The effects of add-on exenatide to insulin on glycemic variability and hypoglycemia in patients with type 1 diabetes mellitus.

OBJECTIVE: To investigate the effect of add-on exenatide to insulin on glycemic excursion and the counter-regulatory hormone in response to hypoglycemia in patients with type 1 diabetes mellitus (T1DM). METHODS: 30 patients with T1DM were recruited and randomly assigned to exenatide + insulin-treated group (group 1, n = 15) or insulin-only-treated group (group 2, n = 15) for 4 weeks. All patients had continuous glucose monitor system (CGMS) applied at before (week-0) and after (week-4) treatment to evaluate the glycemic variability. All patients had an arginine-stimulated test at before and after treatment. Six patients from each group also had hypoglycemic clamp test to assess counter-regulatory hormone level. RESULTS: Patients in the exenatide group had significant reductions in body weight, body mass index (BMI), total insulin dose, bolus insulin dose, fructosamine, and glycemic excursion after 4 weeks' treatment. Compared with patients in group 2, the mean amplitude of glycemic excursion (MAGE) and coefficient of variation (CV) of exenatide group decreased significantly. Similarly, a significant decrease of glucagon (GLC) in the arginine-stimulated test was found in group 1. No significant changes of GLC, growth hormone (GH), cortisol (COR), epinephrine (E), and norepinephrine (NE) were found in both groups during hypoglycemia clamp test. However, patients who had residual islet function in group 1 showed an upward trend of basic C-peptide (C-P) and GLC during the hypoglycemia period. CONCLUSION: Although exenatide could inhibit glucagon secretion during euglycemia or hyperglycemia in patients with T1DM, it has no effect on GLC and counter-regulatory hormones during hypoglycemia clamp in patients with no functional residual islet test.

A comparison of clinical efficacy and economic value in Basalin- and Lantus-treated patients with type 2 diabetes using continuous glucose monitoring system.

AIM: To determine the clinical non-inferiority of recombinant glargine-Basalin vs glargine-Lantus, in treatment of type 2 diabetes mellitus (T2DM) using continuous glucose monitoring system (CGMS). METHODS: One hundred patients with T2DM were recruited. They were either regularly taking Basalin (Basalin group) or Lantus (Lantus group) (n = 50 each). CGMS was employed to real-time monitor blood glucose profile for 4 days (from day 1 to day 5). To exclude the effect of patient background, the study design was to have a blinded crossover from glargine-Basalin to glargine-Lantus on day 3, and vice versa. 24-hour mean blood glucose (24hMBG), 24-hour standard deviation of blood glucose (24hSDBG), 24-hour mean amplitude of glycemic excursion (24hMAGE), and number of glycemic excursion (NGE) every 24 h (24hNGE) were calculated for each glargine from 100 patients. RESULTS: No significant difference of 24hMBG, 24hSDBG, 24hMAGE, and 24hNGE (p > 0.05 for all) was found between Basalin and Lantus treatments. The glucose area under the curve and time when blood glucose was below 3.9 mmol/L, between 3.9 and 10.0 mmol/L, or above 10.0 mmol/L were similar between Basalin and Lantus treatment. The frequency of hypoglycemic episodes was also similar. However, the mean cost of Basalin was only 72% of Lantus's in one treatment course. CONCLUSION: Glargine-Basalin is non-inferior in clinical efficacy compared to glargine-Lantus. In view of the large difference in the cost of glargine-Basalin, it would be much more cost-effective for our patients.

An Intensive Diabetes Screening and Treatment Program Improves Diagnosis, Treatment and Outcomes of Diabetes in Patients Admitted with Cardiac Diseases.

Aim: Patients with cardiac diseases, especially ischemic heart disease, are known to have a high prevalence of diabetes mellitus (DM). They are at risk of having inadequate glucose control. An intensive diabetes screening and treatment program was developed to identify and treat DM in patients admitted with cardiac diseases. Methods: Adult inpatients of 2 cardiac wards, namely Ward-A and Ward-B, at Nanjing Hospital, Nanjing, China, were studied. Patients were randomly assigned into either ward. In addition to routine examination and treatment, an intensive screening and treatment program to identify and treat patients with DM or impaired glucose regulation (IGR) was only applied in Ward-A patients. The glycated serum protein concentration, the length of hospitalization, and medical and total hospital cost were compared between the 2 wards. Results: The prevalence of DM was 17.85% in Ward-B. With implementation of this program, DM was higher in Ward-A (29.7%) and the prevalence of IRG was 7.8%. The overall prevalence of abnormal glucose metabolism was 37.5% in Ward-A. This program is associated with significantly reduced medical cost and length of inhospital days in patients requiring percutaneous coronary intervention (PCI) and reduced both the medical and total hospital costs in patients without PCI of Ward-A as compared with those of Ward-B who received standard treatment. Conclusion: The intensive screening and treatment program increases diagnosis rate of DM and IRG in inpatient with cardiac diseases, more effectively controls hyperglycemia, and is associated with shorter length of inhospital days and lower medical and total hospital costs. The trial registry number: ChiCTR-IPR-15007487.

