1.
Comparison between serum insulin levels and its resistance with biochemical, clinical and anthropometric parameters in South Indian children and adolescents.
Abstract
There is a rising trend in the prevalence of insulin resistance among obese, overweight children and adolescents. The serum insulin and its correlation with biochemical, clinical and anthropometric parameters were evaluated in 185 children and adolescents (59 control, 52 obese, 49 overweight, 25 congenital heart disease) of age group 10-17 years. The levels of serum insulin were measured by ELISA. Serum insulin levels were found to be significantly increased in children who were obese, overweight and had congenital heart disease, than controls. Serum insulin levels positively correlated with BMI, WHR, and serum C-peptide, serum leptin, total cholesterol, triglycerides, LDL-cholesterol, systolic and diastolic blood pressure. Fasting glucose levels were found to be negatively correlated with serum insulin levels. HDL-cholesterol levels were non-significant among the study groups. We identified nine obese children (five girls and four boys) with the features of metabolic syndrome and 69% of obese and overweight children were identified with insulin resistance. Insulin resistance was strongly associated with metabolic syndrome and its components, especially with central obesity and hypertriglyceridemia.
- PMID:
- 22211009
- [PubMed - in process]
Latent Autoimmune Diabetes of Adults Is Phenotypically Similar to Type 1 Diabetes in a Minority Population.
Source
Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-University of California-Los Angeles Medical Center, Torrance, California 90509.
Abstract
Context:Latent autoimmune diabetes of adults (LADA) is a form of autoimmune diabetes that has been classified as part of type 1 diabetes or as a distinct clinical entity. Its precise place as a disease category is therefore controversial.Objective:The objective of this study was to further examine this issue by comparing the phenotypes of LADA and type 1 diabetes in a predominately minority population.Patients and Methods:We studied 126 subjects who were anti-glutamic acid decarboxylase antibody-positive in two separate studies-63 subjects in an outpatient study (study 1), and 63 inpatients after resolution of ketoacidosis (study 2). Clinical and biochemical phenotyping was performed in all patients in each group.Results:Few significant differences were found in the clinical or biochemical phenotypes in patients classified as LADA when compared with type 1 diabetes. Adiposity, body mass index, waist/hip ratio, fasting plasma C-peptide, serum high-density lipoprotein cholesterol, and triglycerides were all similar. The only distinguishing feature was a history of hypertension (study 1) or systolic blood pressure (study 2). Also, a history of ketoacidosis did not influence the phenotype of LADA in the outpatients in any discernable way.Conclusions:We conclude that LADA and type 1 diabetes are phenotypically indistinguishable in this predominantly minority population with a mean duration of glutamic acid decarboxylase antibody-positive diabetes of about 8 yr.
[Correlations between clinical signs and hormonal parameters in young women with hirsutism].
Source
I. Javakhishvili Tbilisi State University, Department of Gynecology, Obstetrics and Reproductology, Medical faculty; I. Zhordania Institute of Human Reproduction, Tbilisi, Georgia.
Abstract
Hyperandrogenism is the pathological condition, which clinical signs are "androgendependent dermopathies" (seborrhea, acne, hirsutism, alopecia) and not in every cases evidence with hyperandrogenemia. Free testosterone is the most frequent marker of hyperandrogenism, but its determination routinely not feasible in all laboratories. Therefore, some models for calculating free and bioavailable testosterone have been developed. In women the testosterone sources are not only ovaries and adrenal glands, but also abdominal and peripheral fat. There are many investigations to definite correlations between body mass index, androgens and sex hormone binding globulin. The aim of this study was to define the correlations between clinical, biochemical markers of hyperandrogenism and body mass index, with regard of abdominal obesity in young women with hirsutism. 83 female adolescents (14-20 year) with hirsutism and 20 female adolescents in control group were included. C-peptide, estradiol, total testosterone, sex hormone binding globulin (SHBG) were measured. Free androgen index (FAI), free (cFT) and bioavailable (Bio-T) testosterone were calculated. The levels of C-peptide and glucose were used to compute Homa-IR (homeostasis model assessment for insulin resistance). There were detected significant high levels by all hormonal parameters of hyperandrogenism in women with hirsutism, than in control group. In patients with abdominal obesity were also found significant high levels by all calculated parameters of hyperandrogenism and significant low level of steroid-bind globulin, than in patients with central obesity. In two groups by hirsutism degree were not detected any differences between androgen markers. The findigs of this research suggest, that android obesity in female adolescents with hirsutism can cause harder hyperandrogenism and elevate free androgen index, free and bioavailable testosterone levels. The prophylactic reduction of body mass index may prevent complications.
- PMID:
- 22201077
- [PubMed - in process]
Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells.
