The role of incretin-based therapy in the long term optimal management of type 2 diabetes

Dyslipidemia: A Review of Pathophysiology and Lipoprotein Disorders

Stanley K. Zimmerman and James L. Vacek

Affiliation: University of Kansas Hospital and Medical Center, Kansas City, KS, USA

ABSTRACT

Coronary heart disease affects millions of patients around the world, and its prevalence makes understanding the variety of risk factors that contribute to coronary artery disease (CAD) paramount for any clinician. One important risk factor that has been identified is dyslipidemia and the spectrum of lipid disorders that this entails. The relationship between dyslipidemia and CAD is well established, and clinically it is important to understand the basic pathophysiology for disease prevention and treatment. Fats are essential to life and are metabolized and circulated in the body through the lipid transport system. Their storage, regulation, and processing are maintained in a fine balance, but with simple alterations can lead to profound consequences including heart attack, stroke, and peripheral vascular disease. An understanding of basic pathophysiology of lipids, their role in the body, and how disruption in their metabolism manifests into systemic disease is a vital part of caring for the ever increasing number of patients with dyslipidemia. Therapeutic approaches to clinical dyslipidemias are described in a prior review on the topic previously published in the Journal of Clinical Metabolism & Diabetes (April 2011 issue) as a companion to the present article.

Keywords: dyslipidemia, coronary heart disease, lipid transport system, lipoproteins, coronary artery disease, lipoprotein disorders

Correspondence: James Vacek, Mid America Cardiology, University of Kansas Hospital and Medical Center, 39th and Rainbow Blvd Kansas City, KS 66061, USA. Tel:
1 913 5889600; e-mail: jlvacek@mac.md

Current Questions on Proteinuria and Albuminuria

Anna V Oláh^1*, Bertalan Fodor² and János Mátyus³

Affiliations: ¹Department of Laboratory Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; ²Faculty of Health, University of Miskolc, Miskolc, Hungary; ³Department of Medicine, University of Miskolc, Miskolc, Hungary

ABSTRACT

According to current clinical trials, albumin excretion not only indicates kidney damage but it is also a risk factor for the progression of kidney disease and future cardiovascular events. While proteinuria is considered as a marker of kidney function, microalbuminuria, first of all, indicates cardiovascular risk. Sensitivity of the laboratory tests is method dependent, some of the previously used tests do not meet the clinical requirements, and the error of urine collection makes the results misleading. To avoid these preanalytical problems, recent guidelines suggest the calculation of albumin and creatinine ratio (ACR) and protein and creatinine ratio (PCR) from the values measured from the first morning urine, as these ratios correlate well with the corresponding results of properly collected 24-hour urine. For the clinical diagnosis of albuminuria, the sensitive immunoturbidimetric assays are recommended. Because of poor sensitivity, urinary albumin dipsticks are not recommended for the measurement of albuminuria. For the diagnosis of proteinuria, wide-range urinary protein reagents are available with high sensitivity. The traceability of calibrator to a reference material is a critical requirement. For these reasons, proteinuria and albuminuria of a patient should be monitored in the same laboratory, using a fixed method and cut-off value. Protein, albumin, and creatinine should be measured from the same urine sample, practically using the same analyzer. The ACR values should be reported together with gender-dependent reference ranges. As the PCR range is wider, the same cut-off value can be used for men and women. We discuss the interpretation and diagnostic algorithm of proteinuria and albuminuria.

Keywords: ACR, albuminuria, cardiovascular disease, chronic kidney disease, proteinuria, protein/creatinine

Correspondence: Anna V Oláh, Department of Laboratory Medicine, Medical and Health Science Center, University of Debrecen, Nagyerdei krt. 98, Debrecen, POB 70, H-4032, Hungary; e-mail: olaha@dote.hu

Oedema Associated With Improved Glycaemic Control in a 15-Year-Old Nigerian Girl With Type 1 Diabetes Mellitus Complicated by Ketoacidosis

Alphonsus N. Onyiriuka and Frances A. Ehirim

Affiliation: Department of Child Health, University of Benin Teaching Hospital, Benin, Nigeria

ABSTRACT

In this article, we reported a recent case of a 15-year-old grossly underweight ( weighed 29 kg) Nigerian girl diagnosed of type 1 diabetes mellitus 4 years ago and who defaulted from follow-up but presented with diabetic ketoacidosis. Her glycaemic control was poor because of poor compliance. Following treatment with insulin infusion, she developed facial swelling on the fifth day of admission, followed by pitting ankle and pretibial oedema two days later. The natural history of insulin-induced oedema was observed in this patient because the oedema resolved 7 days later without any specific therapy, such as administration of diuretics. The aim of this article was to review existing medical literature on the subject of insulin-induced oedema and raise the awareness of clinicians of the occurrence of oedema as an uncommon complication of insulin therapy. In conclusion, insulin-induced oedema should be considered in the differential diagnosis of oedema in children and adolescents with type 1 diabetes mellitus.

