Insulin Resistance: From Mechanisms to Therapeutic Strategies

Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. In this review, we summarize the functions of insulin in glucose metabolism in typical metabolic tissues and describe the mechanisms proposed to underlie insulin resistance, that is, ectopic lipid accumulation in liver and skeletal muscle, endoplasmic reticulum stress, and inflammation. In addition, we suggest potential therapeutic strategies for addressing insulin resistance.

Magnetic Resonance-Based Assessments Better Capture Pathophysiologic Profiles and Progression in Nonalcoholic Fatty Liver Disease

Background@#Several noninvasive tools are available for the assessment of nonalcoholic fatty liver disease (NAFLD) including clinical and blood biomarkers, transient elastography (TE), and magnetic resonance imaging (MRI) techniques, such as proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE). In the present study, we aimed to evaluate whether magnetic resonance (MR)-based examinations better discriminate the pathophysiologic features and fibrosis progression in NAFLD than other noninvasive methods. @*Methods@#A total of 133 subjects (31 healthy volunteers and 102 patients with NAFLD) were subjected to clinical and noninvasive NAFLD evaluation, with additional liver biopsy in some patients (n=54). @*Results@#MRI-PDFF correlated far better with hepatic fat measured by MR spectroscopy (r=0.978, P<0.001) than with the TE controlled attenuation parameter (CAP) (r=0.727, P<0.001). In addition, MRI-PDFF showed stronger correlations with various pathophysiologic parameters for cellular injury, glucose and lipid metabolism, and inflammation, than the TE-CAP. The MRI-PDFF and TE-CAP cutoff levels associated with abnormal elevation of serum alanine aminotransferase were 9.9% and 270 dB/m, respectively. The MRE liver stiffness measurement (LSM) showed stronger correlations with liver enzymes, platelets, complement component 3, several clinical fibrosis scores, and the enhanced liver fibrosis (ELF) score than the TE-LSM. In an analysis of only biopsied patients, MRE performed better in discriminating advanced fibrosis with a cutoff value of 3.9 kPa than the TE (cutoff 8.1 kPa) and ELF test (cutoff 9.2 kPa). @*Conclusion@#Our results suggest that MRI-based assessment of NAFLD is the best non-invasive tool that captures the histologic, pathophysiologic and metabolic features of the disease.

Magnetic Resonance-Based Assessments Better Capture Pathophysiologic Profiles and Progression in Nonalcoholic Fatty Liver Disease

Background@#Several noninvasive tools are available for the assessment of nonalcoholic fatty liver disease (NAFLD) including clinical and blood biomarkers, transient elastography (TE), and magnetic resonance imaging (MRI) techniques, such as proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE). In the present study, we aimed to evaluate whether magnetic resonance (MR)-based examinations better discriminate the pathophysiologic features and fibrosis progression in NAFLD than other noninvasive methods. @*Methods@#A total of 133 subjects (31 healthy volunteers and 102 patients with NAFLD) were subjected to clinical and noninvasive NAFLD evaluation, with additional liver biopsy in some patients (n=54). @*Results@#MRI-PDFF correlated far better with hepatic fat measured by MR spectroscopy (r=0.978, P<0.001) than with the TE controlled attenuation parameter (CAP) (r=0.727, P<0.001). In addition, MRI-PDFF showed stronger correlations with various pathophysiologic parameters for cellular injury, glucose and lipid metabolism, and inflammation, than the TE-CAP. The MRI-PDFF and TE-CAP cutoff levels associated with abnormal elevation of serum alanine aminotransferase were 9.9% and 270 dB/m, respectively. The MRE liver stiffness measurement (LSM) showed stronger correlations with liver enzymes, platelets, complement component 3, several clinical fibrosis scores, and the enhanced liver fibrosis (ELF) score than the TE-LSM. In an analysis of only biopsied patients, MRE performed better in discriminating advanced fibrosis with a cutoff value of 3.9 kPa than the TE (cutoff 8.1 kPa) and ELF test (cutoff 9.2 kPa). @*Conclusion@#Our results suggest that MRI-based assessment of NAFLD is the best non-invasive tool that captures the histologic, pathophysiologic and metabolic features of the disease.

