detected in the spironolactone group. There was a significant reduction in renal VEGF, transforming growth factor (TGF)-beta, and type IV collagen mRNA levels in the spironolactone- and combination regimen-treated groups. Twenty-four hour urine monocyte chemotactic protein-1 levels were comparable in all four groups but did show a decreasing trend in the losartan and combination regimen groups. Twenty-four hour urine malondialdehyde levels were significantly decreased in the spironolactone- and combination regimen-treated groups. CONCLUSION: These results suggest that losartan alone and a combined regimen of spironolactone and losartan could ameliorate albuninuria by reducing renal VEGF expression. Also, simultaneous treatment with spironolactone and losartan may have protective effects against diabetic nephropathy by decreasing TGF-beta and type IV collagen expression and by reducing oxidative stress in a type 2 diabetic rat model.

Optimal Waist Circumference Cutoff Values for Metabolic Syndrome Diagnostic Criteria in a Korean Rural Population

The Korean Society for the Study of Obesity (KSSO) has defined the waist circumference cutoff value of central obesity as 90 cm for men and 85 cm for women. The purpose of this investigation was to determine the corresponding waist circumference values. A total of 3,508 persons in the Korean Rural Genomic Cohort Study were enrolled in this survey. Receiver operating characteristic (ROC) curve analysis was used to find appropriate waist circumference cutoff values in relation to insulin resistance determined by homeostasis model assessment for insulin resistance (HOMA-IR), body mass index (BMI), and components of metabolic syndrome. The optimal waist circumference cutoff values were 87 cm for men and 83 cm for women by ROC analysis to HOMA-IR and 86 cm for men and 83 cm for women by ROC analysis to value with more than two components of metaobolic syndrome. By using a BMI > or =25 kg/m2, 86 cm for men and 82 cm for women were optimal waist circumference cutoff values. In this study, we suggest that the most reasonable waist circumference cutoff values are 86-87 cm for men and 82-83 cm for women.

A case of dyke-davidoff-masson syndrome associated with hypopituitarism and diabetes mellitus / 대한내과학회지

Dyke-Davidoff-Masson syndrome (DDMS) is a rare condition characterized by asymmetric cerebral hemispheric growth with unilateral atrophy, ipsilateral compensatory osseous hypertrophy, hyperpneumatization of the paranasal sinuses and mastoid cells, and contralateral paresis. Varying degrees of hemiparesis, hemiplegia, seizures, mental retardation, and facial asymmetry can be associated with DDMS. We report the case of a 26-year-old man with DDMS associated with hypopituitarism who complained of polydipsia and polyuria. After an oral glucose tolerance test, he was diagnosed with type 2 diabetes. There is no report of DDMS associated with other pituitary dysfunction or hyperglycemia. Clinicians should consider the possibility of coexisting pituitary dysfunction or type 2 diabetes in patients with DDMS, as it is obviously important for the patient's outcome.

A case of acromegaly with empty sella syndrome associated with colonic neoplasm / 대한내과학회지

Acromegaly is a disorder caused by hypersecretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). The most common cause of acromegaly is a pituitary GH-producing adenoma. Complete or partial disappearance of the adenoma, probably as a result of hemorrhage or infarction, may lead to empty sella. A case of acromegaly with empty sella syndrome has rarely been reported in Korea. It has been suggested that acromegaly might be associated with the incidence of colon neoplasm. Here, we describe a case of acromegaly with empty sella syndrome in a patient who was diagnosed with colon cancer.

A TSH-secreting pituitary microadenoma diagnosed with inferior petrosal sinus sampling: Case report / 대한내과학회지

Thyroid stimulating hormone (TSH)-secreting pituitary adenomas are rare tumors of the pituitary gland and represent 1~2% of all pituitary adenomas. A TSH-secreting pituitary adenoma shows as a normal or elevated thyrotropin level in a hyperthyroid patient. We present a 32-year-old woman who was diagnosed with a TSH-secreting pituitary microadenoma. She had a high free T4, with a normal TSH and alpha-subunit. Bilateral inferior petrosal sinus sampling (IPSS) was done to confirm the alpha-subunit secreting adenoma, and the concentration of the alpha-subunit was high on the tumor side. The pituitary microadenoma was removed, and her TSH and free T4 levels decreased to normal. IPSS may help give an accurate diagnosis in the patient with a normal alpha-subunit.