Keywords: Insulin therapy, oedema, childhood diabetes mellitus, Nigeria

Correspondence: Dr A.N. Onyiriuka, Department of Child Health, University of Benin Teaching Hospital, PMB 1111, Benin CITY, Nigeria. Tel: +234 803 252 9437; e-mail: alpndiony@yahoo.com

The Role of IRS-1 Serine Phosphorylation in Insulin Resistance induced by Stress and Nutrient Signaling

Wenshuo Zhang and Xiao Jian Sun

Affiliation: Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Chicago, Chicago, IL, USA

ABSTRACT

Obesity and overeating are linked to insulin resistance and type 2 diabetes, and caloric restriction is known to alleviate insulin resistance and improve the outcome of diabetes. Insulin resistance is characterized by attenuation in the efficacy of insulin to promote nutrient clearance and partitioning, and is worsened by elevated levels of inflammatory hormones, hyperglycemia, hyperinsulinemia, and hyperaminoacidemia, all of which may occur secondary to chronic nutrient excess. These agents induce a resistant state through stress and nutrient signaling pathways that upregulate the activity of serine kinases, which in turn negatively feed back on insulin signaling molecules. The insulin receptor substrate (IRS) proteins are key upstream insulin signaling mediators which, when serine phosphorylated, fail to effectively transmit the insulin signal downstream, resulting in insulin resistance. In this review, we focus on the role of overnutrition-induced IRS-1 serine phosphorylation on specific sites within the IRS-1 molecule that have been demonstrated to be critical regulatory targets with respect to insulin signaling. The means by which upregulation of stress- and nutrient-associated kinases, specifically Erk and mTOR/p70S6K, lead to serine phosphorylation of IRS-1 and insulin resistance are discussed.

Keywords: insulin resistance, obesity, insulin receptor substrate (IRS), MAPK, mTOR, p70S6K

Correspondence: Xiao Jian Sun, Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Chicago, Chicago, IL 60540, USA. e-mail: xsun@medicine.bsd.uchicago.edu

Dyslipidemia: A Review of Pathophysiology and Lipoprotein Disorders

Stanley K. Zimmerman and James L. Vacek

Affiliation: University of Kansas Hospital and Medical Center, Kansas City, KS, USA

ABSTRACT

Coronary heart disease affects millions of patients around the world, and its prevalence makes understanding the variety of risk factors that contribute to coronary artery disease (CAD) paramount for any clinician. One important risk factor that has been identified is dyslipidemia and the spectrum of lipid disorders that this entails. The relationship between dyslipidemia and CAD is well established, and clinically it is important to understand the basic pathophysiology for disease prevention and treatment. Fats are essential to life and are metabolized and circulated in the body through the lipid transport system. Their storage, regulation, and processing are maintained in a fine balance, but with simple alterations can lead to profound consequences including heart attack, stroke, and peripheral vascular disease. An understanding of basic pathophysiology of lipids, their role in the body, and how disruption in their metabolism manifests into systemic disease is a vital part of caring for the ever increasing number of patients with dyslipidemia. Therapeutic approaches to clinical dyslipidemias are described in a prior review on the topic previously published in the Journal of Clinical Metabolism & Diabetes (April 2011 issue) as a companion to the present article.

Keywords: dyslipidemia, coronary heart disease, lipid transport system, lipoproteins, coronary artery disease, lipoprotein disorders

Correspondence: James Vacek, Mid America Cardiology, University of Kansas Hospital and Medical Center, 39th and Rainbow Blvd Kansas City, KS 66061, USA. Tel: +1 913 5889600; e-mail: jlvacek@mac.md

Thyroid Autoimmunity in Subjects with Type 1 Diabetes Mellitus: An Analysis of Prevalence Within a Defined Geographical Area in Sicily, Italy

ABSTRACT

BACKGROUND

Thyroid autoimmunity is the most prevalent immunological process affecting subjects with type 1 diabetes. Aim of this work was to investigate thyroid autoimmunity in a large cohort of type 1 diabetic subjects all coming from a defined geographical area.