Abstract
We sought to assess the potential of human cord blood-derived mesenchymal stem cells (CB-MSCs) to derive insulin-producing, glucose-responsive cells. We show here that differentiation protocols based on step-wise culture conditions initially described for human embryonic stem cells (hESCs) lead to differentiation of cord blood-derived precursors towards a pancreatic endocrine phenotype, as assessed by marker expression and in vitro glucose-regulated insulin secretion. Transplantation of these cells in immune-deficient animals shows human c-peptide production in response to a glucose challenge. This data suggests that human cord blood may be a promising source for regenerative medicine approaches for the treatment of diabetes mellitus.
Differentiation of mesenchymal stem cells derived from pancreatic islets and bone marrow into islet-like cell phenotype.
Source
Molecular Biotechnology Centre (MBC), University of Turin, Turin, Italy.
Abstract
BACKGROUND:
Regarding regenerative medicine for diabetes, accessible sources of Mesenchymal Stem Cells (MSCs) for induction of insular beta cell differentiation may be as important as mastering the differentiation process itself.
METHODOLOGY/PRINCIPAL FINDINGS:
In the present work, stem cells from pancreatic islets (human islet-mesenchymal stem cells, HI-MSCs) and from human bone marrow (bone marrow mesenchymal stem cells, BM-MSCs) were cultured in custom-made serum-free medium, using suitable conditions in order to induce differentiation into Islet-like Cells (ILCs). HI-MSCs and BM-MSCs were positive for the MSC markers CD105, CD73, CD90, CD29. Following this induction, HI-MSC and BM-MSC formed evident islet-like structures in the culture flasks. To investigate functional modifications after induction to ILCs, ultrastructural analysis and immunofluorescence were performed. PDX1 (pancreatic duodenal homeobox gene-1), insulin, C peptide and Glut-2 were detected in HI-ILCs whereas BM-ILCs only expressed Glut-2 and insulin. Insulin was also detected in the culture medium following glucose stimulation, confirming an initial differentiation that resulted in glucose-sensitive endocrine secretion. In order to identify proteins that were modified following differentiation from basal MSC (HI-MSCs and BM-MSCs) to their HI-ILCs and BM-ILCs counterparts, proteomic analysis was performed. Three new proteins (APOA1, ATL2 and SODM) were present in both ILC types, while other detected proteins were verified to be unique to the single individual differentiated cells lines. Hierarchical analysis underscored the limited similarities between HI-MSCs and BM-MSCs after induction of differentiation, and the persistence of relevant differences related to cells of different origin.
CONCLUSIONS/SIGNIFICANCE:
Proteomic analysis highlighted differences in the MSCs according to site of origin, reflecting spontaneous differentiation and commitment. A more detailed understanding of protein assets may provide insights required to master the differentiation process of HI-MSCs to functional beta cells based only upon culture conditioning. These findings may open new strategies for the clinical use of BM-MSCs in diabetes.
Alkaline phosphatase: can it be considered as an indicator of liver fibrosis in non-alcoholic steatohepatitis with type 2 diabetes?
Source
Department of Endocrinology, Faculty of lstanbul Medicine, Istanbul University, Istanbul, Turkey. gonenckocabay@yahoo.com
Abstract
OBJECTIVE:
While isolated hepatosteatosis is a benign disease, in minority of cases non-alcoholic steatohepatitis (NASH) may even lead to cirrhosis in long-term. In order to find the stage of the disease and determine the prognosis, a liver biopsy is indicated. In this study, we studied the relationship of liver histopathological findings with serum levels of hepatic enzymes.
METHODS:
We recruited 52 cases of NASH with Type 2 diabetes mellitus. Diagnosis of NASH was made based on biochemical tests, ultrasound images and liver biopsy.
RESULTS:
Steatosis was mild in 57.7%, moderate in 30.8%, and severe in 11.6% of patients. While no infiltration was found in 78.8% of cases, there was a grade-1 infiltration in 15.4% and a grade-2 infiltration in 5.8% of cases. Similarly, no fibrosis was found in 42.3% of patients, but there was a stage-1 fibrosis in 50%, and a stage-2 fibrosis in 7.7% of cases. In patients with severe steatosis, serum levels of AST were higher than mild or moderate stage steatosis. Accordingly, in patients with no inflammation, serum levels of ALT were higher than in patients with inflammation. However, in patients with fibrosis, triglycerides levels were significantly lower and ALP was significantly higher than in patients without fibrosis. The correlation analysis indicated a positive association between serum levels of ALP and C-peptide.
CONCLUSION:
In addition to conventional risk factors such as age, presence of diabetes, female sex; higher levels of ALP may be considered as a risk factor linked to hepatic fibrosis in patients with NASH and type 2 diabetes (Tab. 6, Ref. 8).
- PMID:
- 22180989
- [PubMed - in process]
Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals.