Relationship between Menopausal Status and Metabolic Syndrome Components in Korean Women / 당뇨병

BACKGROUND: Postmenopausal status is associated with a 60% increased risk for metabolic syndrome. It is thought to be associated with decreased estrogens and increased abdominal obesity in postmenopausal women with metabolic syndrome. The purpose of this study was to investigate the association between metabolic syndrome components and menopausal status. METHODS: A total of 1,926 women were studied and divided into three groups according to their menstrual stage (premenopausal, perimenopausal or postmenopausal). The presence of metabolic syndrome was assessed using the National Cholesterol Education Program's (NCEP) Adult Treatment Panel III criteria. RESULTS: The prevalence of metabolic syndrome was 7.1% in premenopause, 9.8% in perimenopause, and 24.2% in postmenopause. The strong correlation was noted between the metabolic syndrome score and waist circumference in postmenopause (r = 0.56, P < 0.01) and perimenopause (r = 0.60, P < 0.01). Along the menopausal transition, the risk of metabolic syndrome increased with high triglyceride after the age-adjusted (odds ratio (OR) 1.517 [95% confidence interval (CI) 1.014~2.269] in perimenopausal women and OR 1.573 [95% CI 1.025~2.414] in postmenopausal women). In addition, the prevalence of metabolic syndromeincreased in accordance with elevated alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) levels. CONCLUSION: Triglyceride and waist circumference were important metabolic syndrome components, though ALT and GGT may also be related for predicting metabolic syndrome during the transition to menopause.

Short Insulin Tolerance Test Can Determine the Effects of Thiazolidinediones Treatment in Type 2 Diabetes

PURPOSE: The short insulin tolerance test is a simple and reliable method of estimating insulin sensitivity. This study was designed to compare the insulin sensitizing effects of thiazolidinediones (TZDs) on the degree of insulin resistance, determined by a short insulin tolerance test (Kitt) in type 2 diabetic patients. PATIENTS AND METHODS: Eighty-three subjects (mean age = 57.87 +/- 10.78) with type 2 diabetes mellitus were enrolled and received daily one dose of rosiglitazone (4mg) or pioglitazone (15mg). The mean follow-up duration was 25.39 +/- 9.66 months. We assessed insulin sensitivity using HOMA-IR and the short insulin tolerance test before and after TZDs treatment. RESULTS: When we compared patients' characteristics before and after TZDs treatment, the mean fasting glucose level was significantly decreased (183.27 +/- 55.04 to 137.35 +/- 36.42mg/dL, p or = 2.5%/min; 3.50 +/- 0.75%/min to 2.75 +/- 1.12%/min, p = 0.002). CONCLUSION: The glucose lowering effects of TZDs by improving insulin resistance could be determined by using Kitt. However, Kitt may be a beneficial tool to determine TZDs' effects only when patients' Kitt values are less than 2.5%/min.

Beneficial Effects of Thiazolidinediones on Diabetic Nephropathy in OLETF Rats

PURPOSE: Diabetic nephropathy is the most serious of complications in diabetes mellitus. Thiazolidinedione (TZD) is thought to ameliorate diabetic nephropathy; however, the mechanism underlying this effect has not been elucidated. We hypothesized that the vascular endothelial growth factor (VEGF) participates in the pathogenesis of diabetic nephropathy and that TZD may be beneficial for the treatment of diabetic nephropathy because of the effect it has on VEGF. MATERIALS AND METHODS: 23 Otsuka- Long-Evans-Tokushima-Fatty (OLETF) rats and eight control Long-Evans-Tokushima-Otsuka (LETO) rats were divided into the following four groups: LETO group, control OLETF group, pioglitazone treated group (10mg/kg/day), and rosiglitazone treated group (3mg/kg/day). RESULTS: A progressive increase in urinary protein excretion was observed in the diabetic rats. Glomerular VEGF expression in the control OLETF rats was significantly higher than in the control LETO rats. However, there was a significant reduction in both the glomerular VEGF expression and the VEGF mRNA levels after treatment with pioglitazone and rosiglitazone. The twenty-four hour urine protein levels were significantly decreased in both groups of the treated OLETF rats. CONCLUSION: These results suggest that TZD may have beneficial effects on diabetic nephropathy by reducing the VEGF expression.

