A Population Kinetic Analysis of Prehepatic Insulin Secretion

Quantification of insulin secretion from beta-cells is important for the understanding of the development of type 2 diabetes (T2D).

OBJECTIVES

The aim of this work is to perform a population kinetic covariate analysis of the prehepatic insulin secretion in T2D in response to an oral glucose tolerance test (OGTT) by combined use of insulin, glucose, and C-peptide (CP) data from different population groups.

METHODS

Data were collected from 149 with normal glucose tolerance (NGT), 29 with impaired glucose tolerance (IGT), and 43 T2D subjects who all underwent an OGTT. A population analysis with nonlinear mixed-effects was performed to identify significant covariates influencing the prehepatic insulin secretion.

RESULTS

Obese subjects have higher basal insulin (PB.0001) and CP level (PB.0001) than subjects with normal weight. Obesity leads to a higher insulin production (PB.0005), secretion (PB.05) from the beta-cell and lower clearance from the plasma (PB.05) than a normal weight subject. Gender, glucose tolerance, and obesity have no effects on the average hepatic insulin extraction during OGTT. The insulin clearance is the same in subjects with various glucose tolerances. Compared to the NGT subjects with normal weight, obesity leads to a 25% increase in insulin production rate, while T2D and IGT reduce the insulin production rate by 62% and 22%, respectively. The T2D has significant impact on the kinetic parameters (PB.05) that control the insulin release, resulting in a delayed and depressed insulin secretion. The differences in insulin concentration between the subject groups are mainly caused by insulin secretion.

CONCLUSION

The study shows that by a population kinetic analysis that simultaneously makes use of plasma insulin and CP data from OGTT it is possible to estimate the prehepatic insulin secretion and liver extraction and identify important population covariates.

Regulation of Bone Mineral Density in Morbidly Obese Women

INTRODUCTION

Body weight influences both bone turnover and body mass index, and a high body mass index is protective against osteoporotic and hip fractures in men and women. There is an inverse relationship between body mass index and osteoclast activity in normal postmenopausal women and an increase in bone resorption following weight loss.

OBJECTIVES

In this review we analyze the most relevant aspects of bone mineral density regulation in morbidly obese women and its evolution after bariatric surgery.

METHODS

We selected the most important studies about bone regulation and their evolution after bariatric surgery.

RESULTS

The main studies are focused on the relationship of vitamin D, insulin growth factor-I, leptin, and adipocytokines on bone metabolism.

CONCLUSION

The protective effect of fat on bone is partly lost after surgery but patients persist with higher bone mass density and are not clearly related with vitamin D, insulin growth factor-I, leptin, and adipocytokines. Lean mass, rather than fat mass, is more strongly related to bone mineral density of the femoral neck in middle-aged, aged, 45 years old, elderly men and women, around 65 years old than fat mass.

Telomere Length Regulation and Reproduction: Current Concepts and Putative Threats To Ovarian Reserve

Ovarian aging is an inevitable process and is the basis of reproductive exhaustion in women. It is also the driving force behind the most dramatic endocrine transition in the female—the menopause. In addition to the oocyte loss that occurs with age, a significant increase in meiotic errors occurs in oocytes as women reach their late 30s and 40s, increasing the risk of embryonic aneuploidy and miscarriage. Despite the magnitude of the impact of ovarian senescence on multiple facets of women’s health, the complex determinants of ovarian aging have not been fully elucidated.

Telomeres consist of repetitive arrays of the nucleotide sequence (5'-TTAGGG-3')n that cap the ends of chromosomes providing stability to the genome. Because they shorten with successive rounds of DNA replication, they are regarded as markers of cell replicative history and senescence; telomere attrition has been postulated to play a role in aging and the development of age-related disease by mediating the onset of cellular senescence and imposing a limit on the proliferative life span of certain cell types. Mounting evidence also suggests that telomeres may represent a marker linking cellular aging, oocyte quality, and reproductive aging. Data supporting a theory of reproductive senescence that involves regulation of telomere homeostasis will be presented in this review. In addition, telomeres acting as targets of reactive oxygen species and other exogenous stresses may represent a putative link between environmental exposures and reproductive outcomes in women. Emerging evidence supporting this theory will also be discussed in the review.

The Clinical Application of Genetic Testing in Type 2 Diabetes

Relation Between Dietary Calcium and Vitamin D and Risk of Diabetes and Cancer: A Review and Perspective

ABSTRACT

The number of people with type 2 diabetes mellitus has been increasing worldwide. In experimental animal studies, calcium and vitamin D have been shown to improve pancreatic b-cell function and peripheral insulin sensitivity and several epidemiologic findings, including our own, have shown that calcium and vitamin D intake may have a preventive effect against type 2 diabetes. Evidence has also accumulated in support of a protective role of calcium and vitamin D against carcinogenesis of several types of cancers. Intriguingly, diabetes has been revealed to be a cancer risk factor in recent years, and we have reported crucial data in regard to this issue based on a longitudinal survey of a middle-aged and older Japanese population. In this brief review article, we attempt to elucidate the fundamental relationship between dietary calcium and vitamin D intake and the risk of diabetes and cancer, and we propose a model to provide new insight into mechanisms of pathogenesis of these lifestyle-related diseases.

