The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene.

BACKGROUND: Aldosterone synthase (CYP11B2) deficiency is a rare autosomal recessive disorder, usually presenting with severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood. Neonatal screening for congenital adrenal hyperplasia, another cause of salt wasting, using 17-hydroxyprogesterone measurement would fail to detect aldosterone synthase deficiency, a diagnosis which may be missed until the patient presents with salt-wasting crisis. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation for suspected patients would facilitate clinical management of the patient and assessment of the genetic implication in their offspring. CASE PRESENTATION: We describe a 33-year old Chinese man who presented in infancy with life-threatening hyponatraemia and failure to thrive, but remained asymptomatic on fludrocortisone since. Chromosomal analysis confirmed a normal male karyotype of 46, XY. Plasma steroid profile showed high plasma renin activity, low aldosterone level, and elevated 18-hydroxycorticosterone, compatible with type 2 aldosterone synthase deficiency. The patient was heterozygous for a novel CYP11B2 mutation: c.977C > A (p.Thr326Lys) in exon 3. He also carried a heterozygous mutation c.523_525delAAG (p.Lys175del) in exon 6, a known pathogenic mutation causing aldosterone synthase deficiency. Sequencing of CYP11B2 in his parents demonstrated that the mother was heterozygous for c.977C > A, and the father was heterozygous for c.523_525delAAG. CONCLUSION: Although a rare cause of hyperreninaemic hypoaldosteronism, aldosterone synthase deficiency should be suspected and the diagnosis sought in patients who present with life-threatening salt-wasting in infancy, as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted. To our knowledge, this is the first Chinese patient in which the molecular basis of aldosterone synthase deficiency has been identified.

Non-alcoholic fatty liver disease and type 2 diabetes: An update.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) is rising, along with the epidemic of diabesity. NAFLD is present in >70% of individuals with type 2 diabetes. Although the mutually detrimental relationship between NAFLD and type 2 diabetes has been well established, a multitude of recent studies have further shown that type 2 diabetes is closely linked to the development of cirrhosis, hepatocellular carcinoma, liver-related morbidity and mortality. In contrast, NAFLD also negatively impacts type 2 diabetes both in terms of its incidence and related adverse clinical outcomes, including cardiovascular and chronic kidney diseases. In response to these global health threats, clinical care pathways for NAFLD and guidelines for metabolic dysfunction-associated fatty liver disease have been developed. Several antidiabetic agents have been evaluated for their potential hepatic benefits with promising results. Furthermore, type 2 diabetes patients are increasingly represented in clinical trials of novel therapeutics for NAFLD. However, despite the wealth of knowledge in NAFLD and type 2 diabetes, lack of awareness of the disease and the potential weight of this problem remains a major challenge, especially among clinicians who are outside the field of hepatology and gastroenterology. This review therefore aimed to provide all diabetes care providers with a summary of the latest evidence that supports NAFLD as an emerging diabetic complication of increasing importance, and to present the current recommendations, focusing on the assessment and therapeutic strategies, on the management of NAFLD among type 2 diabetes patients.

High dosage of Exendin-4 increased early insulin secretion in differentiated beta cells from mouse embryonic stem cells.

AIM: To investigate early insulin release (EIR) and late insulin release (LIR) upon glucose challenge as well as important insulin signaling factors in differentiated insulin-producing cells from embryonic stem cells(ESCs). METHODS: A recently published protocol was modified by increasing the concentration of Exendin-4 (from 0.1 nmol/L to 10 nmol/L) together with an additional 5-day culture in low glucose (5.5 mmol/L) medium after differentiation. Gene expression profile, insulin content, C-peptide, EIR and LIR were determined. RESULTS: Compared to a lower concentration of Exendin-4 (0.1 nmol/L), a higher concentration of Exendin-4 (10 nmol/L) increased glucose-responsive insulin secretion, especially EIR. Moreover, 10 nmol/L Exendin-4 increased the expression of the following genes: insulin 1, Pdx-1 (an important transcription factor, newly recognized insulin signaling factors), Epac1 and Epac2 (exchange proteins directly activated by cAMP 1 and 2), and sulfonylurea receptor 1 (SUR1, the subunit of the K(ATP) channel). CONCLUSION: According to current knowledge, our modified protocol with a higher concentration of Exendin-4 (10 nmol/L) together with an additional 5-day 5.5 mmol/L glucose culture after differentiation improved the efficiency of differentiation toward the beta cell phenotype, which was possibly the result of stimulated expression of Pdx-1, Epac 1, and Epac 2, which in turn inhibited the K(ATP) channel through combination with SUR1, leading to increased EIR upon glucose challenge.