A Case of Graves' Disease Coexistent with Pulmonary Sarcoidosis / 결핵및호흡기질환

Sarcoidosis is a multisystemic granulomatous disease with an of unknown etiology, involving bilateral hilar lymphadenopathy, pulmonary, skin and eye lesions. However, involvement of the endocrine system in sarcoidosis is quite rare, and the coexistence of both diseases is extremely unusual. We describe a 60-year-old woman presenting with sarcoidosis and Graves' disease. She was admitted for evaluation of dry cough, dyspnea, palpitation and general weakness. Both thyroid glands were enlarged diffusely. The thyroid function tests showed suppressed serum thyrotropin and an increased thyroid hormone level. The levels of the TSH receptor antibody, anti-thyroglobulin antibody and anti-microsomal antibody were higher than normal. The radionuclide scan(131I) showed increased iodine uptake. The chest X-ray revealed pulmonary hilar enlargement and high resolution CT showed both hilar lymph nodes enlargement and tiny parenchymal nodules. The transbronchial lung biopsy showed a noncaseating granuloma without necrosis. We report this case of pulmonary sarcoidosis plus Graves' disease with a review of the relevant literatures.

Recurrent Acute Pancreatitis in a Patient with Type IIb hyperlipoproteinemia: A Case Report and Review of the Literature in Korea

Hyperlipidemia is a rare cause of pancreatitis. It has been believed that free fatty acids released from hydrolyzed serum chylomicrons or triglycerides and chylomicrons induce hyperlipidemic pancreatitis by damaging acinar cells and capillaries. Type I, IV or V hyperlipidemic (Fredrickson's classification) pancreatitides have distinctive features of increased and heightened serum chylomicron and triglyceride levels. In contrast, type IIb hyperlipidemia usually doesn't have increased chylomicrons. It is a dominant inherited genetic disorder and doesn't manifest the subjective symptom before combining vascular complications such as coronary artery disease. Only a few cases of type IIb hyperlipidemic pancreatitis have been reported. We experienced a male patient with recurrent hyperlipidemic pancreatitis combined with type IIb hyperlipidemia. We present the case report and a review of the literature of hyperlipidemic pancreatitis, especially cases in Korea.

Limited Effect of CpG ODN in Preventing Type 1 Diabetes in NOD Mice

Type 1 diabetes is considered as Th1 cell mediated autoimmune disease and the suppression of Th1 cells or the activation of Th2 cells has been regarded as a plausible immunologic intervention for the prevention of type 1 diabetogenesis in a rodent model. CpG ODN is an immunostimulatory sequence primarily present in bacterial DNA, viral DNA and BCG. CpG ODN is conventionally classified as a Th1 cell activator, which has been clinically applied to cancer, allergy and infectious disease. Recently, there was a promising report of that CpG ODN administration suppressed the development of type 1 diabetes in NOD mice by inducing Th2 cell mediated cytokine. However, the antidiabetogenic effect of CpG ODN on NOD mice is controversial. Thus, two studies were serially undertaken with various kinds of CpG motif to find a more optimal sequence and administration method. In the first study, CpG ODN was vaccinated four times and pancreatic inflammation and the quantity of serum insulin subsequently evaluated. In the second study, the amounts of IFN gamma and IL-4 in sera were measured as representative cytokines of Th1 and Th2 cells, respectively. As a result, vaccination or continuous injection of CpG ODN failed to show a preventive effect on type 1 diabetogenesis in NOD mice. Structural differences of CpG ODN also had no affect on the result. CpG ODN also consistently showed affect on the pancreatic pathology. The productions of IFN gamma and IL-4 were detected only in the K and D type CpG ODN administration groups. Comparison of the two cytokines leads to the conclusion that CpG ODN generated a Th1-weighted response in both study groups. It was assumed that CpG ODN failed to produce Th2-weighted cytokine milieu, which can overcome the genetically determined phenotype of NOD mice. Given these results, it was concluded that the immunotherapeutic application of CpG ODN on Type 1 diabetes had clear limitations.

