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Volume 31(2); June 2016
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Review Articles
Endocrine Risk Factors for Cognitive Impairment
Jae Hoon Moon
Endocrinol Metab. 2016;31(2):185-192.   Published online April 25, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.185
  • 4,350 View
  • 46 Download
  • 22 Web of Science
  • 22 Crossref
AbstractAbstract PDFPubReader   

Cognitive impairment, including Alzheimer's disease and other kinds of dementia, is a major health problem in older adults worldwide. Although numerous investigators have attempted to develop effective treatment modalities or drugs, there is no reasonably efficacious strategy for preventing or recovering from cognitive impairment. Therefore, modifiable risk factors for cognitive impairment have received attention, and the growing literature of metabolic risk factors for cognitive impairment has expanded from epidemiology to molecular pathogenesis and therapeutic management. This review focuses on the epidemiological evidence for the association between cognitive impairment and several endocrine risk factors, including insulin resistance, dyslipidemia, thyroid dysfunction, vitamin D deficiency, and subclinical atherosclerosis. Researches suggesting possible mechanisms for this association are reviewed. The research investigating modifiable endocrine risk factors for cognitive impairment provides clues for understanding the pathogenesis of cognitive impairment and developing novel treatment modalities. However, so far, interventional studies investigating the beneficial effect of the "modification" of these "modifiable risk factors" on cognitive impairment have reported variable results. Therefore, well-designed, randomized prospective interventional studies are needed.

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  • Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease
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  • Role of the Orexin System on the Hypothalamus-Pituitary-Thyroid Axis
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Close layer
Kisspeptin Regulation of Neuronal Activity throughout the Central Nervous System
Xinhuai Liu, Allan E. Herbison
Endocrinol Metab. 2016;31(2):193-205.   Published online May 27, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.193
  • 5,649 View
  • 72 Download
  • 37 Web of Science
  • 36 Crossref
AbstractAbstract PDFPubReader   

Kisspeptin signaling at the gonadotropin-releasing hormone (GnRH) neuron is now relatively well characterized and established as being critical for the neural control of fertility. However, kisspeptin fibers and the kisspeptin receptor (KISS1R) are detected throughout the brain suggesting that kisspeptin is involved in regulating the activity of multiple neuronal circuits. We provide here a review of kisspeptin actions on neuronal populations throughout the brain including the magnocellular oxytocin and vasopressin neurons, and cells within the arcuate nucleus, hippocampus, and amygdala. The actions of kisspeptin in these brain regions are compared to its effects upon GnRH neurons. Two major themes arise from this analysis. First, it is apparent that kisspeptin signaling through KISS1R at the GnRH neuron is a unique, extremely potent form or neurotransmission whereas kisspeptin actions through KISS1R in other brain regions exhibit neuromodulatory actions typical of other neuropeptides. Second, it is becoming increasingly likely that kisspeptin acts as a neuromodulator not only through KISS1R but also through other RFamide receptors such as the neuropeptide FF receptors (NPFFRs). We suggest likely locations of kisspeptin signaling through NPFFRs but note that only limited tools are presently available for examining kisspeptin cross-signaling within the RFamide family of neuropeptides.

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Close layer
Bone Metabolism
Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis
Yibin Kang
Endocrinol Metab. 2016;31(2):206-212.   Published online May 13, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.206
  • 4,690 View
  • 51 Download
  • 33 Web of Science
  • 33 Crossref
AbstractAbstract PDFPubReader   

Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs) and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1) in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β) is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.