Source
E Kauh, Merck Sharp and Dohme Corp., Whitehouse Station, United States.
Abstract
Objective: Use of glucocorticoids for anti-inflammatory efficacy is limited by their side effects. This study examined, in the same individuals, prednisone's acute, dose-dependent effects on inflammation as well as biomarkers of glucose regulation and bone homeostasis.Design: In this randomized, double-blind, parallel-design trial of healthy adults demonstrating cutaneous allergen-induced hypersensitivity, patients received placebo or prednisone 10, 25, or 60 mg daily for 7 days.Methods: Effects on peripheral white blood cell count, ex-vivo whole blood lipopolysaccharide (LPS)-stimulated TNF-α release, and response to cutaneous allergen challenge were assessed concurrently with biomarkers for glucose tolerance and bone turnover.Results: Differential peripheral white blood cell counts changed significantly within hours of prednisone administration. Ex-vivo, LPS-stimulated TNF-α was significantly reduced by all prednisone doses on days 1 and 7. The late phase cutaneous allergen reaction was significantly reduced with prednisone 60 mg vs. placebo on days 1 and 7. Oral glucose tolerance tests revealed significant increases in glycemic excursion on days 1 and 7; whereas, increases in insulin and C-peptide excursions were more notable on day 7 with all doses of prednisone. The bone formation markers osteocalcin, PINP, and PICP decreased significantly on days 1 and 7 vs. placebo.Conclusions: In healthy, young adults, prednisone treatment has significant effects on glucose tolerance and bone formation markers within hours of treatment, in parallel with anti-inflammatory effects, after single doses as low as 10 mg.
Induction of insulin-dependent diabetes mellitus by total pancreatectomy for pancreatic islet transplantation in cynomolgus monkeys.
Source
Department of General Surgery, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.
Abstract
BACKGROUND/PURPOSE:
In order to perform a preclinical trial of pancreatic islet transplantation (PIT) in nonhuman primates, insulin-dependent diabetes mellitus (IDDM) must be induced. Methods for IDDM induction are administration of streptozotocin (STZ) or total pancreatectomy (TP). While STZ-induced IDDM is not always reliable, TP is appropriate for IDDM induction. However, TP is very difficult because of the complex surgical procedure required, necessary confirmation of IDDM, and difficulty in postoperative management. In this study, we tried to establish a reliable IDDM model for PIT in cynomolgus monkeys.
METHODS:
TP was performed in 5 male cynomolgus monkeys (Macaca fascicularis). This was followed by scheduled measurements of blood glucose, C-peptide levels, insulin levels, oral intake, and insulin requirements. IDDM induction was confirmed by serum C-peptide levels and intravenous glucose tolerance test (IVGTT). Allogeneic PIT was performed 14 days later with immunosuppressive therapy.
RESULTS:
TP successfully induced IDDM in all animals, confirmed by reduction of fasting serum C-peptide levels. Negative responses of serum C-peptide levels and insulin in IVGTT provided further confirmation of IDDM induction. No mortality or morbidity was encountered in any of the animals.
CONCLUSIONS:
TP successfully induced IDDM for PIT in cynomolgus monkeys.
The antiapoptotic effects of sulphurous mineral water and sodium hydrosulphide on diabetic rat testes.
Source
Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Abstract
Background/Aims: It is well known that diabetes mellitus is associated with the impairment of testicular function. In the present study, we aimed to study the effects of sulphurous mineral water or sodium hydrosulphide (NaHS) on apoptotic testicular damage in rats with streptozotocin (STZ)-induced diabetes. Methods: Sulphurous mineral water (as drinking water) or NaHS (14 μmol/kg body weight/day, I.P.) was administered for 7 wks to rats with STZ-induced diabetes. Results: Hyperglycaemia, an overproduction of glycated haemoglobin (HbA1C) and a decline in serum insulin, C-peptideand insulin-like growth factor-I (IGF-I) were observed in diabetic rats. A decline in the serum testosterone level and an impairment of spermatogenesis, as indicated by a histopathological examination of diabetic rats, demonstrated significant testicular damage. Sulphurous mineral water and NaHS treatment may have improved the level of testicular GSH by blocking the overexpression of some apoptosis-related regulatory proteins such as Bax/Bcl-2, cytochrome c, caspase-9 and -3, and p53. This anti-apoptotic potential was associated with an increase in serum testosterone level and the amelioration of hyperglycaemia-related biochemical parameters. The histopathological examination was in harmony with the biochemical and molecular findings. Conclusion: Our study provides the first indication that sulphurous mineral water and NaHS may have a novel anti-apoptotic potential that could be a useful treatment in preventing diabetes-induced testicular dysfunction.
Copyright © 2011 S. Karger AG, Basel.