In Vivo and In Vitro Quantification of Glucose Kinetics: From Bedside to Bench

Like other substrates, plasma glucose is in a dynamic state of constant turnover (i.e., rates of glucose appearance [Ra glucose] into and disappearance [Rd glucose] from the plasma) while staying within a narrow range of normal concentrations, a physiological priority. Persistent imbalance of glucose turnover leads to elevations (i.e., hyperglycemia, Ra>Rd) or falls (i.e., hypoglycemia, Ra

In Vivo and In Vitro Quantification of Glucose Kinetics: From Bedside to Bench

Like other substrates, plasma glucose is in a dynamic state of constant turnover (i.e., rates of glucose appearance [Ra glucose] into and disappearance [Rd glucose] from the plasma) while staying within a narrow range of normal concentrations, a physiological priority. Persistent imbalance of glucose turnover leads to elevations (i.e., hyperglycemia, Ra>Rd) or falls (i.e., hypoglycemia, Ra

Effect of Rifaximin on Hepatic Fibrosis in Bile Duct-ligated Rat Model / 대한소화기학회지

BACKGROUND/AIMS: The translocation of bacteria and their lipopolysaccharides from the gut can promote fibrosis in cirrhotic patients. The aim of this study was to investigate the effects of rifaximin on hepatic fibrosis in a bile duct-ligated rat model. METHODS: The bile duct ligation (BDL) was carried out for eight days (acute injury model: sham-operated rats [G1], BDL rats [G2], and BDL rats treated with rifaximin [G3]) or 22 days (chronic injury model: sham-operated rats [G4], BDL rats [G5], and BDL rats treated with rifaximin [G6]). Rifaximin (50 mg/kg/day) was administered daily via gavage after BDL. Liver function, serum tumor necrosis factor-alpha (TNF-α), and hepatic hydroxyproline levels were measured. Moreover, a histological analysis of fibrosis contents was performed using sirius red stain. RESULTS: In the acute injury model, the liver function and TNF-α level were not improved after the rifaximin treatment. The hydroxyproline levels (µg/g liver tissue) in G1, G2, and G3 were 236.4±103.1, 444.8±114.4, and 312.5±131.6, respectively; and fibrosis contents (%) were 0.22±0.04, 1.64±0.53, and 1.66±0.44, respectively. The rifaximin treatment did not ameliorate acute BDL-induced fibrosis. In the chronic injury model, the hydroxyproline levels in G4, G5, and G6 were 311.5±72.9, 1,110.3±357.9, and 944.3±209.3, respectively; and fibrosis contents (%) were 0.19±0.03, 5.04±0.18, and 4.42±0.68, respectively (G5 vs. G6, p=0.059). The rifaximin treatment marginally ameliorated chronic BDL-induced fibrosis. CONCLUSIONS: Rifaximin did not reduce inflammation and fibrosis in bile duct-ligated rat model.

The role of amino acid-induced mammalian target of rapamycin complex 1(mTORC1) signaling in insulin resistance

Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance.

Use of in vivo magnetic resonance spectroscopy for studying metabolic diseases

Owing to the worldwide obesity epidemic and the sedentary lifestyle in industrialized countries, the number of people with metabolic diseases is explosively increasing. Magnetic resonance spectroscopy (MRS), which is fundamentally similar to magnetic resonance imaging, can detect metabolic changes in vivo noninvasively. With its noninvasive nature, 1H, 13C and 31P MRS are being actively utilized in clinical and biomedical metabolic studies to detect lipids and important metabolites without ionizing radiation. 1H MRS can quantify lipid content in liver and muscle and can detect other metabolites, such as 2-hydroxyglutarate, in vivo. Of interest, many studies have indicated that hepatic and intramyocellular lipid content is inversely correlated with insulin sensitivity in humans. Thus, lipid content can be utilized as an in vivo biomarker for detecting early insulin resistance. Employing 13C MRS, hepatic glycogen synthesis and breakdown can be directly detected, whereas 31P MRS provides in vivo adenosine triphosphate (ATP) synthesis rates by saturation transfer methods in addition to ATP content. These in vivo data can be very difficult to assess by other methods and offer a critical piece of metabolic information. To aid the reader in understanding these new methods, fundamentals of MRS are described in this review in addition to promising future applications of MRS and its limitations.

