Objectives: Diabetic nephropathy (DN) is a major leading cause of kidney failure. Recent studies showed that serological microRNAs (miRs) could be utilized as biomarkers to identify disease pathogenesis; the DN-related miRs, however, remained to be explored. Methods: A prospective case-control study was conducted. The clinical significance of five potential miRs (miR-21, miR-29a, miR-29b, miR-29c and miR192) in type 2 Diabetes Mellitus (T2DM) patients who have existing diabetic retinopathy with differential Albumin:Creatinine Ratio (ACR) and estimated Glomerular Filtration Rate (eGFR) was performed using quantitative RT-PCR analysis. The subjects with diabetic retinopathy enrolled in Taipei City Hospital, Taiwan, were classified into groups of normal albuminuria (ACR<30mg/g; N=12); microalbuminuria (30mg/g300mg/g; N=21) as well as 18 low-eGFR (eGFR<60ml/min) and 32 high-eGFR (eGFR>60ml/min). The level of serum miRs was statistically correlated with age, Glucose AC, ACR, eGFR and DN progression. Results: The levels of miR-21, miR-29a and miR-192 were significantly enriched in the overt proteinuria group compared with microalbuminuria and/or overt proteinuria groups. It was shown that only miR-21 level was significantly up-regulated in low-eGFR group compared with high-eGFR patients. Interestingly, Pearson's correlation coefficient analysis demonstrated that DN progressors showed significantly greater levels of miR-21, miR-29a, miR-29b and miR-29c in comparison with non-progressors implying the clinical potential of DN associated miRs in monitoring and preventing disease advancement. Conclusion: Our findings showed that miR-21, miR-29a/b/c and miR-192 could reflect DN pathogenesis and serve as biomarkers during DN progression.

Context There is a medical need for effective insulin-independent antidiabetic drugs that have the capability to promote pancreatic β-cell function and have a low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients. R-form verapamil (R-Vera), which is able to enhance the survival of β-cells and has higher cardiovascular safety margin compared to racemic verapamil, was developed as a novel approach for the T2DM treatment. Objective This randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of three doses of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone. Methods Subjects were randomly assigned in an equal ratio to receive R-Vera 450, 300, 150 mg per day or matching placebo, in combination with metformin. The primary endpoint was change in hemoglobin A1c (HbA1c) after 12 weeks of treatment. Results A total of 184 eligible subjects were randomized to receive either R-Vera or placebo plus metformin. At week 12, significant reductions in HbA1c were observed for R-Vera 300 mg/day (-0.36, P = 0.0373) and 450 mg/day (-0.45, P = 0.0098) compared to placebo. The reduction in HbA1c correlated with decreasing fasting plasma glucose levels and improved HOMA2-β score. Treatment with R-Vera was well tolerated with no hypoglycemic episodes occurring during the trial. Conclusion Addition of R-Vera twice daily to ongoing metformin therapy significantly improved glycemic control in T2DM patients. The favorable efficacy and safety profile of R-Vera 300 mg/day can be considered as the appropriate dose for clinical practice.