Species incompatibilities in the pig-to-macaque islet xenotransplant model affect transplant outcome: a comparison with allotransplantation.
Source
Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
Abstract
Graham ML, Bellin MD, Papas KK, Hering BJ, Schuurman H-J. Species incompatibilities in the pig-to-macaque islet xenotransplant model affect transplant outcome: a comparison with allotransplantation. Xenotransplantation 2011; 18: 328-342. © 2011 John Wiley & Sons A/S. Abstract: Background: Porcine islet transplantation into diabetic non-human primates is considered most relevant in translational research supporting a clinical application. Most studies have focused on immunosuppressive protocols, while metabolic aspects have mainly been utilized in graft monitoring. We evaluated data from our group regarding human and non-human primate (NHP) allotransplantation and pig-to-NHP xenotransplantation to identify incompatibilities in metabolic factors and their consequences for transplant outcomes. Methods: Basic gluco-metabolic parameters (fasting blood glucose, C-peptide, and response to stimulation with arginine or glucose) were derived from literature (humans), 72 macaques, and 47 adult Landrace pigs. Islet preparations from 15 human deceased donors, 61 macaques, and 23 adult pigs were compared with respect to yield, fractional viability assessed by oxygen consumption normalized for DNA, and in vitro glucose-induced insulin release. Metabolic parameters at day 75 after a single islet transplantation in the liver were compared for 19 patients and 9 macaques receiving an allotransplant and 11 macaques receiving a porcine xenotransplant: recipients received chronic immunosuppression. Results: Pigs differ from NHPs and humans by a much lower C-peptide level (0.42 vs. 1.3 to 2.0 ng/ml, respectively) and a 2- to 7-fold lower C-peptide response to arginine stimulation. In contrast, NHPs have the highest metabolic demand as evidenced by a high C-peptide and high C-peptide response to arginine stimulation; values are about twice higher than in humans. For manufactured islet preparations, these differences are reflected by glucose-stimulated insulin release (the stimulation index for pigs is 1.5, for humans 3.8, and for macaques 7.7), but not by fractional viability, which was in the same range. The day 75 outcome after transplantation assessed by C-peptide was similar for allotransplanted humans and NHPs (80 to 90% good graft function) and lower in xenografted NHPs (36% good graft function); gluco-metabolic parameters were in accordance with graft function, albeit different between species because normoglycemia under exogenous insulin is maintained more aggressively in patients than in NHPs. In xenografted NHPs, the shift in glycemic control with respect to normal values, combined with low values of circulating porcine C-peptide, resembled more the normal condition in a pig than that in a macaque. Conclusions: The substantially lower glucose-induced insulin response in adult porcine islet preparations as opposed to islets manufactured from humans or macaques combined with the much higher need for insulin in macaques than in humans creates an imbalance between the metabolic demand and the engrafted islet mass in the pig-to-NHP xenograft recipient. Engrafted islet mass is affected by dose, suggesting that a much higher dose level of islets is necessary in the xenogeneic setting than in human or NHP allotransplantation, and pig islets need to be given at a higher dose in macaques than the anticipated effective dose in humans. To cope with differences in metabolic demand and presumably also metabolic dynamics, a liberal regime in supportive exogenous insulin might be essential to achieve long-term survival. These intrinsic characteristics of the NHP model deserve consideration to optimally design experimental studies with the perspective of translational value of results.
© 2011 John Wiley & Sons A/S.
A cross-sectional characterization of insulin resistance by phenotype and insulin clamp in East asian americans with type 1 and type 2 diabetes.
Source
Asian American Diabetes Initiative, Joslin Diabetes Center, Boston, Massachusetts, United States of America.
Abstract
OBJECTIVE:
Classic features of type 1 and type 2 diabetes may not apply in Asian Americans, due to shared absence of common HLA DR-DQ genotype, low prevalence of positive anti-islet antibodies and low BMI in both types of diabetes. Our objective was to characterize diabetic phenotypes in Asian Americans by clamp and clinical features.
MATERIALS/METHODS:
This was a cross-sectional study conducted in a referral center. Thirty East young Asian American adult volunteers (27.6±5.5 years) with type 1, type 2 diabetes or controls underwent hyperinsulinemic euglycemic clamp to assess insulin resistance and DEXA to assess adiposity.
RESULTS:
Gender, BMI, waist/hip ratio, leptin, LDL, anti-GAD, anti-IA2 antibodies and C-reactive protein were similar among three groups. Serum C-peptide, adiponectin, free fatty acid, HDL concentrations and truncal fat by DEXA, were different between diabetic groups. Glucose disposal rate by clamp was lowest in type 2 diabetes, followed by type 1 diabetes and controls (5.43±2.70, 7.62±2.59, 8.61±2.37 mg/min/kg, respectively, p = 0.001). Free fatty acid concentration universally plummeted during steady state of the clamp procedure regardless of diabetes types in all three groups. Adipocyte fatty acid binding protein in the entire cohort (r = -0.625, p = 0.04) and controls (r = -0.869, p = 0.046) correlated best with insulin resistance, independent of BMI.