METHODS

Data were analyzed from 374 patients who were treated in a diabetes center in western Sicily (Italy), over a 2.5 year period. TPO-Ab, TSH, FT3, and FT4 were measured and documented at least once in all these patients.

RESULTS

During the period of the survey TPO-Ab were present in 108 patients, resulting in an overall prevalence of 28.8%; the female-to-male ratio was > 2:1. TPO-Ab+ patients showed an age at diabetes onset significantly higher. The thyroid status of most of these patients was euthyroidism (54 subjects) but overt hypothyroidism (38 subjects), subclinical hypothyroidism (13 subjects), and hyperthyroidism (three subjects) were also present. Subjects with overt hypothyroidism were significantly older than others and showed an age at diabetes diagnosis higher than euthyroid subjects.

CONCLUSIONS

Our data confirm the strong association between thyroid autoimmunity and type 1 diabetes in a Sicilian population. Therefore, in type 1 diabetic patients, an active search for the presence of autoimmune thyroiditis is warranted, particularly in female subjects.

Podocyte Biomarkers in Urine: Relevance and Potential

Akihiro Fukuda and Roger C. Wiggins

Affiliation: Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA

Correspondence: Akihiro Fukuda, Department of Internal Medicine, Division of Nephrology, University of Michigan, 1562 MSRB II. 1150 W Medical Center Drive, Ann Arbor, MI 48109-0600, USA. Tel: (734) 936-1904; Fax: (734) 763-0982; e-mail: mrgiants@fc.miyazaki-u.ac.jp

ABSTRACT

Proteinuria and/or albuminuria are widely used for noninvasive assessment of kidney diseases. However, proteinuria is a nonspecific indicator of many forms of kidney injury, systemic disease, and physiologic alteration in glomerular filtration of proteins. This includes diabetic nephropathy and causes of proteinuria that progress to end-stage kidney disease (ESKD) and those that do not. Therefore proteinuria per se is not considered to be sufficiently precise an endpoint to serve either as a diagnostic tool for specific diseases of the kidney or as a surrogate for ESKD in clinical trials, although within a defined disease setting proteinuria is a powerful monitoring tool. Progression of glomerular diseases is the mechanism by which cumulative glomerular injury results in progressive loss of kidney structure and function eventually causing ESKD. Several lines of evidence strongly suggest that a major cause of glomerulosclerosis is podocyte depletion from glomeruli. Since podocytes are resident on the outer surface of the glomerular basement membrane, when they or their products detach they can be detected in urine. This potentially provides a noninvasive mechanism for monitoring podocyte well-being and raises the possibility that biomarkers of podocyte injury, stress, or loss could be used in combination with proteinuria to more reliably detect and monitor progression and response to treatment. Several potential urine podocyte biomarkers have been described including podocytes themselves and fragments of podocytes, podocyte proteins and mRNAs, and exosomes. Here we review recent urine podocyte biomarkers that could potentially complement proteinuria for monitoring the progression process in the clinic.

The Cardiometabolic Syndrome and Risk of Mortality From Cardiovascular Diseases and All Causes Among African Americans and White Americans

Longjian Liu¹, Zuolu Liu², Marshal Ma³, Fuzhong Xue⁴ and Eliot Sorel⁵

Affiliations: ¹Department of Epidemiology and Biostatistics, Drexel University School of Public Health, Philadelphia, Pennsylvania, USA; ²Temple University School of Medicine, Philadelphia, Pennsylvania, USA; ³Bureau of Epidemiology, Pennsylvania Department of Health, Harrisburg, Pennsylvania, USA; ⁴Department of Epidemiology and Biostatistics, Shandong University School of Public Health, Jinan, Shandong Province, China and ⁵The George Washington University School of Medicine and Health Sciences, and School of Public Health and Health Services, Washington, DC, USA

Correspondence: Longjian Liu, MD, PhD, MSc, FAHA, Associate Professor, Department of Epidemiology and Biostatistics, Drexel University School of Public Health, Philadelphia, PA 19102, USA. Tel: +215 762 1370; Fax: 215 762 1174; e-mail: Longjian.Liu@drexel.edu

ABSTRACT

AIM

Studies using representative national data to prospectively examine associations between cardiometabolic syndrome (CMS) and mortality risk from cardiovascular diseases (CVD) and all causes by race/ethnicity are scarce. We tested the association using the Third National Health and Nutrition Examination Survey Linked Mortality File (1988–2006).

