Volume 3, Number 1, May 2006

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TOPICEDITORIALObesity, diabetes and cardiovascular disease: is the fat lady singing?
Peter J Grant

Diabetes Vasc Dis Res 2006;3:5-6.

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TOPICREVIEWThrifty genes for obesity and the metabolic syndrome – time to call off the search?
John R Speakman

Over the last 50 years there has been a major epidemic of obesity and associated co-morbidities, the so-called 'metabolic syndrome', mostly in the western world but with an increasingly global dimension. The development of such chronic diseases has a strong genetic component, yet the timescale of their increase cannot reflect a population genetic change. Consequently, the most accepted model is that obesity and its sequelae are a result of a gene-environment interaction, an ancient genetic selection to deposit fat efficiently that is maladaptive in modern society. Why we have this genetic predisposition has been a matter of much speculation.
Following the seminal contribution of Neel,¹ there has been a broad consensus that over evolutionary time we have been exposed to regular periods of famine, during which fatter individuals would have enjoyed a selective advantage by their greater survival. Consequently, individuals with genes promoting the efficient deposition of fat during periods between famines ('thrifty genes') would be favoured. In the modern environment this genetic predisposition prepares us for a famine that never comes, and an epidemic of obesity with all the attendant chronic illnesses follows.
In this review I present details of the evidence supporting the famine hypothesis and then show that this idea has five fundamental flaws. In essence, famines are a relatively modern phenomenon and occur only about once every 100–150 years. Consequently, most human populations have only experienced at most 100 famine events in their evolutionary history. Famines involve increases in total mortality that only rarely exceed 10% of the population. Moreover, most people in famines die of disease rather than starvation and the age distribution of mortality during famine would not result in differential mortality between lean and obese individuals. A simple genetic model shows that famines provide insufficient selective advantage over an insufficient time period for a thrifty gene to have any penetration in the modern human population.
Over the 40 or so years since Neel proposed the thrifty gene hypothesis, no convincing candidates for these genes have been discovered. My analysis suggests that perhaps it is time to call off the search.

Diabetes Vasc Dis Res 2006;3:7-11.

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TOPICREVIEWAdipose tissue metabolism, diabetes and vascular disease – lessons from in vivo studies
Lucinda KM Summers

There is an epidemic of obesity, insulin resistance and cardiovascular disease. Adipose tissue plays a major metabolic role and produces hormones with important physiological effects. In vitro studies remove regulatory factors, such as blood flow, making results difficult to interpret, and animal studies cannot necessarily be extrapolated to humans. Fortunately, adipose tissue can be studied in vivo with microdialysis, adipose tissue vein cannulation, measurement of blood flow using ¹³³Xenon washout, stable isotope tracers and biopsies. In vivo studies have shown that adipose tissue is an efficient buffer against the postprandial flux of non-esterified fatty acids (NEFA) in the circulation, protecting other tissues. When there is excess adipose tissue, this buffering effect may be impaired. The postprandial blood flow response is also reduced, potentially causing an atherogenic lipid profile and atheroma. A systems biology approach, combining in vivo techniques with genomics, proteomics and metabolomics, will clarify links between adipose tissue and vascular disease.

Diabetes Vasc Dis Res 2006;3:12-21.

ORIGINAL PAPERTNF and TNF receptor expression and insulin sensitivity in human omental and subcutaneous adipose tissue – influence of BMI and adipose distribution
Manuela Good, Felicity M Newell, Larisa M Haupt, Jonathan P Whitehead, Louise J Hutley, Johannes B Prins

Tumour necrosis factor (TNF)a is implicated in the relationship between obesity and insulin resistance/ type 2 diabetes. In an effort to understand this association better we (i) profiled gene expression patterns of TNF, TNFR1 and TNFR2 and (ii) investigated the effects of TNF on glucose uptake in isolated adipocytes and adipose tissue explants from omental and subcutaneous depots from lean, overweight and obese individuals.
TNF expression correlated with expression of TNFR2, but not TNFR1, and TNF and TNFR2 expression increased in obesity. TNFR1 expression was higher in omental than in subcutaneous adipocytes. Expression levels of TNF or either receptor did not differ between adipocytes from individuals with central and peripheral obesity. TNF only suppressed glucose uptake in insulin-stimulated subcutaneous tissue and this suppression was only observed in tissue from lean subjects.
These data support a relationship between the TNF system and body mass index (BMI), but not fat distribution, and suggest depot specificity of the TNF effect on glucose uptake. Furthermore, adipose tissue from obese subjects already appears insulin 'resistant' and this may be a result of the increased TNF levels.