CONCLUSIONS:
Type 2 diabetes in Asian Americans was associated with insulin resistance despite having low BMI as type 1 diabetes, suggesting a potential role for targeting insulin resistance apart from weight loss. Adipocyte fatty acid binding protein, strongly associated with insulin resistance, independent of adiposity in the young Asian American population, may potentially serve as a biomarker to identify at-risk individuals. Larger studies are needed to confirm this finding.
C-Peptide Increases Na,K-ATPase Expression via PKC- and MAP Kinase-Dependent Activation of Transcription Factor ZEB in Human Renal Tubular Cells.
Source
Section of Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Abstract
BACKGROUND:
Replacement of proinsulin C-peptide in type 1 diabetes ameliorates nerve and kidney dysfunction, conditions which are associated with a decrease in Na,K-ATPase activity. We determined the molecular mechanism by which long term exposure to C-peptide stimulates Na,K-ATPase expression and activity in primary human renal tubular cells (HRTC) in control and hyperglycemic conditions.
METHODOLOGY/PRINCIPAL FINDINGS:
HRTC were cultured from the outer cortex obtained from patients undergoing elective nephrectomy. Ouabain-sensitive rubidium ((86)Rb(+)) uptake and Na,K-ATPase activity were determined. Abundance of Na,K-ATPase was determined by Western blotting in intact cells or isolated basolateral membranes (BLM). DNA binding activity was determined by electrical mobility shift assay (EMSA). Culturing of HRTCs for 5 days with 1 nM, but not 10 nM of human C-peptide leads to increase in Na,K-ATPase α(1)-subunit protein expression, accompanied with increase in (86)Rb(+) uptake, both in normal- and hyperglycemic conditions. Na,K-ATPase α(1)-subunit expression and Na,K-ATPase activity were reduced in BLM isolated from cells cultured in presence of high glucose. Exposure to1 nM, but not 10 nM of C-peptide increased PKCε phosphorylation as well as phosphorylation and abundance of nuclear ERK1/2 regardless of glucose concentration. Exposure to 1 nM of C-peptide increased DNA binding activity of transcription factor ZEB (AREB6), concomitant with Na,K-ATPase α(1)-subunit mRNA expression. Effects of 1 nM C-peptide on Na,K-ATPase α(1)-subunit expression and/or ZEB DNA binding activity in HRTC were abolished by incubation with PKC or MEK1/2 inhibitors and ZEB siRNA silencing.
CONCLUSIONS/SIGNIFICANCE:
Despite activation of ERK1/2 and PKC by hyperglycemia, a distinct pool of PKCs and ERK1/2 is involved in regulation of Na,K-ATPase expression and activity by C-peptide. Most likely C-peptide stimulates sodium pump expression via activation of ZEB, a transcription factor that has not been previously implicated in C-peptide-mediated signaling. Importantly, only physiological concentrations of C-peptide elicit this effect.
Phase I, Dose-Escalation Study of BKM120, an Oral Pan-Class I PI3K Inhibitor, in Patients With Advanced Solid Tumors.
Source
Johanna C. Bendell and Howard A. Burris, Sarah Cannon Research Institute, Nashville, TN; Jordi Rodon and José Baselga, Vall d'Hebron University Hospital, Barcelona, Spain; Maja de Jonge and Jaap Verweij, Erasmus University Medical Center, Rotterdam, the Netherlands; Diana Birle, Novartis Institutes for Biomedical Research, Cambridge, MA; David Demanse, Stefan S. De Buck, Malte Peters, and Michael Goldbrunner, Novartis Pharma, Basel, Switzerland; and Qinhua C. Ru, Novartis Oncology, Florham Park, NJ.