METHODS

CMS is defined using criteria from the National Cholesterol Education Program, with minor modifications based on criteria from the American Heart Association. Associations between CMS and mortality risk in those aged ≥35 years old were examined prospectively using Cox proportional hazard regression models.

RESULTS

The results indicate that almost one third of Americans aged ≥35 years have CMS. There were significant differences in prevalence of CMS components between African American and White participants. Multivariable-adjusted hazard ratios (95% CI) of CMS for CVD and all cause mortality were 1.34 (1.10–1.64), and 1.36 (1.21–1.54) in African Americans, and 1.31 (1.17–1.46) and 1.22 (1.13–1.31) in Whites. The CMS-mortality associations were greatly reduced after adjustment for inflammatory biomarkers.

CONCLUSIONS

CMS significantly predicts CVD and all cause mortality. The high prevalence of CMS poses a serious health problem in the United States. Specific attention should be paid to the significant race/ethnicity differences in CMS components rates and the effects of inflammatory disorders on CMS-mortality association when designing programs for prevention and treatment of the syndrome.

Clinical Implications of Visfatin/PBEF/Nampt for Development of Vascular Inflammation and Atherosclerosis

Concepción Peiró, Tania Romacho, and Carlos F. Sánchez-Ferrer

Affiliation: Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain

Correspondence: Concepción Peiró, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain. Tel: +34 914972409; Fax: +34 914975353 e-mail: concha.peiro@uam.es

ABSTRACT

In the last years, the adipose tissue has been acknowledged as an endocrine organ that releases a heterogeneous series of compounds, the so-called adipokines. In 2005, visfatin was first identified as a new adipokine with insulin-mimetic properties, identical to the pre-B cell colony-enhancing factor (PBEF) and exhibiting intrinsic nicotinamide phosphoribosyltransferase (Nampt) enzymatic activity. For this reason, this adipocytokine is currently termed visfatin/PBEF/Nampt. The circulating levels of visfatin/PBEF/Nampt are elevated in metabolic conditions, such as obesity and type 2 diabetes, and although this observation is subject to controversy, they positively correlate with markers of systemic inflammation. In the context of cardiovascular diseases, visfatin/PBEF/Nampt is emerging as a new clinical marker of atherosclerosis, endothelial dysfunction, and vascular damage with a potential prognostic value. A growing bulk of evidence further unveils that visfatin/PBEF/Nampt can not only be a clinical marker, but also an active player in promoting vascular inflammation and atherosclerosis. Hence, through its actions on cytokine and chemokine secretion, macrophage survival, leukocyte recruitment by endothelial cells, vascular smooth muscle inflammation, and plaque destabilization, visfatin/PBEF/Nampt arises as an active player in plaque development and progression. Further in depth research is required to understand the mechanisms mediating the cellular actions of this adipocytokine and to identify the factors that regulate its cellular synthesis and release in different clinical situations. Such knowledge will help determine whether visfatin/PBEF/Nampt can represent a valuable therapeutical target in the context of cardio-metabolic diseases.

Incretin-based Therapies: An Update from Literature

Type 2 diabetes represents a chronic metabolic disease characterised by insulin-resistance and a progressive decline of pancreatic β-cell glucose-mediated insulin secretion. Beyond traditional therapeutic approaches, which are directed either to improve β-cell dysfunction, or to enhance insulin sensitivity, a relatively new concept of treatment for type 2 diabetes is based on the effects of several intestinal hormones, called incretins, which are normally secreted after a meal and contribute to glucose homeostasis by enhancing insulin secretion and inhibiting glucagon release in pancreatic islets in a glucose-dependent manner. Glucagon-like peptide-1 (GLP-1) is the incretin hormone that mainly enhances glucose-dependent insulin secretion and inhibits glucagon release. The resulting “incretin-based therapies”, based either on the development of mimetics of the GLP-1, or on the inhibition of the incretins degrading enzyme dipeptidyl peptidase 4 (DPP-4), have been reported to improve glycemic control with minimal risk of hypoglycemia in type 2 diabetic patients. Incretin-based therapy can exert several beneficial effects on blood pressure, myocardial function, dyslipidemia and, limited to GLP-1 analogues, body weight. Furthermore, in rodent models of diabetes, but not yet in humans, both GLP-1 receptor agonists and DPP-4 inhibitors have been demonstrated to improve pancreatic islets mass and preserve β-cell function. Along with a safety profile similar to other anti-diabetic agents, these glycemic and extraglycemic effects of incretin-based therapies make them promising therapeutic options in order to reduce the burden of cardiovascular risk, which still represents the major cause of mortality in type 2 diabetic patients.