Diabetes Vasc Dis Res 2006;3:26-33.

ORIGINAL PAPERDivergent effects of angiotensin-converting enzyme inhibition on blood pressure and endothelial function in obese humans
Ian L Williams, Philip J Chowienczyk, Stephen B Wheatcroft, Ameet G Patel, Roy A Sherwood, Ajay M Shah, Mark T Kearney

Endothelial dysfunction is a pivotal early event in the development of atherosclerosis and a characteristic feature of obesity. This study was designed to investigate the effect of angiotensin-converting enzyme (ACE) inhibition on endothelial function in people who were obese but otherwise healthy. We performed a double-blind, randomised, placebo-controlled study examining the effect of the ACE inhibitor perindopril (4 mg per day) on flow-mediated vasodilatation (FMD) of the brachial artery, arterial blood pressure, glucose homeostasis and inflammatory cytokines. Eighteen obese subjects (all body mass index > 30 kg/m²) were randomised to receive perindopril or placebo for four weeks. Perindopril led to a fall in systolic blood pressure from 131 (standard error of mean [SEM] 3) to 117(5) mmHg and diastolic blood pressure from 74(4) mmHg to 68(4) mmHg, both p<0.001. Despite this fall in blood pressure, ACE inhibition had no effect on FMD, 8.2 (1.2)% versus 8.3 (1.5)%, p=0.9. ACE inhibition had no effect on insulin, lipids or circulating cytokines. In healthy obese humans, despite a significant reduction in blood pressure, ACE inhibition had no effect on FMD.

Diabetes Vasc Dis Res 2006;3:34-38.

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TOPICORIGINAL PAPEREffects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy
Paulos Berhanu, Mark S Kipnes, Mehmood A Khan, Alfonso T Perez, Stuart F Kupfer, Robert G Spanheimer, Seleshi Demissie, Penny R Fleck

The aim of this study was to evaluate changes in lipid profiles in patients with type 2 diabetes after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin and other lipid-altering therapies.
A total of 305 patients were enrolled in this open-label study. Patients had been taking stable dosages of rosiglitazone and statins for > 90 days. At baseline, patients discontinued rosiglitazone and started pioglitazone 30 mg/day, but continued statins and other lipid-altering therapies. The primary end point was change from baseline in fasting triglyceride levels.
At 17 weeks after treatment conversion, patients had significant reductions in triglycerides (-15.2%), total cholesterol (-9.0%), and low-density lipoprotein (LDL) particle concentration (-189 nmol/L), and increases in LDL cholesterol (+2.2%), high-density lipoprotein (HDL) cholesterol (+1.8%), and LDL particle diameter (+0.23 nm).
In conclusion, after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin therapy, patients with type 2 diabetes had marked improvements in lipid profiles along with stable glycaemic control.

Diabetes Vasc Dis Res 2006;3:39-44.

ORIGINAL PAPERSuccess rates of percutaneous coronary intervention of chronic total occlusions and long-term survival in patients with diabetes mellitus
David M Safley, John A House, Barry D Rutherford, Steven P Marso

The objectives of this study were to evaluate angiographic and clinical outcomes among patients with diabetes mellitus (DM) who underwent percutaneous coronary intervention (PCI) for a chronic total occlusion (CTO). We compared them with matched patients undergoing PCI of a non-CTO lesion. All patients had documented DM. Matching was performed using a propensity score for CTO.
There were 506 patients with DM and CTO who were matched with a non-CTO group. Results showed that angiographic success rates were lower with CTO (75% vs. 93%, p<0.001). In-hospital major adverse cardiac event (MACE – death, urgent bypass surgery, Q-wave myocardial infarction or target vessel revascularisation) rates were equivalent (CTO 3.2% vs. non-CTO 2.6%, p=0.57). Survival was not different five years after revascularisation of CTO (75%) vs. non-CTO (79%) (p=0.20). In addition, when DM patients with CTO were analysed according to angiographic success of PCI, there were no significant differences in either in-hospital (success 1.6% vs. failure 2.4%, p=0.7) or 1-year mortality (success 22.2% vs. failure 26.8%, p=0.3).
We conclude that PCI of CTO is safe in patients with DM. Angiographic failure is not associated with an increase in MACE rates or mortality as compared to matched non-CTO patients. However, there is not a measurable improvement in survival in this DM-CTO population.