Abstract
PURPOSEThis phase I dose-escalation study investigated the maximum-tolerated dose (MTD), safety, preliminary activity, pharmacokinetics (PK), and pharmacodynamics of BKM120, a potent and highly specific oral pan-Class I PI3K inhibitor. PATIENTS AND METHODSThirty-five patients with advanced solid tumors received daily BKM120 12.5 to 150 mg. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Assessments included archival tumor molecular status, response by Response Evaluation Criteria in Solid Tumors (RECIST), positron emission tomography tracer uptake ([(18)F]fluorodeoxyglucose positron emission tomography [FDG-PET]), fasting plasma C-peptide, and phosphorylated ribosomal protein S6 (pS6) in skin biopsies.ResultsOverall, treatment was well tolerated. Dose-limiting toxicities were grade 2 mood alteration (80 mg), grade 3 epigastralgia, grade 3 rash, grade 2 and grade 3 mood alteration (100 mg), and two grade 4 hyperglycemia (150 mg). The MTD was 100 mg/d. Frequent treatment-related adverse events included rash, hyperglycemia, diarrhea, anorexia, and mood alteration (37% each); nausea (31%); fatigue (26%); pruritus (23%); and mucositis (23%). BKM120 demonstrated rapid absorption, half-life of ∼40 hours, ∼three-fold steady-state accumulation, dose-proportional exposure, and moderate interpatient variability. One patient demonstrated a confirmed partial response (triple-negative breast cancer); seven patients (20%) were on study for ≥ 8 months. BKM120 demonstrated dose-dependent pharmacodynamic effects on [(18)F]FDG-PET, fasting C-peptide, fasting blood glucose, and pS6. No significant trends were seen to correlate tumor molecular alterations with clinical activity. CONCLUSIONThis study demonstrates feasibility and proof-of-concept of class I PI3K inhibition in patients with advanced cancers. BKM120, at the MTD of 100 mg/d, is safe and well tolerated, with a favorable PK profile, clear evidence of target inhibition, and preliminary antitumor activity.
Insulin- and Obesity-Related Variables in Early-Stage Breast Cancer: Correlations and Time Course of Prognostic Associations.
Source
Pamela J. Goodwin, Mount Sinai Hospital and Princess Margaret Hospital, University of Toronto; Kathleen I. Pritchard and Maureen E. Trudeau, Sunnybrook Odette Cancer Centre, University of Toronto; Jarley Koo, St Michael's Hospital, University of Toronto; Nicky Hood, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto; Marguerite Ennis, Applied Statistician, Markham, Ontario; and Sara K. Taylor, British Columbia Cancer Agency, Kelowna, British Columbia, Canada.
Abstract
PURPOSETo investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time. PATIENTS AND METHODSFive hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model. RESULTS: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses. CONCLUSIONBaseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.
Ayurvedic treatments for diabetes mellitus.
Source
Department of Pediatrics, Child and Adolescent Care Centre, 15 Parthasarathypuram, T. Nagar, Chennai, India, 600017.
Abstract
BACKGROUND:
Patients with diabetes frequently use complimentary and alternative medications including Ayurvedic medications and hence it is important to determine their efficacy and safety.
OBJECTIVES:
To assess the effects of Ayurvedic treatments for diabetes mellitus.
SEARCH METHODS:
We searched The Cochrane Library (issue 10, 2011), MEDLINE (until 31 August 2011), EMBASE (until 31 August 2011), AMED (until 14 October 2011), the database of randomised trials from South Asia (until 14 October 2011), the database of the grey literature (OpenSigle, until 14 October 2011) and databases of ongoing trials (until 14 October 2011). In addition we performed hand searches of several journals and reference lists of potentially relevant trials.
SELECTION CRITERIA:
We included randomized trials of at least two months duration of Ayurvedic interventions for diabetes mellitus. Participants of both genders, all ages and any type of diabetes were included irrespective of duration of diabetes, antidiabetic treatment, comorbidity or diabetes related complications.
DATA COLLECTION AND ANALYSIS:
Two authors independently extracted data. Risk of bias of trials was evaluated as indicated in the Cochrane Handbook for Systematic Reviews of Intervention.
MAIN RESULTS:
Results of only a limited number of studies could be combined, in view of different types of interventions and variable quality of data. We found six trials of proprietary herbal mixtures and one of whole system Ayurvedic treatment. These studies enrolled 354 participants ( 172 on treatment, 158 on controls, 24 allocation unknown). The treatment duration ranged from 3 to 6 months. All these studies included adults with type 2 diabetes mellitus.With regard to our primary outcomes, significant reductions in glycosylated haemoglobin A1c (HbA1c), fasting blood sugar (FBS) or both were observed with Diabecon, Inolter and Cogent DB compared to placebo or no additional treatment, while no significant hypoglycaemic response was found with Pancreas tonic and Hyponidd treatment. The study of whole system Ayurvedic treatment did not provide data on HbA1c and FBS values. One study of Pancreas tonic treatment did not detect a significant change in health-related quality of life. The main adverse effects reported were drug hypersensitivity (one study, one patient in the treatment arm); hypoglycaemic episodes (one study, one participant in the treatment arm; none had severe hypoglycaemia) and gastrointestinal side effects in one study (1 of 20 in the intervention group and 0 of 20 participants in the control group). None of the included studies reported any deaths, renal, hematological or liver toxicity.With regard to our secondary outcomes, post prandial blood sugar (PPBS) was lower among participants treated with Diabecon, was unchanged with Hyponidd and was higher in patients treated with Cogent DB. Treatment with Pancreas tonic and Hyponidd did not affect lipid profile significantly, while patients treated with Inolter had significantly higher HDL- and lower LDL-cholesterol as well as lower triglycerides. Cogent DB treated participants also had lower total cholesterol and triglycerides.Studies of treatment with Diabecon reported increased fasting insulin levels; one study of treatment with Diabecon reported higher stimulated insulin levels and fasting C-peptide levels in the treatment group. There was no significant difference in fasting and stimulated C-peptide and insulin levels with Hyponidd, Cogent DB and Pancreas tonic treatment. The study of Inolter did not assess these outcomes.No study reported on or was designed to investigate diabetic complications, death from any cause and economic data.