Glycogenic hepatopathy as an unusual etiology of deranged liver function in a patient with type 1 diabetes: A case report.

RATIONALE: Deranged liver function is a common finding among patients with diabetes mellitus. We report a case of liver biopsy-proven glycogenic hepatopathy (GH) in a patient with long-standing poorly controlled type 1 diabetes (DM1), presented with recurrent transaminitis. PATIENT CONCERNS: A 28-year-old Chinese woman was noted to have deranged liver function with transaminases elevated to more than 15 times the upper limit of normal. DIAGNOSIS: She had underlying long-standing poorly controlled DM1. Blood tests including hepatitis serology and autoimmune panel were negative. Liver biopsy confirmed the diagnosis of GH, showing an increase in glycogen deposition with intact liver parenchymal architecture, and no inflammation or significant fibrosis. INTERVENTIONS: Her glycemic control was optimized. OUTCOMES: Her transaminase levels normalized upon subsequent follow-up with improved glycemic control. LESSONS: GH is suspected when transaminase flare occurs in patients with poorly controlled DM1, usually with exaggerated hemoglobin A1c levels, especially after drug-induced, viral, autoimmune and metabolic liver diseases are excluded. The gold standard of diagnosis is liver biopsy. When diagnosis of GH is ascertained, the mainstay of treatment is to optimize glycemic control. Typically, the transaminases may become normal within days to months after improvement of glycemic control. Compared to non-alcoholic fatty liver disease, GH is associated with favorable prognosis and runs a benign course, making this differentiation clinically important.

Improved functional recovery to I/R injury in hearts from lipocalin-2 deficiency mice: restoration of mitochondrial function and phospholipids remodeling.

AIMS: Recent clinical and experimental evidences demonstrate an association between augmented circulating lipocalin-2 [a pro-inflammatory adipokine] and cardiac dysfunction. However, little is known about the pathophysi-ological role of lipocalin-2 in heart. The present study was designed to compare the heart functions of mice with normal (WT) or deficient lipocalin-2 (Lcn2-KO) expression. METHODS AND RESULTS: Echocardiographic analysis revealed that the myocardial contractile function was significantly improved in hearts of Lcn2-KO mice, under both standard chow and high fat diet conditions. The heart function before and after I/R injury (20-min of global ischemia followed by 60-min of reperfusion) was assessed using the Langendorff perfusion system. Compared to WT littermates, hearts from Lcn2-KO mice showed improved functional recovery and reduced infarct size following I/R. Under baseline condition, the mitochondrial function of Lcn2-KO hearts was significantly enhanced, as demonstrated by biochemical analysis of respiratory chain activity and markers of biogenesis, as well as electron microscopic investigation of the mitochondrial ultrastructure. Acute or chronic administration of lipocalin-2 impaired cardiac functional recovery to I/R and dampened the mitochondrial function in hearts of Lcn2-KO mice. These effects were associated with an extensive modification of the fatty acyl chain compositions of intracellular phospholipids. For example, lipocalin-2 facilitated the redistribution of linoleic acid (C18:2) among different types of phospholipids, including cardiolipin, a structurally unique phospholipid located mainly on the inner membrane of mitochondria. CONCLUSIONS: Lack of lipocalin-2 improved the functional recovery of isolated mice hearts subjected to I/R, which is associated with restoration of mitochondrial function and phospholipids remodeling.