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Close layer
Thyroid
Clinical Relevance of Environmental Factors in the Pathogenesis of Autoimmune Thyroid Disease
Wilmar M. Wiersinga
Endocrinol Metab. 2016;31(2):213-222.   Published online May 13, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.213
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AbstractAbstract PDFPubReader   

Genetic factors contribute for about 70% to 80% and environmental factors for about 20% to 30% to the pathogenesis of autoimmune thyroid disease (AITD). Relatives of AITD patients carry a risk to contract AITD themselves. The 5-year risk can be quantified by the so-called Thyroid Events Amsterdam-score, based on serum thyroid-stimulating hormone, thyroid peroxidase (TPO)-antibodies and family history. Subjects at risk may ask what they can do to prevent development of AITD. This review summarizes what is known about modulation of exposure to environmental factors in terms of AITD prevention. To stop smoking decreases the risk on Graves disease but increases the risk on Hashimoto disease. Moderate alcohol intake provides some protection against both Graves and Hashimoto disease. Low selenium intake is associated with a higher prevalence of thyroid autoimmunity, but evidence that selenium supplementation may lower TPO antibodies and prevent subclinical hypothyroidism remains inconclusive. Low serum vitamin D levels are associated with a higher prevalence of TPO antibodies, but intervention studies with extra vitamin D have not been done yet. Stress may provoke Graves hyperthyroidism but not Hashimoto thyroiditis. Estrogen use have been linked to a lower prevalence of Graves disease. The postpartum period is associated with an increased risk of AITD. Taking together, preventive interventions to diminish the risk of AITD are few, not always feasible, and probably of limited efficacy.

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Close layer
Obesity and Metabolism
High-Density Lipoprotein, Lecithin: Cholesterol Acyltransferase, and Atherosclerosis
Alice Ossoli, Chiara Pavanello, Laura Calabresi
Endocrinol Metab. 2016;31(2):223-229.   Published online June 10, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.223
  • 4,996 View
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AbstractAbstract PDFPubReader   

Epidemiological data clearly show the existence of a strong inverse correlation between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and the incidence of coronary heart disease. This relation is explained by a number of atheroprotective properties of HDL, first of all the ability to promote macrophage cholesterol transport. HDL are highly heterogeneous and are continuously remodeled in plasma thanks to the action of a number of proteins and enzymes. Among them, lecithin:cholesterol acyltransferase (LCAT) plays a crucial role, being the only enzyme able to esterify cholesterol within lipoproteins. LCAT is synthetized by the liver and it has been thought to play a major role in reverse cholesterol transport and in atheroprotection. However, data from animal studies, as well as human studies, have shown contradictory results. Increased LCAT concentrations are associated with increased HDL-C levels but not necessarily with atheroprotection. On the other side, decreased LCAT concentration and activity are associated with decreased HDL-C levels but not with increased atherosclerosis. These contradictory results confirm that HDL-C levels per se do not represent the functionality of the HDL system.

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Obesity and Metabolism
Recent Advances in Diagnostic Strategies for Diabetic Peripheral Neuropathy
Jong Chul Won, Tae Sun Park
Endocrinol Metab. 2016;31(2):230-238.   Published online May 27, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.230
  • 7,292 View
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  • 49 Web of Science
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AbstractAbstract PDFPubReader   

Diabetes is an increasing epidemic in Korea, and associated diabetic peripheral neuropathy (DPN) is its most common and disabling complication. DPN has an insidious onset and heterogeneous clinical manifestations, making it difficult to detect high-risk patients of DPN. Early diagnosis is recommended and is the key factor for a better prognosis and preventing diabetic foot ulcers, amputation, or disability. However, diagnostic tests for DPN are not clearly established because of the various pathophysiology developing from the nerve injury to clinical manifestations, differences in mechanisms according to the type of diabetes, comorbidities, and the unclear natural history of DPN. Therefore, DPN remains a challenge for physicians to screen, diagnose, follow up, and evaluate for treatment response. In this review, diagnosing DPN using various methods to assess clinical symptoms and/or signs, sensorineural impairment, and nerve conduction studies will be discussed. Clinicians should rely on established modalities and utilize current available testing as complementary to specific clinical situations.