AUTHORS' CONCLUSIONS:
Although there were significant glucose-lowering effects with the use of some herbal mixtures, due to methodological deficiencies and small sample sizes we are unable to draw any definite conclusions regarding their efficacy. Though no significant adverse events were reported, there is insufficient evidence at present to recommend the use of these interventions in routine clinical practice and further studies are needed.
Effects of Body Temperature Maintenance on Glucose, Insulin, and Corticosterone Responses to Acute Hypoxia in the Neonatal Rat.
Source
1Aurora St. Luke's Medical Center.
Abstract
One of the biggest challenges of premature birth is acute hypoxia. Hypothermia during acute hypoxic periods may be beneficial. We hypothesized that prevention of hypothermia during neonatal hypoxia disrupts glucose homeostasis and places additional metabolic challenges on the neonate. Pups at PD2 and PD8 were exposed to 8% O2 for 3 h, during which they were allowed to either spontaneously cool or were kept isothermic. There was also a time control group that was subjected to normoxia and kept isothermic. Plasma glucose, insulin, C-peptide, corticosterone and catecholamines were measured from samples collected at baseline, 1 h, 2 h, and 3 h. In PD2 rats, hypoxia alone resulted in no change in plasma glucose by 1 h, an increase by 2 h, and a subsequent decrease below baseline values by 3 h. Hypoxia with isothermia in PD2 rats elicited a large increase in plasma insulin at 1 h. In PD8 rats, hypoxia with isothermia resulted in an initial increase in plasma glucose, but by 3 h, glucose had decreased significantly to below baseline levels. Hypoxia with and without isothermia elicited an increase in plasma corticosterone at both ages and an increase in plasma epinephrine in PD8 rats. We conclude that the insulin response to hypoxia in PD8 rats is associated with an increase in glucose similar to an adult; however, insulin responses to hypoxia in PD2 rats were driven by something other than glucose. Prevention of hypothermia during hypoxia further disrupts glucose homeostasis and increases metabolic challenges.
B-type natriuretic peptide (BNP) affects the initial response to intravenous glucose: a randomised placebo-controlled cross-over study in healthy men.
Source
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Abstract
AIMS/HYPOTHESIS:
B-type natriuretic peptide (BNP) is a hormone released from cardiomyocytes in response to cell stretching and elevated in heart failure. Recent observations indicate a distinct connection between chronic heart failure and diabetes mellitus. This study investigated the role of BNP on glucose metabolism.
METHODS:
Ten healthy volunteers (25 ± 1 years; BMI 23 ± 1 kg/m(2); fasting glucose 4.6 ± 0.1 mmol/l) were recruited to a participant-blinded investigator-open placebo-controlled cross-over study, performed at a university medical centre. They were randomly assigned (sequentially numbered opaque sealed envelopes) to receive either placebo or 3 pmol kg(-1) min(-1) BNP-32 intravenously during 4 h on study day 1 or 2. One hour after beginning the BNP/placebo infusion, a 3 h intravenous glucose tolerance test (0.33 g/kg glucose + 0.03 U/kg insulin at 20 min) was performed. Plasma glucose, insulin and C-peptide were frequently measured.
RESULTS:
Ten volunteers per group were analysed. BNP increased the initial glucose distribution volume (13 ± 1% body weight vs 11 ± 1%, p < 0.002), leading to an overall reduction in glucose concentration (p < 0.001), particularly during the initial 20 min of the test (p = 0.001), accompanied by a reduction in the initial C-peptide levels (1.42 ± 0.13 vs 1.62 ± 0.10 nmol/l, p = 0.015). BNP had no impact on beta cell function, insulin clearance or insulin sensitivity and induced no adverse effects.
CONCLUSIONS/INTERPRETATION:
Intravenous administration of BNP increases glucose initial distribution volume and lowers plasma glucose concentrations following a glucose load, without affecting beta cell function or insulin sensitivity. These data support the theory that BNP has no diabetogenic properties, but improves metabolic status in men, and suggest new questions regarding BNP-induced differences in glucose availability and signalling in various organs/tissues.