Keywords: calcium, vitamin D, type 2 diabetes, cancer, colorectal cancer

Correspondence: Mitsuhiko Noda, Department of Diabetes and Metabolic Medicine, National Center for Global Health and Medicine, 1-2-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. Tel: +81 3 3202 7181; Fax: +81 3 3207 1038; e-mail: mnoda@hosp.ncgm.go.jp

Diabetes Treatment with Insulin Glargine and Risk of Malignancy

Adipotoxicity Revisited: Shifting from Metabolic to Cardiometabolic Risk Profile

REVIEW ARTICLE

Christian H Anderwald^1,2

Affiliations: ¹Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria and ²Mariahilf Community Pharmacy, Arnoldstein, Austria

ABSTRACT

Obesity represents a major challenge to health care systems worldwide. Due to quantitatively and qualitatively unbalanced nutrition, approximately one-half or more of the population in Western societies is overweight or obese. Obese people are more prone to develop specific diseases from the (cardio-) metabolic syndrome; that is, obesity-related diseases, which comprise, among others, type-2 diabetes mellitus, cardiovascular disease, and also cancer.

Thus, more attention is paid to the underlying pathophysiological mechanism of obesity-related diseases (ORD). Whereas Lipotoxicity only refers to the deleterious effects of free fatty acids (FFA), the more novel term Adipotoxicity seeks to describe all harmful actions due to increased fat (a) in the nutrition, (b) in the entire body, (c) on the related hormones and metabolites, and (d) in tissues unrelated to fat storage (muscle and liver).

In conclusion, effective strategies are needed to prevent the obesity pandemic and to develop specific treatment options for patients with ORD.

Keywords: obesity, type-2 diabetes mellitus, free fatty acids, lipids, economic burden

Correspondence: Christian H Anderwald, Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Waehringer Guertel 18-20 A-1090, Vienna, Austria. Tel: +43 1 40400 7249; Fax: +43 1 40400 7790; e-mail: christianheinz.anderwald@meduniwien.ac.at

Trying to Balance Quality: Can We Assume that Improving the Quality of Care Delivery also Improves Quality of Life?

REVIEW ARTICLE


Sheena Mc Hugh^1, Margaret Collins² and Ivan Perry¹

Affiliations: ¹Department of Epidemiology and Public Health, University College Cork, Cork, Ireland and ²University of California Cooperative Extension, Tuolumne County, Sonora, California, USA

ABSTRACT

OBJECTIVE
To examine the measurement of quality of life (QoL) in the evaluation of interventions that aim to improve the quality of care for patients with diabetes.

METHOD
A literature review was conducted using three electronic databases (MEDLINE of the National Library of Medicine, PubMed of the National Centre for Biotechnology Information, and the Cochrane Library) to obtain articles published between 1998 and June 2009. Systematic reviews pertaining to chronic disease management and quality improvement at the professional and organizational level of diabetes care delivery were selected.

RESULTS
Twelve systematic reviews satisfied the inclusion criteria. Although a number of the reviews included studies that reported to measure QoL, on further investigation few of the studies involved accurate measurement of the outcome. The majority of studies purporting to assess the outcome actually measured concepts such as psychological well-being and health status, most often using the SF-36. While most review authors acknowledged the lack of data on patient-reported outcomes, a number of the reviews were ambiguous as to what measures were included and what outcomes were being evaluated.

CONCLUSION
The results of this review suggest that there is still ‘‘infrequent and inappropriate’’ measurement of outcomes such as QoL. Quality improvement interventions and chronic disease management programs often lack a theoretical framework to guide the selection of relevant and useful indicators. Without consistent and accurate measurement, we cannot assess the potential trade-off between quality of care and
QoL.

Keywords: diabetes, chronic disease management, quality in healthcare, quality improvement, quality of life, quality indicators
 
Correspondence: Sheena Mc Hugh, Department of Epidemiology & Public Health, University College Cork, Brookfield Health Sciences Complex, College Road, Cork, Ireland. Tel: +353-21-420-5253; Fax: +353-21-420-1923; e-mail: s.mchugh@ucc.ie

Role for Cell Division Autoantigen 1 in Mediating TGF-β Downstream Signaling and Extracellular Matrix Protein Production in Diabetic Atherosclerosis

REVIEW ARTICLE

Zemin Cao^1, Mark E Cooper^1, Terri J Allen^1, Ban-Hock Toh² and Zhonglin Chai¹

Affiliations: ¹Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia and ²Autoimmunity Laboratory, Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia

ABSTRACT

Atherosclerosis is associated with the development of various cardiovascular diseases, including myocardial infarction and stroke, which represent some of the leading causes of death in the western world. The presence of diabetes is an important risk factor for the development and progression of atherosclerosis. Excess accumulation of extracellular matrix (ECM) proteins in the vasculature is considered to play an important role in these vascular diseases. Cell division autoantigen 1 (CDA1) was identified as a key player in modulating downstream signaling of transforming growth factor-beta (TGF-b) leading to regulation of the production of ECM proteins, sharing anti-proliferative and profibrotic properties with TGF-b. The gene and protein expression levels of CDA1 were elevated in the aortas of diabetic apolipoprotein E knockout mice, accompanied by increased levels of TGF-b, connective tissue growth factor (CTGF), and various ECM proteins. In cultured mouse vascular smooth muscle cells, TGF-b treatment was associated with increased CDA1 expression. Knockdown of CDA1 by siRNA, delivered by retroviral and adenoviral constructs, was associated with reduced TGF-b signaling, shown by attenuated Smad3 phosphorylation and its transcriptional activities on TGF-b stimulation. By contrast, overexpression of CDA1 increased the gene expression of TGF-b, TGF-b receptor type 1, CTGF, and other ECM proteins. It appears that CDA1 plays an important role in mediating TGF-b signaling and ECM proteins production in the vasculature and in particular in diabetes-associated atherosclerosis.

Keywords: Atherosclerosis, diabetes Mellitus, TGF-b, cell division autoantigen 1, extracellular matrix proteins, CTGF

Correspondence: Zemin Cao, Diabetic Complications Division, Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Road Central, Victoria 8004, Australia. Tel:
61 385321231; Fax:
61 385321100; e-mail: zemin.cao@bakeridi.edu.au

Role of Incretin Therapies in the Management of Type 2 Diabetes Mellitus

Recent Diabetes Trials and Their Implications on Clinical Practice

REVIEW ARTICLE


Marcus Campbell^1, Donna Leverone^2, Benjamin Epstein^2,3 and James Taylor⁴

Affiliations: ¹Clinical Pharmacology Services, Tampa, Florida, USA; ²Departments of Pharmacotherapy and Translational Research and Medicine, University of Florida, Gainesville, Florida, USA; ³East Coast Institute for Research, Jacksonville, Florida, USA and ⁴Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida, USA

ABSTRACT

Patients with type 2 diabetes are at increased risk for various microvascular and macrovascular complications. The United Kingdom Prospective Diabetes Study (UKPDS) trial clearly demonstrated that reducing A1C resulted in a significant reduction in microvascular disease in patients with type 2 diabetes. Historically, there has been little evidence to indicate that reductions in A1C also reduce macrovascular events. Recent trials have attempted to answer this question and to address whether more stringent A1C goals would be beneficial in managing patients with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), the Veterans Affairs Diabetes Trial (VADT), and UKPDS follow-up studies all provide some insight into these controversies, although their results are somewhat contradictory. The ADVANCE and VADT trials showed no statistically significant benefit of intensive glucose control on reduction of macrovascular endpoints. In the ACCORD trial, intensive therapy decreased the rate of nonfatal myocardial infarction but increased the rate of death from cardiovascular causes and death from any cause. The UKPDS follow-up study did show significant reductions in some macrovascular and other diabetes-related endpoints, despite loss of glycemic control differences between groups during the follow-up study. This manuscript compares these trials and their clinical implications in managing patients with type 2 diabetes.

Keywords: diabetes, ACCORD, ADVANCE, VADT, UKPDS

Correspondence: James Taylor, Department of Pharmacotherapy and Translational Research, University of Florida, PO Box 100486, Gainesville, FL 32610, USA. Tel: +1 352 273 6239; Fax: +1 352 273 6242; e-mail: jtaylor@cop.ufl.edu

Efficacy of Exenatide Formulations in Glycemic and Weight Control in Patients not Reaching Targets with Oral Agents: Strategies to Improve Cardiometabolic Risk in Type 2 Diabetes Mellitus

REVIEW ARTICLE


Dace L Trence

Affiliation: Diabetes Care Center, University of Washington Medical Center, Seattle, Washington, USA

ABSTRACT

Diabetes mellitus type 2 (T2DM) incidence is exploding worldwide and an approach to treatment, targeting not just hyperglycemia, but also the co-morbid components of weight, blood pressure, and lipids is available through the incretin class of drugs. Exenatide, available as a twice daily injectable, soon to be available as a once weekly injectable, has beneficial effects on glucose, as well as blood pressure and lipids. These benefits are seen when exenatide is used as monotherapy, as well as in combination with sulfonylurea and/or metformin in those patients where target treatment goals for hyperglycemia have not been reached. These benefits appear sustained over at least 2 years’ use. Once weekly exenatide appears to be even more effective than twice daily exenatide, with fewer side effects. More anti-exenatide antibody formation is seen with the once weekly formulation, the significance of which remains unclear. Data on the direct beneficial effects on the cardiovascular system are also accumulating, not just in animal models, but also in limited human studies.

Keywords: exenatide, metformin, sulfonylurea, combination diabetes theraphy, metabolic syndrome

Correspondence: Dace L Trence, Diabetes Care Center, university of Washington Medical Center, 4225 Roosevelt Way NE/ Suite 101, Seattle, WA 98105, USA. Tel: +206-598-4882; Fax: +206-598-4976; e-mail: dtrence@u.washington.edu