Dysregulated adipokines in the pathogenesis of type 2 diabetes and vascular disease

Obesity is commonly associated with type 2 diabetes and vascular disease. Changes in body composition in the obese state lead to a dysregulation of secretion of adipocyte-secreted hormones known as adipokines. Adipokines such as leptin and adiponectin are known to be involved in many physiological and pathological processes. Current knowledge suggests that adipokines provide potential therapeutic targets against type 2 diabetes and vascular disease.

Patients with early age-related macular degeneration exhibit signs of macro- and micro-vascular disease and abnormal blood glutathione levels

Background: This pilot study aimed to investigate systemic and retinal vascular function and their relationship to circulatory markers of cardiovascular risk in early age-related macular degeneration (AMD) patients without any already diagnosed systemic vascular pathologies. Methods: Fourteen patients diagnosed with early AMD and 14 age- and gender-matched healthy controls underwent blood pressure, carotid intima-media thickness (C-IMT) and peripheral arterial stiffness measurements. Retinal vascular reactivity was assessed by means of dynamic retinal vessel analysis (DVA) using a modified protocol. Blood analyses were conducted for glutathione levels and plasma levels of total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Results: The AMD patients showed significantly greater C-IMT (p = 0.029) and augmentation index (AIx) (p = 0.042) than the age-matched controls. In addition, they demonstrated a shallower retinal arterial dilation slope (Slope AD) (p = 0.005) and a longer retinal venous reaction time (RT) to flickering light (p = 0.026). Blood analyses also revealed that AMD patients exhibited higher oxidized glutathione (GSSG) (p = 0.024), lower redox index (p = 0.043) and higher LDL-C (p = 0.033) levels than the controls. Venous RT parameter correlated positively with blood GSSG levels (r = 0.58, p = 0.038) in AMD subjects, but not in the controls (p > 0.05). Conclusions: Patients diagnosed with early AMD exhibit signs of systemic and retinal vascular alterations that correlated with known risk markers for future cardiovascular morbidity. © 2013 Springer-Verlag Berlin Heidelberg.

Abnormal retinal vascular function and lipid levels in a sample of healthy UK South Asians

Background/aims To investigate ethnic differences in retinal vascular function and their relationship to traditional risk indicators for cardiovascular disease (CVD). Methods A total of 90 normoglycaemic subjects (45 South Asian (SA) and 45 age- and gender-matched white Europeans (WEs)) were recruited for the present study. Retinal vessel reactivity to flickering light was assessed by means of the dynamic retinal vessel analyser according to a modified protocol. Fasting plasma glucose, triglycerides (TG), total, LDL and HDL cholesterol were also measured in all individuals. Results SA individuals showed higher fasting triglyceride (p=0.001) and lower HDL levels (p=0.007), leading to a higher TG:HDL-C ratio (p=0.001) than age-matched WE subjects. Additionally, in SAs, the retinal arterial reaction time in response to flicker stimulation was significantly longer in the last flicker cycle than in the WEs (p=0.039), and this change correlated positively with measured plasma TG levels (r=0.60; p=0.01). No such relationship was observed in the WEs (p>0.05). Conclusion Even in the absence of overt vascular disease, in otherwise healthy SAs there are potential signs of retinal vascular function impairment that correlates with established plasma markers for CVD risk.

Intermittent fasting:a dietary intervention for prevention of diabetes and cardiovascular disease?

Intermittent fasting, in which individuals fast on consecutive or alternate days, has been reported to facilitate weight loss and improve cardiovascular risk. This review evaluates the various approaches to intermittent fasting and examines the advantages and limitations for use of this approach in the treatment of obesity and type 2 diabetes. © The Author(s) 2013.

Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology and endothelial dysfunction