Pathogenesis of insulin resistance / 대한내과학회지

No abstract available.

A Case of Apical Hypertrohic Cardiomyopathy Associated with Pheochromocytoma / 대한내분비학회지

Pheochromocytomas often present with cardiovascular manifestations, such as arrhythmia, angina pectoris and acute myocardial infarction and so on. Both dilated and nonobstructive hypertrophic cardiomyopathies are also rare complications of pheochromocytomas. In hypertrophic cardiomyopathy, an apical variant form constitutes about 25% of cases in Japan, but only 1 to 2% of those in non-Japanese populations, including Korea. The cause of apical hypertrophic cardiomyopathy (AHC) remains unknown. Recently, some cases of AHC associated with pheochromocytomas have been reported, with catecholamine thought to be an important cause. AHC associated with a pheochromocytoma has never been previously reported in Korea. Herein is reported our experience of a case of apical hypertrophic cardiomyopathy associated a pheochromocytoma with a review of the literature

A Case of Masked Hypoglycemia during Lactic Acidosis / 대한내분비학회지

Severe hypoglycemia induces neuroglycopenic symptoms, including mental alteration, as glucose is the exclusive fuel for the central nervous system. However, some reports have shown that non-glucose fuels, like lactates and ketones, could be utilized by the brain during severe hypoglycemia. Herein, a case of extreme hypoglycemia in a 44-year old woman, subsequently diagnosed as congestive heart failure accompanied by ischemic hepatitis and lactic acidosis, is presented. In two episodes of extreme hypoglycemia, she was fully alert without obvious neurological deficits. In this unusual case, an increased supply of lactate might have maintained the cerebral function and prevented cerebral injury during the hypoglycemia that was induced as a result of starvation and hepatic and cardiac dysfunctions

A Case of Masked Hypoglycemia during Lactic Acidosis / 대한내분비학회지

Severe hypoglycemia induces neuroglycopenic symptoms, including mental alteration, as glucose is the exclusive fuel for the central nervous system. However, some reports have shown that non-glucose fuels, like lactates and ketones, could be utilized by the brain during severe hypoglycemia. Herein, a case of extreme hypoglycemia in a 44-year old woman, subsequently diagnosed as congestive heart failure accompanied by ischemic hepatitis and lactic acidosis, is presented. In two episodes of extreme hypoglycemia, she was fully alert without obvious neurological deficits. In this unusual case, an increased supply of lactate might have maintained the cerebral function and prevented cerebral injury during the hypoglycemia that was induced as a result of starvation and hepatic and cardiac dysfunctions

Thyroid Hormone Receptor Dynamics in Thyroid Hormone Response Elements of the Human Type 1 Iodothyronine Deiodinase Gene / 대한내분비학회지