RHS6 coordinately regulates the Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4.

BACKGROUND: Asthma is a Th2 cell-driven inflammatory disease and a major public health concern. The cis-acting element Rad50 hypersensitive site 6 (RHS6) in the Th2 locus control region is essential for regulation of the Th2 cytokine genes; however, its role in allergic airway inflammation and underlying molecular mechanisms of the regulation by RHS6 are poorly understood. OBJECTIVE: We sought to understand the role of RHS6 in the development of allergic airway inflammation and its molecular mechanism for Th2 cytokine expression. METHODS: We used an ovalbumin-induced allergic inflammation model with RHS6-deficient mice to examine the role of RHS6 in this process. To examine molecular mechanism of RHS6 for Th2 cytokine expression, we used DNA affinity chromatography and mass spectrometry, quantitative RT-PCR, ELISA, intracellular cytokine staining, chromatin immunoprecipitation, and co-immunoprecipitation. RESULTS: Deletion of RHS6 caused a dramatic resistance to allergic airway inflammation. RHS6 recruited transcription factors GATA3, SATB1, and IRF4, which play important roles in expression of all three Th2 cytokine genes. RHS6 deficiency caused inhibition of transcription factor-induced Th2 cytokine gene expression. CONCLUSION: RHS6 is a critical regulatory element for allergic airway inflammation and for coordinate regulation of Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4.

Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations.

OBJECTIVE: The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). PARTICIPANTS: A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry. EVIDENCE: Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues. CONSENSUS PROCESS: Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors. CONCLUSIONS: LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.

Prevalence of type 5 familial hemophagocytic lymphohistiocytosis in Korea and novel mutations in STXBP2.

Familial hemophagocytic lymphohistiocytosis (F-HLH or FHL) is a potentially fatal immune dysregulation syndrome with a heterogeneous genetic background. Most recently, STXBP2 has been identified as the causative gene of type 5 FHL (FHL5) with a worldwide distribution. In this study, we investigated the prevalence of FHL5 in Korea. About 50 Korean pediatric patients with HLH who lacked pathogenic mutations in PRF1, UNC13D, or in STX11 from the previous series of 72 patients with HLH were analyzed for STXBP2 mutations by conventional sequencing analyses. As a result, we found one patient with two novel mutations of STXBP2: c.184A>G and c.577A>C. c.184A>G (p.Asn62Asp) was located within a highly conserved region of the STXBP2 protein and predicted to be deleterious. c.577A>C in exon 7 resulted in incomplete splicing mutation with exon 7 skipping concurrent with exon 7-retained transcript with p.Lys193Gln substitution. The frequency of FHL5 was ~1% (1/72) in Korean pediatric patients with HLH. This is the first study on FHL5 in Korea, and the data from a nationwide patient cohort provide another piece of genetic profiles of FHL.

Visfatin and its genetic variants are associated with obesity-related morbidities and cardiometabolic risk in severely obese children.