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Close layer
Obesity and Metabolism
Diabetes Drugs and Cardiovascular Safety
Ji Cheol Bae
Endocrinol Metab. 2016;31(2):239-244.   Published online June 10, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.239
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AbstractAbstract PDFPubReader   

Diabetes is a well-known risk factor of cardiovascular morbidity and mortality, and the beneficial effect of improved glycemic control on cardiovascular complications has been well established. However, the rosiglitazone experience aroused awareness of potential cardiovascular risk associated with diabetes drugs and prompted the U.S. Food and Drug Administration to issue new guidelines about cardiovascular risk. Through postmarketing cardiovascular safety trials, some drugs demonstrated cardiovascular benefits, while some antidiabetic drugs raised concern about a possible increased cardiovascular risk associated with drug use. With the development of new classes of drugs, treatment options became wider and the complexity of glycemic management in type 2 diabetes has increased. When choosing the appropriate treatment strategy for patients with type 2 diabetes at high cardiovascular risk, not only the glucose-lowering effects, but also overall benefits and risks for cardiovascular disease should be taken into consideration.

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Close layer
Obesity and Metabolism
Current Challenges in Diabetic Nephropathy: Early Diagnosis and Ways to Improve Outcomes
Sang Soo Kim, Jong Ho Kim, In Joo Kim
Endocrinol Metab. 2016;31(2):245-253.   Published online May 27, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.245
  • 5,757 View
  • 88 Download
  • 48 Web of Science
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AbstractAbstract PDFPubReader   

Diabetes is often associated with chronic kidney disease (CKD) and is the primary cause of kidney failure in half of patients who receive dialysis therapy. Given the increasing prevalence of diabetes and its high morbidity and mortality, diabetic nephropathy is a serious drawback in individual patients and a tremendous socioeconomic burden on society. Despite growing concern for the management of diabetic nephropathy, the prevalence of CKD with diabetes is the same today as it was 20 years ago. The current strategy to manage diabetic nephropathy, including the control of hyperglycemia, dyslipidemia, and blood pressure and the wide-spread use of renin-angiotensin-aldosterone system inhibitors, is well established to be beneficial in the early stages of diabetic nephropathy. However, the effects are uncertain in patients with relatively progressed CKD. Therefore, early diagnosis or risk verification is extremely important in order to reduce the individual and socioeconomic burdens associated with diabetic nephropathy by providing appropriate management to prevent the development and progression of this condition. This review focuses on recent research and guidelines regarding risk assessment, advances in medical treatment, and challenges of and future treatments for diabetic nephropathy.

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Close layer
Obesity and Metabolism
Current Challenges in Diabetic Retinopathy: Are We Really Doing Better?
Jae Hyuck Lee, Su Jeong Song
Endocrinol Metab. 2016;31(2):254-257.   Published online June 10, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.254
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  • 35 Download
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AbstractAbstract PDFPubReader   

Management of diabetic complications has been a worldwide major global health issue for decades. Recent studies from many parts of the world indicate improvement in this area. However, it is unknown if such an improvement is being realized in Koreans. Although there is limited information regarding diabetic retinopathy management among Koreans, recent epidemiologic studies have indicated improved screening rates and less frequent visual impairment among type 2 diabetics. Moreover, results achieved with new diagnostic and treatment modalities aimed to improve diabetic retinopathy management are encouraging for both physicians and patients.

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Obesity and Metabolism
Cardiovascular Effects of Glucagon-Like Peptide-1 Receptor Agonists
Yu Mi Kang, Chang Hee Jung
Endocrinol Metab. 2016;31(2):258-274.   Published online April 25, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.258
  • 5,849 View
  • 86 Download
  • 30 Web of Science
  • 33 Crossref
AbstractAbstract PDFPubReader   

Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family, and GLP-1 receptor agonists (RAs) have been introduced as a new class of antidiabetic medications in the past decade. The benefits of GLP-1 RAs are derived from their pleiotropic effects, which include glucose-dependent insulin secretion, suppressed glucagon secretion, and reduced appetite. Moreover, GLP-1 RAs also exert beneficial roles on multiple organ systems in which the GLP-1 receptors exist, including the cardiovascular system. Cardiovascular effects of GLP-1 RAs have been of great interest since the burden from cardiovascular diseases (CVD) has been unbearably increasing in a diabetic population worldwide, despite strict glycemic control and advanced therapeutic techniques to treat CVD. Preclinical studies have already demonstrated the beneficial effects of GLP-1 on myocardium and vascular endothelium, and many clinical studies evaluating changes in surrogate markers of CVD have suggested potential benefits from the use of GLP-1 RAs. Data from numerous clinical trials primarily evaluating the antihyperglycemic effects of multiple GLP-1 RAs have also revealed that changes in most CVD risk markers reported as secondary outcomes have been in favor of GLP-1 RAs treatment. However, to date, there is only one randomized clinical trial of GLP-1 RAs (the ELIXA study) evaluating major cardiovascular events as their primary outcomes, and in this study, a neutral cardiovascular effect of lixisenatide was observed in high-risk diabetic subjects. Therefore, the results of ongoing CVD outcome trials with the use of GLP-1 RAs should be awaited to elucidate the translation of benefits previously seen in CVD risk marker studies into large clinical trials with primary cardiovascular outcomes.

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Close layer
Editorial
Obesity and Metabolism
Prediction of Diabetes Using Serum C-Peptide
Hye Seung Jung
Endocrinol Metab. 2016;31(2):275-276.   Published online June 22, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.275
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PDFPubReader   
Close layer
Original Articles
Clinical Study
Diagnostic Role of Captopril Challenge Test in Korean Subjects with High Aldosterone-to-Renin Ratios
Jung Hee Kim, Kyeong Seon Park, A Ram Hong, Chan Soo Shin, Seong Yeon Kim, Sang Wan Kim
Endocrinol Metab. 2016;31(2):277-283.   Published online May 13, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.277
  • 5,081 View
  • 52 Download
  • 13 Web of Science
  • 13 Crossref
AbstractAbstract PDFPubReader   
Background

Diagnosis of primary aldosteronism (PA) begins with aldosterone-to-renin ratio (ARR) measurement followed by confirmative tests. However, the ARR has high false positive rates which led to unnecessary confirmatory tests. Captopril challenge test (CCT) has been used as one of confirmatory tests, but the accuracy of it in the diagnosis of PA is still controversial. We aimed to examine the clinical efficacy of CCT as a post-screening test in PA.

Methods

In a prospective study, we enrolled subjects with suspected PA who had hypertension and ARR >20 (ng/dL)/(ng/mL/hr). Sixty-four patients who underwent both the saline infusion test and the CCT were included.

Results

The diagnostic performance of plasma aldosterone concentration (PAC) post-CCT was greater than that of ARR post-CCT and ARR pre-CCT in PA (area under the curve=0.956, 0.797, and 0.748, respectively; P=0.001). A cut-off value of 13 ng/dL showed the highest diagnostic odds ratio considering PAC post-CCT at 60 and 90 minutes. A PAC post-CCT of 19 ng/dL had a specificity of 100%, which can be used as a cut-off value for the confirmative test. Determining the diagnostic performance of PAC post-CCT at 90 minutes was sufficient for PA diagnosis. Subjects with PAC post-CCT at 90 minutes <13 ng/dL are less likely to have PA, and those with PAC post-CCT at 90 minutes ≥13 but <19 ng/dL should undergo secondary confirmatory tests.

Conclusion

The CCT test may be a reliable post-screening test to avoid the hospitalization in the setting of falsely elevated ARR screening tests.

Citations

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  • Exclusion Tests in Unilateral Primary Aldosteronism (ExcluPA) Study
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Close layer
Clinical Study
1,5-Anhydro-D-Glucitol Could Reflect Hypoglycemia Risk in Patients with Type 2 Diabetes Receiving Insulin Therapy
Min Kyeong Kim, Hye Seung Jung, Soo Heon Kwak, Young Min Cho, Kyong Soo Park, Seong Yeon Kim
Endocrinol Metab. 2016;31(2):284-291.   Published online May 27, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.284
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AbstractAbstract PDFPubReader   
Background

The identification of a marker for hypoglycemia could help patients achieve strict glucose control with a lower risk of hypoglycemia. 1,5-Anhydro-D-glucitol (1,5-AG) reflects postprandial hyperglycemia in patients with well-controlled diabetes, which contributes to glycemic variability. Because glycemic variability is related to hypoglycemia, we aimed to evaluate the value of 1,5-AG as a marker of hypoglycemia.