BACKGROUND: Type 1 iodothyronine deiodinase (D1), the product of the hdio1 gene, is involved in thyroid hormone activation by the deiodination of thyroxine (T4) to form 3, 5, 3'-triiodothyronine (T3). Recent studies have identified two thyroid hormone response elements (TREs) in the 5 flanking region of the hdio1 gene. TRE1, proximal to TRE in the hdio1 gene, consists of a direct repeat of thyroid hormone receptor (TR) binding octamers with 10 bp separating the two TR binding sites. The upstream TRE, TRE2, is a classical direct repeat of retinoid X receptor (RXR)/TR binding half-sites with a 4-bp separation. There are few studies clarifying the TR dynamics in the TRE of a specific gene with or without the exposure of activated thyroid hormone. We evaluated TR binding patterns in the proximal and distal TREs of the hdio1 gene before and after T3 stimulation. METHODS: We employed chromatin immunoprecipitation (ChIP) technique to investigate the TR-TRE interaction before and after T3 stimulation in human hepatocellular carcinoma HepG2 cell line.Following cross-linking and sonication of the cells, immunoprecipitation was performed overnight at 4degrees C with TR 1, TR 1 and TR 2 antibodies. We analyzed the binding patterns and amounts of TR 1, TR 1 and TR 2 to TRE1 and TRE2 before and after 12 hours stimulation with 100 nM T3 by using conventional and quantitative real-time polymerase chain reactions (RQ-PCR). Reverse transcriptional PCR (RT-PCR) and Western blot with TR 1, TR 1 and TR 2 antibodies were performed to measure the levels of hdio1 mRNA and TR 1, TR 1 and TR 2 proteins before and after 12 hours exposure to 100 nM T3. RESULTS: In TRE1, TR 1 binding was significantly decreased after 12 hours stimulation with 100nM T3 (3.74-->1.97, delta=-47.3%, p3.01, delta=-71.1%, p 2.93, delta=-76.7%, p 9.84, delta=+7.3%). Total TR bindings in TRE2 were significantly decreased after 12 hours stimulation with 100 nM T3 (32.14 --> 15.78, delta=-50.9%, p<0.05). The TR bindings to TRE1 and TRE2 were not significantly different by the amounts of TR antibodies used during ChIP assays. The levels of hdio1 mRNA were significantly increased, 2.03 times, after 12 hours exposure to 100nM T3 (p<0.001). Western blot showed no significant change of the level of each TR isoform protein before and after 12 hours exposure to 100 nM T3. CONCLUSION: Our results demonstrate the dynamics of TR 1 at proximal TRE (TRE1) and the switching phenomenon of TR isoforms at distal TRE (TRE2) of the hdio1 gene after T3 stimulation. Further investigation, however, is needed to clarify the mechanisms of these observations.

A Case of Renal Cell Carcinoma with Thyroid Metastasis / 대한내분비학회지

Metastatic thyroid cancer is uncommon but must be distinguished from primary thyroid cancer because of the differences in management and prognosis. Although renal cell carcinoma is one of the most common tumors that metastasize to the thyroid gland, such a case has never been reported in Korea. We describe the first case of metastatic renal cell carcinoma in the thyroid gland. A 66-year-old man presented with a neck mass detected about 6 weeks previously. He had undergone left nephrectomy due to renal cell carcinoma 8 years before and had remained disease-free thereafter. Computed tomography of the neck showed a 5 cm-sized thyroid mass. Fine needle aspiration cytology revealed some malignant cells containing intranuclear inclusions which were assumed to be papillary thyroid carcinoma. The patient underwent total thyroidectomy. Histologic diagnosis of the thyroid mass was metastatic renal cell carcinoma and further evaluation with chest computed tomography showed two enlarged mediastinal lymph nodes suggesting metastases. The previous history of malignancy should be scrutinized when managing a thyroid mass in patients with a prior or concomitant malignancy, and the possibility of metastasis should be carefully considered.

The Effect of T3 on Thyroid Hormone Receptor Dynamics in Thyroid Hormone Response Element of Chicken Lysozyme Silencer / 대한내분비학회지