Best Practice to Manage Patients with Type 2 Diabetes with an HbA1c Between 6.5 and 7.5

The majority of patients with type 2 diabetes do not reach the treatment goals with metformin therapy during the progress of the disease. Therefore, an escalation of therapeutic efforts is required as metabolic control deteriorates. Metformin is the first-line drug due to its efficacy, its effect on insulin resistance, ist weight neutrality, its pharmacological profile, and the lack of risk for causing hypoglycemia. Following this initial pharmacological monotherapy step, the escalation of antidiabetic treatment has many options for second-line combinations. These options are discussed in this manuscript. As a basis for this manuscript besides stating national and international evidence-based guidelines a literature search in PubMed, Scopus, and Embase was performed to retrieve preclinical and prospective randomized controlled clinical trial data of the antidiabetic agents. On the basis of these data, a comparison of the antidiabetic treatment combinations is made.

A Population Kinetic Analysis of Prehepatic Insulin Secretion

Regulation of Bone Mineral Density in Morbidly Obese Women

Vagal Nerve Transection During Pouch Formation in Laparoscopic Roux-Y-Gastric Bypass for Technical Simplification

Laparoscopic Roux-Y gastric bypass is one of the most often performed procedures to treat morbid obesity. During the procedure, the vagal nerve is tempted to be preserved by most surgeons due to the fear of postoperative side effects such as dumping, diarrhea, and abdominal pain. To keep postoperative morbidity and mortality low it is mandatory to simplify the operative procedure and to avoid leakage at the anastomosis. Division of the minor omentum including the anterior branch of the vagal nerve allows a better view to create the small gastric pouch in primary bypass procedures. In revisional surgery, an anastomosis close to the esophagus including total vagotomy may be necessary to allow an uncomplicated postoperative course. So far the available data does not report significant differences after gastric bypass with and without vagotomy, respectively.

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

Micro- and Macrovascular Risk and Complications In T2DM Males With Obstructive Sleep Apnea

BACKGROUND

Obstructive sleep apnea syndrome (OSAS) is a comorbidity of obesity. OSAS is also an independent risk factor for type 2 diabetes (T2DM). OSAS promotes incident major adverse cardiovascular events (MACE). The prevalence of OSAS and its association with MACE are poorly documented in T2DM, a high-risk population.

METHODS

We analyzed 580 consecutive male T2DM outpatients in whom OSAS was diagnosed through combined evaluation, including (hetero)anamnesis, Epworth's Sleepiness Scale (ESS), overnight oximetry, and confirmed by polysomnography. OSAS (+) (n=66) were compared to OSAS (–) (n=514) regarding cardiovascular (CV) risk factors, microvascular complications, MACE, and UKPDS 10-year absolute CVD risk.

RESULTS

Mean (1 SD) age was 63 (11) years, diabetes duration 13 (9) years. Metabolic syndrome (MetS) prevalence was 77%, and HbA 7.5 (1.5)%. OSAS prevalence was 11.4%. There were no differences in age, diabetes duration, smoking, blood pressure (BP), and lipids (except for triglycerides) between OSAS (+) and (–). There were significant differences in the ESS score, BMI, waist, relative/absolute fat, skeletal muscle, conicity index, and visceral fat, all significantly higher in OSAS (+). Micro- and macrovascular complication prevalences were high, though not significantly different, in both groups, except for stroke prevalence, which was doubled in OSAS (+): 15 vs 7%; P=.05). Fasting triglycerides and cystatin-C levels were significantly higher in OSAS (+), the increase in the latter being unrelated to differences in eGFR between groups. UKPDS Risk Engine input variables and predicted risk were all similar in both groups, with a 10-year risk for CAD 20% and 22%, respectively in OSAS (–) and OSAS (+) patients (NS).