Abstract.A 38-year-old male patient presented with general weakness, polydipsia and a body weight loss of 10 kg in two years. Hypopituitarism with central hypothyroidism and central adrenal insufficiency were noted at Taipei City Hospital (Taipei, Taiwan). However, hypogonadotropic hypergonadism was also observed. The patient was diagnosed with an intracranial β-human chorionic gonadotropin (β-hCG) secreting germ-cell tumor, and brain magnetic resonance imaging revealed that the tumor involved the pineal gland, stalk, posterior pituitary gland, right basal ganglion, hypothalamus, corpus callosum and posterior hippocampus. The cerebrospinal fluid (CSF) β-hCG level was 1936 IU/l, while the α-fetoprotein (AFP) level was <0.24 ng/ml. The serum AFP level of the patient was 3.28 ng/ml, and the β-hCG level was 178 IU/l with a CSF:serum β-hCG ratio >2:1. The patient was successfully treated with chemotherapy and radiotherapy, as demonstrated by a marked decrease in size of the tumor and in the serum β-hCG levels. Intracranial β-hCG secreting germ-cell tumors are rare in adults and manifest differently compared with patients of early pubertal age. In contrast with the precocious puberty frequently observed in young patients, the diagnosis of adult patients is often delayed and the symptoms are associated with tumor size and location. The present case report described an adult male with an intracranial β-hCG secreting GCT, demonstrating hypopituitarism and asymptomatic hyperandrogenemia, and reviews and discusses the literature relevant to the case. IntroductionPrimary intracranial germ-cell tumors (GCT) are rare tumors. They account for ~0.5-3% of all pediatric primary central nervous system (CNS) tumors in Western regions, but are observed at higher frequencies among pediatric CNS tumors in Asia, accounting for up to 10% (1). The incidence in the Far East area of Japan is 0.1-0.17 per 100,000 per year, according to the Brain Tumor Registry of Japan (2), slightly higher than the incidence rate of 0.1 per 100,000 per year in the United States (3). Primary intracranial GCT typically occurs in children or young adults, with the majority of patients (60-70%) aged under 20 (4). The peak incidence of intracranial germ-cell tumors is in the early pubertal period with a median age of diagnosis at 10-12 years (5). The disease occurs primarily in males, with the ratio of male to female between 2:1 and 3:1 (6). The World Health Organization had classified intracranial germ-cell tumors into three groups as follows: Germinomas, non-germinomatous germ-cell tumors (NGGCTs) and mixed germ-cell tumors (7). The diseases are heterogeneous in terms of histology, tumor characteristics, treatment response and tumor marker secretion. Among NGGCTs, choriocarcinoma secretes β-human chorionic gonadotropin (β-HCG) into the serum and/or the cerebrospinal fluid (CSF), with high levels detected, while yolk sac tumors secrete α-fetoprotein (AFP). Elevation of AFP levels, combined with characteristic magnetic resonance imaging (MRI) results, is diagnos...

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Robust experiment evidence suggests that prolactin can enhance beta-cell proliferation and increase insulin secretion and sensitivity. Apart from acting as an endocrine hormone, it also function as an adipokine and act on adipocytes to modulate adipogenesis, lipid metabolism and inflammation. Several cross-sectional epidemiologic studies consistently showed that circulating prolactin levels positive correlated with increased insulin sensitivity, lower glucose and lipid levels, and lower prevalence of T2D and metabolic syndrome. Bromocriptine, a dopamine receptor agonist used to treat prolactinoma, is approved by Food and Drug Administration for treatment in type 2 diabetes mellitus since 2009. Prolactin lowering suppress insulin secretion and decrease insulin sensitivity, therefore dopamine receptor agonists which act at the pituitary to lower serum prolactin levels are expected to impair glucose tolerance. Making it more complicating, studies exploring the glucose-lowering mechanism of bromocriptine and cabergoline have resulted in contradictory results; while some demonstrated actions independently on prolactin status, others showed glucose lowering partly explained by prolactin level. Previous studies showed that a moderate increase in central intraventricular prolactin levels stimulates hypothalamic dopamine with a decreased serum prolactin level and improved glucose metabolism. Additionally, sharp wave-ripples from the hippocampus modulates peripheral glucose level within 10 minutes, providing evidence for a mechanistic link between hypothalamus and blood glucose control. Central insulin in the mesolimbic system have been shown to suppress dopamine levels thus comprising a feedback control loop. Central dopamine and prolactin levels plays a key role in the glucose homeostasis control, and their dysregulation could lead to the pathognomonic central insulin resistance depicted in the “ominous octet”. This review aims to provide an in-depth discussion on the glucose-lowering mechanism of dopamine receptor agonists and on the diverse prolactin and dopamine actions on metabolism targets.