TRIAL REGISTRATION:
ClinicalTrials.gov: NCT01324739
FUNDING:
The study was funded by Jubilée Fonds of the Austrian National Bank (OeNB-Fonds).
The effects of two bouts of high- and low-volume resistance exercise on glucose tolerance in normoglycemic women.
Source
Exercise Physiology and Biochemistry Laboratory, The Department of Kinesiology, Texas Woman's University in Denton, Denton, Texas.
Abstract
Reed, ME, Ben-Ezra, V, Biggerstaff, KD, and Nichols, DL. The effects of two bouts of high- and low-volume resistance exercise on glucose tolerance in normoglycemic women. J Strength Cond Res 26(1): 251-260, 2012-The purpose of the study was to determine the efficacy of a low-volume, moderate-intensity bout of resistance exercise (RE) on glucose, insulin, and C-peptide responses during an oral glucose tolerance test (OGTT) in untrained women compared with a bout of high-volume RE of the same intensity. Ten women (age 30.1 ± 9.0 years) were assessed for body composition, maximal oxygen uptake, and 1-repetition maximum (1RM) before completing 3 treatments administered in random order: 1 set of 10 REs (RE1), 3 sets of 10 REs (RE3), and no exercise (C). Twenty-four hours after completing each treatment, an OGTT was performed after an overnight fast. Glucose area under the curve response to an OGTT was reduced after both RE1 (900 ± 113 mmol·L·min, p = 0.056) and RE3 (827.9 ± 116.3, p = 0.01) compared with C (960.8 ± 152.7 mmol·L·min). Additionally, fasting glucose was significantly reduced after RE3 (4.48 ± 0.45 vs. 4.90 ± 0.44 mmol·L, p = 0.01). Insulin sensitivity (IS), as determined from the Cederholm IS index, was improved after RE1 (10.8%) and after RE3 (26.1%). The reductions in insulin and C-peptide areas after RE1 and RE3 were not significantly different from those in the C treatment. In conclusion, greater benefits in glucose regulation appear to occur after higher volumes of RE. However, observed reductions in glucose, insulin, C-peptide areas after RE1 suggest that individuals who may not well tolerate high-volume RE protocols may still benefit from low-volume RE at moderate intensity (65% 1RM).
Effect of obesity on declining beta cell function after diagnosis of type 2 diabetes: a possible link suggested by cross-sectional analysis.
Source
Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Abstract
It has been reported that beta cell function progressively declines in patients with type 2 diabetes. The objective of this study was to assess the effect of obesity on declining beta cell function after diagnosis of type 2 diabetes. We conducted a cross-sectional study of 689 consecutive subjects with type 2 diabetes who were admitted to our hospital from 2000 to 2007. Fasting and postprandial serum C-peptide immunoreactivity (CPR) and urinary CPR levels had been measured during admission. The subjects were stratified according to BMI and time since diagnosis. CPR index was calculated as CPR (ng/mL) / plasma glucose (mg/dL) x 100. All CPR measurements were significantly higher in the 263 obese (BMI ≥25) subjects compared to the 426 lean subjects (BMI <25). There was a significant negative correlation between CPR indices and duration of diabetes, suggesting a progressive decline in beta cell function after diagnosis of type 2 diabetes. However, this decline was more apparent in obese subjects (postprandial CPR index 0.059/year) compared to lean subjects (0.025/year). The significant difference in serum CPR indices between the lean and obese subjects was lost in subjects more than 10 years after diagnosis. In conclusion, our observations suggest that beta cell function shows a greater progressive decline in obese subjects than in lean subjects with type 2 diabetes. Treatment of obesity may be an important strategy to preserve beta cell function in patients with type 2 diabetes.
A Human Islet Cell Culture System for High-Throughput Screening.
Source
Broad Institute, Cambridge, MA.
Abstract
A small-molecule inducer of beta-cell proliferation in human islets represents a potential regeneration strategy for treating type 1 diabetes. However, the lack of suitable human beta cell lines makes such a discovery a challenge. Here, we adapted an islet cell culture system to high-throughput screening to identify such small molecules. We prepared microtiter plates containing extracellular matrix from a human bladder carcinoma cell line. Dissociated human islets were seeded onto these plates, cultured for up to 7 days, and assessed for proliferation by simultaneous Ki67 and C-peptide immunofluorescence. Importantly, this environment preserved beta-cell physiological function, as measured by glucose-stimulated insulin secretion. Adenoviral overexpression of cdk-6 and cyclin D(1), known inducers of human beta cell proliferation, was used as a positive control in our assay. This induction was inhibited by cotreatment with rapamycin, an immunosuppressant often used in islet transplantation. We then performed a pilot screen of 1280 compounds, observing some phenotypic effects on cells. This high-throughput human islet cell culture method can be used to assess various aspects of beta-cell biology on a relatively large number of compounds.
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