OBJECTIVE: To investigate laboratory evidence of abnormal angiogenesis, hemorheologic factors, endothelial damage/dysfunction, and age-related macular degeneration (ARMD). DESIGN: Comparative cross-sectional study. PARTICIPANTS: We studied 78 subjects (26 men and 52 women; mean age 74 years; standard deviation [SD] 9.0) with ARMD attending a specialist referral clinic. Subjects were compared with 25 healthy controls (mean age, 71 years; SD, 11). INTERVENTION AND OUTCOME MEASURES: Levels of vascular endothelial growth factor (VEGF, an index of angiogenesis), hemorheologic factors (plasma viscosity, hematocrit, white cell count, hemoglobin, platelets), fibrinogen (an index of rheology and hemostasis), and von Willebrand factor (a marker of endothelial dysfunction) were measured. RESULTS: Median plasma VEGF (225 vs. 195 pg/ml, P = 0.019) and mean von Willebrand factor (124 vs. 99 IU/dl, P = 0.0004) were greater in ARMD subjects than the controls. Mean plasma fibrinogen and plasma viscosity levels were also higher in the subjects (both P < 0.0001). There were no significant differences in other indices between cases and controls. When "dry" (drusen, atrophy, n = 28) and "exudative" (n = 50) ARMD subjects were compared, there was no significant differences in VEGF, fibrinogen, viscosity, or von Willebrand factor levels. There were no significant correlations between the measured parameters. Stepwise multiple regression analysis did not demonstrate any significant clinical predictors (age, gender, smoking, body mass index, history of vascular disease, or hypertension) for plasma VEGF or fibrinogen levels, although smoking status was a predictor of plasma von Willebrand factor levels (P < 0.05). CONCLUSIONS: This study suggests an association between markers of angiogenesis (VEGF), hemorheologic factors, hemostasis, endothelial dysfunction, and ARMD. The interaction between abnormal angiogenesis and the components of Virchow's triad for thrombogenesis may in part contribute to the pathogenesis of ARMD.

What risk factors are associated with Alzheimer's disease?

A large number of risk factors have been associated with Alzheimer’s disease (AD). This article discusses the validity of the major risk factors that have been identified including age, genetics, exposure to aluminium, head injury, malnutrition and diet, mitochondrial dysfunction, vascular disease, immune system dysfunction, and infection. Rare forms of early-onset familial AD (FAD) are strongly linked to the presence of specific gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factors associated with diet, the immune system, mitochondrial function, and infection may all be involved. Life-style changes that may reduce the effect of these risk factors and therefore, the risk of AD are discussed.

Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries

Background: Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution. Methods: The localisation of VEGFs A–C and their receptors (VEGFRs 1–3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting. Results: Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominately localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens. Conclusion: This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A–C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications.

Risk factors for Alzheimer's disease

A large number of possible risk factors have been associated with Alzheimer'sdisease (AD).This chapter discusses the validity of the major risk factors that have been identifiedincluding age, genetics, exposure to aluminum, head injury, malnutrition and diet,mitochondrial dysfunction, vascular disease, immune system dysfunction, and infectionand proposes a hypothesis to explain how these various risk factors may cause ADpathology.Rare forms of early-onset familial AD (FAD) are strongly linked to the presence ofspecific gene mutations, viz. mutations in amyloid precursor protein (APP) andpresenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is amultifactorial disorder in which age-related changes, genetic risk factors, such as allelicvariation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factorsassociated with diet, immune system, mitochondrial function, and infection may all beinvolved.These risk factors interact to increase the rate of normal aging (=allostatic load')which over a lifetime results in degeneration of neurons and blood vessels and as aconsequence, the formation of abnormally aggregated =reactive' proteins such as ß-amyloid (Aß) and tau leading to the development of senile plaques (SP) andneurofibrillary tangles (NFT) respectively. Life-style changes that may reduce theallostatic load and therefore, the risk of dementia are discussed.

Dietary enrichment with almond (Prunus amygdalis) supplementation: effects on CVD risk biomarkers

Epidemiological evidence suggests that diets rich in fruits, vegetables and pulses reduce the risk of CVD. The Physicians Health Study has demonstrated reduction of CHD death with regular nut consumption1. One major modifiable risk factor for CHD is an unhealthy diet. Thus, an almondenrichment study has been undertaken to examine the benefit of almonds (Prunus amygdalis) in healthy individuals either with or without significant risk of vascular disease. Almonds contain various macronutrients (low SFA content, absence of cholesterol and high MUFA content) and micronutrients, including vitamin E, polyphenols and arginine, which afford vascular benefit. The effects of almond consumption (25 g/d for 4 weeks followed by 50 g/d for 4 weeks) were evaluated in three non-smoking subject groups: healthy male volunteers between the ages of 18 and 35 years (n 15); men at risk of heart disease between the ages of 18 and 35 years (n 12); mature men and women >50 years of age (n 18). A fourth control group (n 14) were followed over 8 weeks without dietary almond enrichment as a treatment control. None of the subjects withdrew from the study and 90% completed the study. The interim results of the study showed that in the three active groups there was little evidence for a change in total cholesterol, LDL-cholesterol or HDL-cholesterol. In the mature group there was a trend towards increasing HDL-cholesterol. The mature and ‘at-risk’ groups also showed a significant changes in systolic blood pressure (P<0.05) during almond consumption. The healthy group showed a decrease in diastolic blood pressure (P<0.05). The ‘at-risk’ group showed a significant increase (P<0.05) in flowmediated dilation after 8 weeks of almond consumption. Data analysis is ongoing, with completion of the study in November 2007. The beneficial effects of almond consumption on flow-mediated dilation and blood pressure may be attributed to the high content in almonds of arginine, which serves as a precursor to the vasodilatory molecule, NO.