BACKGROUND: The regulation of gene transcription can be controlled by both positive (enhancer) and negative (silencer) regulatory sequences. Several enhancer and silencer elements have been described in the 5' region of the chicken lysozyme gene. The silencer located at -2.4 kb upstream of the chicken lysozyme gene is composed of two separate modules (F1 and F2) that can function as silencers by themselves, but also show synergistic repression after multimerization. The F1 module is bound by a protein termed NeP1 and F2 module, a F2 thyroid hormone response element (F2-TRE), and can be bound by the thyroid hormone receptor (TR). F2-TRE has an inverted palindromic structure, with high affinity to TR. Although many current reported results have tried to explain the regulatory mechanism of chicken lysozyme gene expression due to the thyroid hormone, there have been few studies that clarify the TR dynamics in the F2-TRE of the chicken lysozyme gene, either with or without exposure of the thyroid hormone. Here, the changes in the TR binding patterns in the F2-TRE of the chicken lysozyme gene are described, both before and after T3 stimulation over time. METHODS: Using the stably transfected rat pituitary somatotroph tumor cell line, GC8 cells, with the F2-TRE inserted 5' to the thymidine kinase (TK) promoter, together with a mouse TRalpha- expressing plasmid, a chromatin immunoprecipitation (ChIP) technique was employed to reveal the TR-TRE interaction before and after T3 stimulation. Following the cross-linking and sonication of the cells, the immunoprecipitation was performed overnight, at 4 degrees C, with TRalpha1, TRbeta1 and TRbeta2 antibodies, respectively. The binding patterns and amounts of TRalpha1, TRbeta1 and TRbeta2 to the F2-TRE, before and after 12 hours of 100 nM T3 stimulation, were analyzed using conventional and quantitative real-time polymerase chain reactions (RQ-PCR). The ChIP technique was used to give a basal value for 20 minutes and 1, 2, 4, 6, 8 and 12 hours after the 100 nM T3 stimulation, and RQ-PCR was then performed. Western blot with TRalpha1, TRbeta1 and TRbeta2 antibodies were also performed. RESULTS: After 12 hours of 100 nM T3 stimulation of the GC8 cells, the TRalpha1 and TRbeta2 binding to the F2-TRE increased, but the TR 1 binding to the F2-TRE decreased, by conventional PCR. Although all the TR isoforms were bound to the F2-TRE by RQ-PCR, the TR 1 binding to the F2-TRE, after 12 hours of 100 nM T3 stimulation, was significantly increased (1.01-->2.73, delta=+170.3%, p2.98, delta=+17.8%). The TRbeta1 binding was significantly decreased compared with that of the basal level (4.59-->2.06, delta=-55.1%, p7.77, delta=-4.4%). The binding patterns and amounts of TRalpha1, TRbeta1 and TRbeta2, both before and after the 100 nM T3 stimulation, were also identified over time. While the TRbeta1 bindings to the F2-TRE after 1 hour of 100 nM T3 stimulation were acutely reduced, those of the TRalpha1 at 20 minutes and 6 hours were increased. The TRbeta2 bindings showed a maximal increase at 20 minutes. The directions of the TR binding patterns, between the before and after 2 hours of 100 nM T3 stimulation, were identical to those for between 4 and 6 hours of T3 stimulation. There was no significant difference in the TR bindings to the F2-TRE in relation to the amounts (1.5 vs. 4.5 microliter) of TR antibodies used during the ChIP assays. The Western blots showed no significant change of the levels of each TR isoform proteins, either before or after 12 hours of exposure to 100 nM T3. CONCLUSION: These results show the dynamic binding patterns of the TR isoforms to the F2-TRE of the chicken lysozyme gene, both before and after T3 stimulation, over time. Further investigation, however, will be needed to clarify the mechanisms of our observations. The ChIP technique may then be used to reveal the dynamic models of the cofactors, as well as TR isoforms, in the TR-regulated transcription machinery.