Plasma Adiponectin and Insulin Resistance in Korean Type 2 Diabetes Mellitus

Insulin resistance, which implies impairment of insulin signaling in the target tissues, is a common cause of type 2 diabetes. Adipose tissue plays an important role in insulin resistance through the dysregulated production and secretion of adipose-derived proteins, including tumor necrosis factor-alpha, plasminogen activator inhibitor-1, leptin, resistin, angiotensinogen, and adiponectin. Adiponectin was estimated to be a protective adipocytokine against atherosclerosis, and also to have an anti-inflammatory effect. In this study, the relationship between fasting plasma adiponectin concentration and adiposity, body composition, insulin sensitivity (ITT, HOMAIR, QUICK), lipid profile, fasting insulin concentration were examined in Korean type 2 diabetes. The difference in the adiponectin concentrations was also examined in diabetic and non-diabetic subjects, with adjustment for gender, age and body mass index. 102 type 2 diabetics and 50 controls were examined. After a 12-h overnight fast, all subjects underwent a 75gram oral glucose tolerance test. Baseline blood samples were drawn for the determinations of fasting plasma glucose, insulin, adiponectin, total cholesterol, triglyceride, LDL-cholesterol, and HDL-cholesterol. The body composition was estimated using a bioelectric impedance analyzer (Inbody 2.0). The insulin sensitivity was estimated using the insulin tolerance test (ITT), HOMAIR and QUICK methods. In the diabetic group, the fasting adiponectin concentrations were significantly lower in men than in women. They were negatively correlated with BMI (r=-0.453), hip circumference (r=-0.341), fasting glucose concentrations (r=-0.277) and HOMAIR (r=-0.233). In addition, they were positively correlated with systolic blood pressure (r=0.321) and HDL-cholesterol (r= 0.291). The systolic blood pressure and HDL-cholesterol were found to be independent variables, from a multiple logistic regression analysis, which influenced the adiponectin concentration. Compared with the non-diabetic group, the adiponectin concentrations were significantly lower in the diabetic group, with the exception of obese males. In conclusion, the plasma adiponectin concentrations were closely related to the insulin resistance parameters in Korean type 2 diabetic patients.

A Case of Drug Induced Nephrogenic Diabetes Insipidus and Hyperprolactinemia in Schizophrenia Simultaneously / 대한내분비학회지

In schizophrenia, when treatment using antipsychotics fails, lithium, which is known as an antimanic drug, can also be administered. It is reported that 12~20% of patients taking lithium develop nephrogenic diabetes lactotrophs. Hyperprolactinemia is induced by typical antipsychotics, as they block the dopamine-2 receptors of latotrophs in the pituitary gland. Therefore, atypical antipsychotics for decreasing the side effect, such as hyperprolactinemia, can be used. However, hyperprolactinemia can be induced by risperidone, one of the atypical antipsychotics. Here, a case of drug induced nephrogenic diabetes insipidus and simultaneous hyperprolactinemia, which occurred in a patient with schizophrenia, is reported.

Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes

VEGF expressed in glomerular podocytes, is known to increase vascular permeability to macromolecules. Angiotensin II can stimulate the release of VEGF, and the protective effects of angiotensin II antagonist against diabetic glomerular injury suggest that the angiotensin II-induced VEGF is an important pathogenetic mechanism in the development of proteinuria during diabetic nephropathy although this mechanism is not fully understood. In this study, the changes of VEGF expression was examined in the experimental diabetic nephropathy to determine whether these changes were modified by renoprotective intervention by blockers of angiotensin II receptors. The streptozotocin- induced diabetic rats were treated with L-158,809, a blocker of angiotensin II receptors, for 12 weeks. Age-matched rats with L-158,809 served as controls. RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of VEGF. A progressive increase in urinary protein excretion was observed in diabetic rats. Glomerular VEGF expression was significantly higher in diabetic rats than in the control groups, with a significant reduction in glomerular VEGF expression and proteinuria in L-158,809- treated diabetic rats. VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys. These results demonstrates that VEGF expression is significantly increased in diabetic podocytes, and angiotensin II receptor antagonist attenuated these changes in VEGF expression and prevented the development of proteinuria in vivo. Attenuation of increased VEGF expression in podocytes could contribute to the renoprotective effects of angiotensin II receptor antagonists in diabetic nephropathy.

A case of two consecutive deliveries in a woman with acromegaly / 대한내과학회지

Acromegaly is a rare pituitary disorder and usually results from GH hypersecretion by a somatotroph adenoma. Disturbed pituitary function might lead to infertility or early pregnancy termination. Pregnancy in acromegaly is very rare. GH is a potent insulin antagonist, and pregnant patients with GH hypersecretion are prone to added glucose intolerance and diabetes. Pregnancy itself may impact the course of a pituitary tumor. In our case, pregnancy was uneventful and normal full-term infant was delivered at 1993 by vaginal delivery after transsphenoidal surgery and bromocriptine therapy. After delivery, GH and IGF-I level wasn't normalized. Postoperative pituitary MRI scan showed residual tumor. Therefore she received subsequent postoperative pituitary radiation (total dose : 5000 cGy). Next year, despite elevated GH and IGF-I, she delivered normal full-term infant. We report a case of two consecutive deliveries in a woman with acromegaly despite elevated GH and IGF-I levels after transsphenoidal surgery and radiation therapy.