Methods

We enrolled 18 adults with type 2 diabetes mellitus (T2DM) receiving insulin therapy and assessed the occurrence of hypoglycemia within a 3-month period. We measured 1,5-AG level, performed a survey to score the severity of hypoglycemia, and applied a continuous glucose monitoring system (CGMS).

Results

1,5-AG was significantly lower in the high hypoglycemia-score group compared to the low-score group. Additionally, the duration of insulin treatment was significantly longer in the high-score group. Subsequent analyses were adjusted by the duration of insulin treatment and mean blood glucose, which was closely associated with both 1,5-AG level and hypoglycemia risk. In adjusted correlation analyses, 1,5-AG was negatively correlated with hypoglycemia score, area under the curve at 80 mg/dL, and low blood glucose index during CGMS (P=0.068, P=0.033, and P=0.060, respectively).

Conclusion

1,5-AG level was negatively associated with hypoglycemia score determined by recall and with documented hypoglycemia after adjusting for mean glucose and duration of insulin treatment. As a result, this level could be a marker of the risk of hypoglycemia in patients with well-controlled T2DM receiving insulin therapy.

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Close layer
Clinical Study
Trends in Diabetes Incidence in the Last Decade Based on Korean National Health Insurance Claims Data
Sun Ok Song, Yong-ho Lee, Dong Wook Kim, Young Duk Song, Joo Young Nam, Kyoung Hye Park, Dae Jung Kim, Seok Won Park, Hyun Chul Lee, Byung-Wan Lee
Endocrinol Metab. 2016;31(2):292-299.   Published online June 10, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.292
  • 4,346 View
  • 47 Download
  • 36 Web of Science
  • 34 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

Epidemiological data is useful to estimate the necessary manpower and resources used for disease control and prevention of prevalent chronic diseases. We aimed to evaluate the incidence of diabetes and identify its trends based on the claims data from the National Health Insurance Service database over the last decade.

Methods

We extracted claims data on diabetes as the principal and first additional diagnoses of National Health Insurance from January 2003 to December 2012. We investigated the number of newly claimed subjects with diabetes codes, the number of claims and the demographic characteristics of this population.

Results

Total numbers of claimed cases and populations with diabetes continuously increased from 1,377,319 in 2003 to 2,571,067 by 2012. However, the annual number of newly claimed diabetic subjects decreased in the last decade. The total number of new claim patients with diabetes codes decreased as 30.9% over 2005 to 2009. Since 2009, the incidence of new diabetes claim patients has not experienced significant change. The 9-year average incidence rate was 0.98% and 1.01% in men and women, respectively. The data showed an increasing proportion of new diabetic subjects of younger age (<60 years) combined with a sharply decreasing proportion of subjects of older age (≥60 years).

Conclusion

There were increasing numbers of newly claimed subjects with diabetes codes of younger age over the last 10 years. This increasing number of diabetic patients will require management throughout their life courses because Korea is rapidly becoming an aging society.

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Clinical Study
Usefulness of Measuring Thyroid Stimulating Antibody at the Time of Antithyroid Drug Withdrawal for Predicting Relapse of Graves Disease
Hyemi Kwon, Won Gu Kim, Eun Kyung Jang, Mijin Kim, Suyeon Park, Min Ji Jeon, Tae Yong Kim, Jin-Sook Ryu, Young Kee Shong, Won Bae Kim
Endocrinol Metab. 2016;31(2):300-310.   Published online April 25, 2016
DOI: https://doi.org/10.3803/EnM.2016.31.2.300
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AbstractAbstract PDFPubReader   
Background

Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse.

Methods

This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal.

Results

Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%.

Conclusion

TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease.

Citations

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