What are the practical implications for treating diabetes in light of recent evidence? Updated recommendations from the Global Partnership for Effective Diabetes Management

The Global Partnership for Effective Diabetes Management was established in 2004 to provide practical guidance to improving glycaemic control for people with type 2 diabetes. Those recommendations have been updated to take account of recent trials assessing the effects of intensive glucose control. We continue to emphasis the importance of early and sustained glycaemic control, aiming for HbA( 1c) 6.5-7% wherever safe and appropriate. Individualisation of targets and the management process is strongly encouraged to accommodate patient circumstances and to avoid hypoglycaemia. Prompt introduction of combinations of agents is suggested when monotherapy is inadequate.Treatments will preferably address the underlying pathophysiology of type 2 diabetes and integrate within a wider programme of care which also aims to reduce modifiable cardiovascular risk factors and better equip patients in the self-management of their condition.

Type 2 diabetes:assessing the relative risks and benefits of glucose-lowering medications

The selection of appropriate pharmacologic therapy for any disease requires a careful assessment of benefit and risk. In the case of type 2 diabetes, this decision typically balances the benefits accrued from improved glycemic control with the risks inherent in glucose-lowering medications. This review is intended to assist therapeutic decision-making by carefully assessing the potential benefit from improved metabolic control relative to the potential risks of a wide array of currently prescribed glucose-lowering agents. Wherever possible, risks and benefits have been expressed in terms of absolute rates (events per 1000 patient-years) to facilitate cross-study comparisons. The review incorporates data from new studies (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation, Action to Control Cardiovascular Risk in Diabetes, and the Veterans Affairs Diabetes Trial), as well as safety issues associated with newer glucose-lowering medications. © 2010 Elsevier Inc. All rights reserved.

The ageing pancreas

Type 2 diabetes is historically associated with older adults, and glucose tolerance is known to decline with advancing age. During the course of natural ageing, changes in many peripheral tissues contribute to this deterioration of glucose homeostasis. Included in this process are changes to the structure and function of the pancreatic islets, which undergo deviation in endocrine responses to glycaemic challenge. Current knowledge about the changes seen in the ageing pancreas is reviewed here.

Review: bariatric surgery:to treat diabesity

In obese patients bariatric surgery is increasing in popularity as a strategy to promote, and maintain, weight loss. In obese type 2 diabetes bypass, bariatric surgery improves glycaemic control g€" often to a greater extent than would be anticipated by weight loss alone. Surgical bypass procedures appear to initially offer a greater glucose-lowering effect than surgical restriction procedures. This review considers the rationale for bariatric surgery as a treatment for diabesity and the implications of the different procedures on the secretion and action of enteral hormones.

Glycaemic memory

Glycaemic memory describes the deferred effects of prior glycaemic status on diabetic complications later in life, independent of more recent glycaemic control. Prospective evidence for glycaemic memory derives from extended studies after trials that compared intensive versus standard glycaemic control. These studies in type 1 diabetes (e.g. DCCT) and type 2 diabetes (e.g. UKPDS) have shown that a period of poor glycaemic control earlier in the course of the disease is associated with an increased burden of complications much later in the course of the disease, even when glycaemic control is latterly improved. The Veterans Affairs Diabetes Trial suggested that more than 12-15 years of poor control in older type 2 patients minimised the benefits of subsequently improved glycaemic control. The delayed adverse effects of hyperglycaemia emphasise the importance of effective early glycaemic control. © SAGE Publications 2008 Los Angeles.