The effective fraction isolated from Radix Astragali alleviates glucose intolerance, insulin resistance and hypertriglyceridemia in db/db diabetic mice through its anti-inflammatory activity.

BACKGROUND: Macrophage infiltration in adipose tissue together with the aberrant production of pro-inflammatory cytokines has been identified as the key link between obesity and its related metabolic disorders. This study aims to isolate bioactive ingredients from the traditional Chinese herb Radix Astragali (Huangqi) that alleviate obesity-induced metabolic damage through inhibiting inflammation. METHODS: Active fraction (Rx) that inhibits pro-inflammatory cytokine production was identified from Radix Astragali by repeated bioactivity-guided high-throughput screening. Major constituents in Rx were identified by column chromatography followed by high-performance liquid chromatography (HPLC) and mass-spectrometry. Anti-diabetic activity of Rx was evaluated in db/db mice. RESULTS: Treatment with Rx, which included calycosin-7-ß-D-glucoside (0.9%), ononin (1.2%), calycosin (4.53%) and formononetin (1.1%), significantly reduced the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and MCP-1) in human THP-1 macrophages and lipopolysaccharide (LPS)-induced activation of NF-κB in mouse RAW-Blue macrophages in a dose-dependent manner. Chronic administration of Rx in db/db obese mice markedly decreased the levels of both fed and fasting glucose, reduced serum triglyceride, and also alleviated insulin resistance and glucose intolerance when compared to vehicle-treated controls. The mRNA expression levels of inflammatory cell markers CD68 and F4/80, and cytokines MCP-1, TNF-α and IL-6 were significantly reduced in epididymal adipose tissue while the alternatively activated macrophage marker arginase I was markedly increased in the Rx-treated mice. CONCLUSION: These findings suggest that suppression of the inflammation pathways in macrophages represents a valid strategy for high-throughput screening of lead compounds with anti-diabetic and insulin sensitizing properties, and further support the etiological role of inflammation in the pathogenesis of obesity-related metabolic disorders.

Adipose tissue and the metabolic syndrome: focusing on adiponectin and several novel adipokines.

The metabolic syndrome represents a cluster of metabolic risk factors that predispose an individual to an increased risk for Type 2 diabetes, cardiovascular diseases and their associated morbidity and mortality. Visceral obesity is thought to be a major culprit. Adipokines secreted from the adipose tissue are now believed to be key factors mediating the metabolic and inflammatory effects of obesity. In this review, we shall examine the evidence suggesting that several novel adipokines, adiponectin, adipocyte fatty acid-binding protein, retinol-binding protein-4 and lipocalin-2, may hold promise as important clinical biomarkers to identify individuals at risk for the metabolic syndrome and related comorbidities.

Inflammatory biomarkers associated with obesity and insulin resistance: a focus on lipocalin-2 and adipocyte fatty acid-binding protein.

Obesity is an important risk factor for a cluster of metabolic and cardiovascular diseases, including insulin resistance, Type 2 diabetes, nonalcoholic fatty liver disease and atherosclerosis. Systemic low-grade inflammation, characterized by elevated circulating concentrations of proinflammatory factors, has recently been proposed to be a key mediator that links obesity with its medical complications. Adipose tissue is now recognized as the major contributor to systemic inflammation associated with obesity. As obesity develops, adipose tissue is infiltrated with activated macrophages. The 'inflamed' adipose tissue secretes a large number of proinflammatory adipokines and/or cytokines, which can act either in an autocrine manner to perpetuate local inflammation or in an endocrine manner to induce insulin resistance and endothelial dysfunction. In this review, we summarize recent advances in several newly identified adipose tissue-derived inflammatory factors, with the focus on lipocalin-2 and adipocyte fatty acid-binding protein (A-FABP). Both lipocalin-2 and A-FABP possess lipid-binding properties and are important integrators of metabolic and inflammatory pathways. A growing body of evidence from experimental, epidemiological and genetic studies suggests that both lipocalin-2 and A-FABP represent a novel class of serum biomarkers for risk prediction and therapeutic intervention of obesity-related medical complications.