CONCLUSIONS

OSAS is frequent in male T2DM patients who exhibit a high-risk cardiometabolic phenotype characterized by severe MetS score and prevalence, central fat accretion, insulin resistance, hypertriglyceridemia, and raised cystatin-C. The data indicate an association between OSAS and stroke prevalence. Using the T2DM-specific UKPDS Risk Engine, absolute 10-year CVD risk estimates were elevated, though not significantly different, between OSAS subgroups in primary CV prevention.

Can We Delay or Even Reverse Diabetic Complications By Islet Transplantation?

Treatment of diabetes is of crucial importance not only for glycemic control but also for the prevention of complications that causes irreversible damage to peripheral nerves, heart, kidney, and eyes. Despite a major effort to obtain prolonged metabolic control, diabetes complication can only be delayed in time. In a recent publication we investigated the effect of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes (1). We reported that islet transplantation induced an amelioration of impaired nociceptive threshold and normalization of nerve conduction velocity in diabetic rats. Cardiomyocyte loss was also reduced by islet transplantation and the observed mild kidney damage of diabetic rats was prevented. We concluded that transplantation of pancreatic islets, besides controlling glycemia, induced regression of neuropathy and prevented cardiovascular alterations, which was always there supporting the potential of islet transplantation. In this review we compare our recently published data with previous reports on prevention and regression of diabetic neuropathy, cardiovascular disease, nephropathy, and retinopathy with a particular attention to those on animal models of diabetes. In details, the potential of islet transplantation in inducing the regression of diabetic complications is discussed.

Sagittal Abdominal Diameter and Waist Circumference as Markers of Early Organ Damage in Patients With Type 2 Diabetes

INTRODUCTION AND OBJECTIVES

In a cohort of 465 patients with type 2 diabetes aged 55–66 years, the association between the anthropometric measures, waist circumference (WC) and sagittal abdominal diameter (SAD) versus subclinical cardiovascular organ damage by measuring pulse wave velocity (PWV) and left ventricular mass index (LVMI), was studied.

METHODS

Blood pressure, weight, height, and WC were measured within primary care. The SAD was measured by using standardized caliper equipment. Blood samples were taken for analysis of HbA1c and serum lipids. The LVMI was measured by M-mode echocardiography. Aortic PWV was measured by applanation tonometry (Sphygmocor) over the carotid and femoral arteries. The baseline characteristics were compared with data from a control group with nondiabetic patients that were randomly recruited from the general population.

RESULTS

The diabetic cohort was more obese than the age-matched controls and there were significant correlations between aortic PWV and WC (r=0.23; p<.01) and SAD (r=0.25; p<.01) in the diabetic group. The LVMI was also correlated to WC (r=0.26; p<.01) and SAD (r=0.25; p<.01). When analyzed in a multiple regression model, SAD and WC were both associated with PWV and LVMI, independently of age, sex, systolic blood pressure, serum lipids, and HbA1c.

CONCLUSION

Patients with type 2 diabetes were more obese than the nondiabetic controls and both measurements of abdominal obesity, WC or SAD, were associated with markers of early cardiovascular organ damage.

Treatment of Dyslipidemia

A large body of research and clinical outcomes analysis has demonstrated the increased risk of coronary heart disease in patients with dyslipidemia and hyperlipidemia and the effectiveness of targeted intervention. In this article we review the management options for this disease process. The recommended treatment approach starts with lifestyle modifications and suggests primary and secondary medication options for patients who require pharmacologic intervention.

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

Best Practice to Manage Patients with Type 2 Diabetes with an HbA1c Between 6.5 and 7.5

The majority of patients with type 2 diabetes do not reach the treatment goals with metformin therapy during the progress of the disease. Therefore, an escalation of therapeutic efforts is required as metabolic control deteriorates. Metformin is the first-line drug due to its efficacy, its effect on insulin resistance, ist weight neutrality, its pharmacological profile, and the lack of risk for causing hypoglycemia. Following this initial pharmacological monotherapy step, the escalation of antidiabetic treatment has many options for second-line combinations. These options are discussed in this manuscript. As a basis for this manuscript besides stating national and international evidence-based guidelines a literature search in PubMed, Scopus, and Embase was performed to retrieve preclinical and prospective randomized controlled clinical trial data of the antidiabetic agents. On the basis of these data, a comparison of the antidiabetic treatment combinations is made.