Diabetes Vasc Dis Res 2006;3:45-51.

ORIGINAL PAPEREffects of improved metabolic control on platelet reactivity in patients with type 2 diabetes mellitus following coronary angioplasty
Marianne Yngen, Anna Norhammar, Paul Hjemdahl, N Håkan Wallén

The aim of this study was to investigate the impact of improved metabolic control on platelet reactivity in patients with type 2 diabetes undergoing percutaneous coronary intervention (PCI). Twenty-two patients were randomised to intensive insulin or conventional treatment for diabetes. Platelet P-selectin expression was analysed before and three months after PCI.
Metabolic control, as measured by level of glycosy- lated haemoglobin (HbA1C) and platelet P-selectin expression, was similar in the two treatment groups after three months. However, six of the 12 patients in the intensive group had increased levels of HbA1C after three months and three patients of the 10 in the conventionally treated group showed improved metabolic control.
A re-analysis was performed, based on metabolic control. It showed that patients with improved control at three months (HbA_1C 6.1%+0.7 at baseline; 5.7%+0.5 at three months; p<0.01; n=9) had lower ADP-induced P-selectin expression (p<0.05) than patients with worsened glycaemic control (HbA_1C 5.9%+1.0 at baseline; 6.5%+1.4 at three months; p<0.01; n=13). Levels of HbA_1C and fasting glucose were correlated to P-selectin expression (R=0.34 and R=0.31; p<0.05).
We conclude from this study that improved glycaemic control reduces platelet reactivity in type 2 diabetes patients following PCI.

Diabetes Vasc Dis Res 2006;3:52-56.

ORIGINAL PAPERRisk factors for stroke in type 2 diabetes mellitus
Nailya Asfandiyarova, Nina Kolcheva, Igor Ryazantsev, Vladimir Ryazantsev

Stroke is a serious complication of diabetes but the risk factors for stroke in these patients are not fully defined.
The aim of this retrospective study was to investigate the risk factors for stroke in patients with type 2 diabetes mellitus (T2DM). The group comprised 208 patients with T2DM, and the mean duration of follow-up was seven years (range 4–11 years). The incidence of stroke was investigated according to lymphocyte proliferation in response to insulin.
Using cimetidine to inhibit cells with histamine receptors and indometacin to inhibit prostaglandin-synthesising cells, a higher incidence of stroke was found in patients with indirect cell-mediated immunity to insulin.
Therefore, one of the risk factors for stroke in patients with T2DM is high activity of cells with histamine receptors and prostaglandin-synthesising cells. These cells suppress cell-mediated immunity to insulin and may have a role in promoting the development of insulin resistance.

Diabetes Vasc Dis Res 2006;3:57-60.

SHORT REPORTPrevalence of microalbuminuria and hypertension in South Asians and white Europeans with type 2 diabetes: a report from the United Kingdom Asian Diabetes Study (UKADS)
Anthony N Dixon, Neil T Raymond, Shanaz Mughal, Asad Rahim, J Paul O'Hare, Sudhesh Kumar, Anthony H Barnett

Microalbuminuria is more common in South Asian individuals compared to white Europeans. The aim of this study was to determine the relationship between blood pressure and microalbuminuria in a cohort of patients with type 2 diabetes in these two ethnic groups. These further data were analysed from 552 patients (311 South Asian patients and 241 white Europeans) who had microalbuminuria screening data collected. Prevalence of microalbuminuria was significantly higher in South Asian compared with white European patients (31% versus 20%, p=0.007). Among patients with normal, untreated blood pressure, the proportion who had microalbuminuria was three times higher among South Asian patients compared with the white European group (30.7% versus 10.1%, p=0.049, relative risk = 3.1 [1.0-9.5]). In addition, despite their higher cardiovascular risk, South Asian patients were less likely to be prescribed a statin or antihypertensive drug treatment.
In conclusion, thresholds and targets for treatment of cardiovascular risk factors in South Asians may need to be lower than those for white Europeans, and targeted intervention will be required to achieve this.

Diabetes Vasc Dis Res 2006;3:22-25.