Clinical observations of idiopathic hypoparathyroidism / 대한내과학회지

BACKGROUND: Idiopathic hypoparathyroidism is a relatively rare disease characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone deficiency of unknown cause. It usually develop at young age and various clinical symptoms and signs accompanied with hypocalcemia develop at late period. And rarely associated with polyglandular autoimmune syndrome during follow-up. So we reviewed retrospectively our clinical experiences in diagnosis and management. METHODS: We observed the 6 cases with idiopathic hypoparathyroidism from 1986 to 2002. Four female and two male patients were examined demographic characteristics, clinical manifestations, laboratory findings, radiologic finding, and occurrence of polyglandular autoimmune syndrome. RESULTS: All patients aged from 18 to 51 years and had no familial history. The most frequent two symptoms of idiopathic hypoparathyroidism were paresthesia (67%) and tetany (67%). The incidence of Chvostek's and Trousseau's sign were 83% and 67%, respectively. From the history taking, patient who had psychotic problem was two, ocular lesion was two, and Graves's disease was one before admission. One patient had transient hypogonadism because of acute illness but recovered during follow-up. One patient developed primary adrenal insufficiency after 2 years. Neuroimaging study revealed bilateral calcification and ECG showed Q-T interval prolong. CONCLUSION: Idiopathic hypoparathyroidism may be suspected in patients with various neurologic symptoms and signs associated with hypocalcemia. It was difficult to predict other endocrine dysfunction at diagnosis. Therefore, we need to follow-up laboratory examinations for early detection of accompanied autoimmune disease in idiopathic hypoparathyroidism patient.

The mechanism of development of insulin resistance in type 2 diabetes mellitus / 대한내과학회지

No abstract available.

A Case of Cerebral Salt Wasting Syndrome associated with Tuberculous Meningitis / 대한내분비학회지

Hyponatremia in patients with central nervous system disorders is suggestive of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and volume restriction is recommended for its correction. However, if volume depletion is present in a situation otherwise compatible with SIADH, cerebral salt wasting syndrome (CSWS) should be considered as the cause of the hyponatremia to avoid hypovolemic shock that may be induced by the standard management of SIADH, i.e. volume restriction. We present a case of a 17-year-old male patient with CSWS associated with tuberculous meningitis. The clinical feature of the patient comprised hyponatremia, excessive natriuresis, polyuria, and hypovolemia. Following the administration of saline and fludrocortisone, natriuresis and polyuria were decreased, and the hyponatremia improved

Lymphocytic Hypophysitis associated with Pregnancy / 대한내분비학회지

Lymphocytic hypophysitis is a rare inflammatory disease of the pituitary gland that is often recognized as a cause of hypopituitarism and may be due to the autoimmune pituitary destruction that usually occurs in women in the peripartum period. We report a rare case of lymphocytic hypophysitis in a 26 year-old woman presenting with nausea and headaches for 2 months after an artificial abortion of her second pregnancy. Magnetic resonance imaging, with enhancement, showed an expanding 1.0x1.0 cm sized sellar mass. The patient underwent transsphenoidal surgery with a preoperative diagnosis of pituitary macroadenoma. A histological examination revealed diffuse lymphocytes and plasma cells infiltration which are characteristic of lymphocytic hypophysitis. Here, we present the first reported case of a pregnant woman with lymphocytic hypophysitis with a review of the literature on this increasingly recognized condition.

A Case of Postpregnancy Spinal Osteoporosis / 대한내분비학회지

Osteoporosis is a common disease of the elderly and occurs especially in the postmenopausal women. Rarely, it occurs during a pregnancy or shortly thereafter and is accompanied by a substantial bone loss, resulting in fractures. The clinical significance of pregnancy-associated osteoporosis has been noted since the 1950s. Although its etiology is still unknown, it has recently been proposed that PTHrP may be an important causative factor in pregnancy-associated osteoporosis. There are three types of the pregnancy-associated osteoporosis, (1) a transient osteoporosis of the hip pregnancy, (2) a postpregnancy spinal osteoporosis and (3) a lactation-associated osteoporosis. Postpregnancy spinal osteoporosis typically occurs within three months after a first delivery and usually involving the axial skeleton accompanied by back pain, bone loss and a fracture. We present a case of postpregnancy spinal osteoporosis that developed three months after a first delivery. Our patient also showed multiple compression fractures in her lumbar spine and biochemical evidence of increased bone resorption.