BACKGROUND: Visfatin is an adipokine, associated with obesity and possibly glucose regulation. OBJECTIVE: The aim of this study was to examine the association of visfatin and its genetic variants with adiposity, cardiometabolic risk factors and obesity-related morbidities in obese children. METHODS: Anthropometric measurements, dual energy X-ray absorptiometry scan, fasting blood samples and oral glucose tolerance tests were performed for 243 obese children. We screened the visfatin gene of 24 obese subjects and then performed genotyping of identified genetic variants in other 219 obese children through direct DNA sequencing. RESULTS: Fasting serum visfatin correlated with measures of obesity and liver enzymes and was elevated in obese children with abnormal glucose tolerance and non-alcoholic fatty liver disease. The two upstream single nucleotide polymorphisms, -3187G>A (rs11977021) and -1537C>T (rs61330082), were at complete linkage disequilibrium. The AA genotype of -3187G>A was associated with higher serum visfatin (6.17 ± 0.76 ng mL(-1) vs. 3.92 ± 0.44 ng mL(-1)) and higher triglyceride (1.39 ± 0.08 mmol L(-1) vs. 1.19 ± 0.07 mmol L(-1)) as compared with the GG genotype. There was also a significant linear increase in serum visfatin across GG to GA to AA genotype of -3187G>A, indicating possible additive effect of A allele. The dominant GA + AA genotype model of +21426G>A (rs2302559) was associated with lower serum visfatin (3.83 ± 0.56 ng mL(-1) vs. 5.13 ± 0.34 ng mL(-1)) and lower plasma glucose (4.37 ± 0.08 mmol L(-1) vs. 4.77 ± 0.12 mmol L(-1)) as compared with the GG genotype. CONCLUSION: Visfatin and its genetic variants were associated with adiposity, obesity-related morbidities and adverse cardiometabolic parameters. This supported our hypothesis that visfatin plays a significant role in the development of obesity-related morbidities and cardiometabolic risk.

Gene and stem cell therapy for diabetes.

Gene and stem cell therapy has been on the scientific agenda in many laboratories for more than 20 years. The literature is enormous, but practical applications have been few. Recently advances in stem cell biology and gene therapy are clarifying some of the issues. I have made a few observations concerning our own studies on bone marrow mesenchymal stem cells cultured to produce a small percentage of insulin-producing cells and human insulin gene engineered into Lenti and AA viruses. The aim of clinical application would still seem to be several years away, if all goes well. The first step will be to produce enough insulin-secreting cells to be of potential value to patients. The next crucial question will be how to persuade the cells to respond to blood glucose levels swiftly and appropriately. With both stem cell and gene therapy, another important factor will be to ensure that any positive results will continue long enough to be preferable to insulin injections.

Mutation spectrum and inhibitor risk in 100 Korean patients with severe haemophilia A.

Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by defects in the F8 gene encoding the coagulation factor VIII. Mutation analysis in HA is important to confirm the diagnosis, genotype-phenotype correlations and for genetic counselling and family study. The aim of this study was to detect causative mutations of F8 in severe HA patients in Korea and to correlate the mutation type with the risk of inhibitor development. A total of 100 unrelated Korean patients with severe HA were enrolled for this study. The Nijeman modification of the Bethesda assay was used to determine the presence of inhibitor. Molecular analysis of F8 was performed using a combination of molecular techniques, including long-distance polymerase chain reaction, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). We identified causative mutations in 98% of severe HA patients (98/100). Inv22 and Inv1 mutations were detected in 30 patients and one patient, respectively. A total of 59 unique mutations were identified in 69 non-inversion patients, including 24 novel mutations. The overall prevalence of inhibitor was 26%. Inhibitor risk was highest in patients with large deletion mutations identified using MLPA (100%). Among those with point mutations, the prevalence of inhibitor was highest when the mutation occurred in the A3 and C2 domains (60% and 50%, respectively). The molecular diagnostic strategy involving multiplex PCR, sequencing and dosage analyses identified causative mutations in most cases of severe HA. The high inhibitor risk was associated with large deletion mutations and point mutations in A3 and C2 domains.

Stem cell therapy for diabetes.

Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.

Dual blockade of the renin-angiotensin-aldosterone system is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy.

INTRODUCTION: Blockade of the renin-angiotensin-aldosterone system (RAAS) by either the angiotensin converting enzyme inhibitor (ACE-I) or the angiotensin II receptor blocker (ARB) has been shown to reduce albuminuria and delay the progression of diabetic nephropathy. This study evaluated the effect of dual blockade of the RAAS by adding an ACEI or an ARB to the administration of either drug alone on albuminuria in Asian type 2 diabetic patients with nephropathy. METHODS: 34 patients were randomly assigned to receive either enalapril 20 mg or losartan 100 mg once daily for eight weeks. Following this, all patients received a combination of enalapril 10 mg and losartan 50 mg daily for eight weeks, followed by enalapril 20 mg and losartan 100 mg daily for another eight weeks. The blood pressure and 24-hour urinary albumin excretion (UAE) were monitored. RESULTS: Following monotherapy with enalapril, there was a mean and standard error (SE) reduction in the UAE and mean arterial pressure (MAP) of 9.8 (SE 6.8) percent (p-value is 0.061) and 5.3 (SE 2.2) mmHg (p-value is 0.026), respectively; the reduction in UAE and MAP following monotherapy with losartan was by 10.9 (SE 14.1) percent (p-value is 0.053) and 4.5 (SE 1.9) mmHg (p-value is 0.034), respectively. Combination therapy with enalapril and losartan further reduced the UAE (11.2 [SE 8.7] percent, p-value is 0.009] despite there being no significant change in the MAP (-1.2 [SE 1.47] mmHg, p-value is 0.42). The adverse effects included dry cough (seven [19.4 percent] patients, resulting in the withdrawal of medication in two patients), and transient hyperkalaemia (two [six percent] patients). CONCLUSION: Dual blockade of the RAAS is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy.

Type 2 diabetic patients with resistant hypertension should be screened for primary aldosteronism.

BP control in diabetic patients is often poor. The contribution of secondary hypertension due to undiagnosed PA in hypertensive type 2 diabetic patients is not well studied. We prospectively screened 100 consecutive Asian type 2 diabetic patients with difficult-to-control or resistant hypertension for PA. PAC (pmol/L) to PRA (ng/mL/h) ratio was measured; those with PAC-to-PRA ratio >550 (corresponding PAC >415) underwent intravenous 0.9% SLT. Patients with PAC >/=140 following SLT had CT adrenals and bilateral AVS. Thirteen patients (13%) were confirmed to have PA, and all had resistant hypertension. Eight had a surgically correctable form of PA. Patients with PA had higher mean (SD) systolic [159.0 (10.6) vs. 146.0 (10.7) mmHg, p=0.001] and diastolic BP [94.6 (6.0) vs. 87.6 (5.9) mmHg, p=0.001], lower serum potassium [3.5 (0.6) vs. 4.3 (0.5) mmol/L, p=0.001], and higher PAC [679.3 (291.0) vs. 239.5 (169.4) pmol/L, p=0.001]. Identification and institution of definitive treatment for PA resulted in better BP control and in a reduction in the use of antihypertensive medications. Our findings demonstrate a high prevalence of PA in type 2 diabetic patients with resistant hypertension. Systematic screening for PA in this select group is recommended, as targeted treatment improves BP control.

Skeletal myoblast transplantation for attenuation of hyperglycaemia, hyperinsulinaemia and glucose intolerance in a mouse model of type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We aimed to demonstrate the feasibility and efficacy of intra-muscular transplantation of human skeletal myoblasts (hSkMs) for attenuation of hyperglycaemia and improvement of insulin sensitivity using a mouse model of type 2 diabetes mellitus. METHODS: KK Cg-Ay/J mice, aged 12 to 14 weeks, underwent an initial intraperitoneal glucose tolerance test (GTT) and were divided into the following groups: KK control group, basal medium (M199) only; KK myoblast group, with hSkM transplantation; KK fibroblast group, with human fibroblast transplantation. Non-diabetic C57BL mice were used as an additional normal control and also had hSkM transplantation. Cells were transplanted intra-muscularly into the skeletal muscles of the mice. All animals were treated with ciclosporin for 6 weeks only. HbA(1c) and fasting GTT, as well as serum adiponectin, cholesterol, insulin and triacylglycerol were studied. RESULTS: Immunohistochemistry studies showed extensive survival of the transplanted hSkMs in the skeletal muscles at 12 weeks, with nuclei of the hSkMs integrated into the host muscle fibres. Repeat GTT showed a significant decrease in glucose concentrations in the KK myoblast group compared with the KK control and KK fibroblast groups. The KK myoblast group also had reduced mean HbA(1c), cholesterol, insulin and triacylglycerol, and increased adiponectin compared with the KK control and KK fibroblast groups. C57BL mice showed no change in glucose homeostasis after hSkM transplant. CONCLUSIONS/INTERPRETATION: Human skeletal myoblast transplantation attenuated hyperglycaemia and hyperinsulinaemia and improved glucose tolerance in the KK mouse. This novel approach of improving muscle insulin resistance may be a potential alternative treatment for type 2 diabetes mellitus.

Recurrent episodes of arthritis in a hyperthyroid patient.

Antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis is a potentially life-threatening adverse effect of antithyroid medications. We present a 22-year-old woman with Graves' disease who developed recurrent episodes of arthritis while on treatment with propylthiouracil. A diagnosis of propylthiouracil-induced ANCA-associated vasculitis was established only after exhaustive rheumatological investigations failed to establish a cause for her arthritis. Anti-myeloperoxidase antibody (anti-MPO) titres were grossly elevated at 172.7 RU/mL (0-20). Her arthritis resolved promptly following the withdrawal of propylthiouracil and the anti-MPO titres declined over 16 months to 66.8 RU/mL. While she did not develop the life-threatening renal or respiratory tract complications, there was a delay in establishing the correct diagnosis with its attendant morbidity. This case highlights the need for greater awareness of this relatively rare adverse effect of antithyroid medications so as to allow its early detection, leading to the prompt cessation of the offending medication.

Parathyroid carcinoma: a case series.

INTRODUCTION: We present 3 patients with parathyroid carcinoma and describe their presentations, clinical profiles, and management. MATERIALS AND METHODS: A case series review of medical records. RESULTS: Two women and 1 man (age range, 32 to 57 years) had parathyroid cancer and primary hyperparathyroidism (PHPT). One patient presented with osteitis fibrosa, 1 with renal stone and a neck mass, and 1 with recurrence of PHPT after excision of supposedly benign parathyroid adenoma 4 years ago. All had severe hypercalcaemia and elevated parathyroid hormone levels that ranged from 4 to 43 times above the normal range. Exploration of the neck clearly identified 1 parathyroid tumour with local invasion; 2 other specimens showed capsular and vascular invasion on frozen section and final histology. All 3 patients underwent parathyroidectomy and ipsilateral hemithyroidectomy. Parathyroid size ranged from 1.3 to 4 cm and no lymph node metastasis was identified. No patient had tumour recurrence after a follow-up period of 1 year. CONCLUSION: Parathyroid carcinoma is a rare endocrine malignancy. Suspicious features include marked hypercalcaemia, neck mass, and local recurrence. Parathyroidectomy with ipsilateral hemithyroidectomy and nodal clearance gives the best chance of reducing local tumour recurrence.

Xenotransplantation of neonatal porcine islets and Sertoli cells into nonimmunosuppressed streptozotocin-induced diabetic rats.

The testis has been shown to be a privileged site for transplantation of allogenic islets in rodents, and the testicular cell aggregates are thought to confer this immunologic privilege. Recently, a group in Mexico reported transplantation of cocultured neonatal porcine islets and Sertoli cells resulting in insulin independence in nonimmunosuppressed type 1 diabetes patients. We have transplanted similar islets alone (naked islets) or cocultured islets with Sertoli cells (islet/Sertoli cells) into an omental site and other locations of nonimmunosuppressed, streptozotocin-induced diabetic male Sprague Dawley (SD) rats. Histologic examination showed viable neonatal porcine islets survived in xenografted rodents for at least 2 days, and some glucagon and inhibin stained cells appear to have survived for 4 days posttransplantation. However, histological examination did not demonstrate any difference in xenograft survival in the islets/Sertoli cells mixture compared to naked islets when transplanted into these nonimmunosuppressed diabetic rats.

Transplantation of neonatal porcine islets and sertoli cells into nonimmunosuppressed nonhuman primates.

A Mexican group reported transplantation of cocultured neonatal porcine islets and Sertoli cells resulting in insulin independence in nonimmunosuppressed type 1 diabetes patients. We have transplanted similar islets alone (naked islets) or cocultured islets with sertoli cells (islet/sertoli cells) into an omental site and other locations of seven nondiabetic, nonimmunosuppressed, nonhuman primates. Porcine endogenous retrovirus was not detected in recipient blood 8 weeks after porcine islet grafts, and porcine C-peptide was detected at a very low level in all animals. Histology examination failed to demonstrate obviously recognizable islets, but in the animals transplanted with islet/Sertoli cells at the omentum site, there were some surviving glucagons, pan-cytokeratin, and inhibin stained cells at 8 weeks.

Anaplastic thyroid carcinoma with destructive thyrotoxicosis in a patient with preexisting multinodular goiter.

Presentation of anaplastic thyroid carcinoma with thyrotoxicosis is extremely rare and its occurrence in a patient with Wegener's granulomatosis has not been reported previously. We describe an elderly lady with Wegener's granulomatosis who developed a rapidly growing anaplastic thyroid carcinoma in a preexisting multinodular goiter and discuss the mechanism of thyrotoxicosis in this patient.