Leeds University Logo

University of Leeds 
Faculty of Biological Sciences

Back to Dr.
Home Page

Tel +44 113 343 3112          Leeds LS2 9JT          Fax +44 113 343 3167

BIOC3600 / BMSC3145 / BIOL5215M / BIOL5235M Lectures 2010: Dr. J.A. Illingworth

Obesity, Diabetes & Cardiovascular Disease

Switch on pop-ups!

Table of Contents


The principal difficulty when studying this material is that that we are not dealing with a conventional, linear, cause and effect situation, but with a complex, interlocking network of interactions, with many parallel connections between the inputs and the outputs. Knockout or inhibition of any one signaling route tends to evoke counter-regulatory responses from all the other parallel routes. Even when a benefit can be observed, it tends to disappear over time. This is the main reason why the obesity problem is proving resistant to interventions, and why it takes so long to devise more effective drug treatments for diabetes and cardiovascular diseases.

The course summary below is intended to aid revision and focus on the main points amid a mass of detail. The links refer to the full set of 218 lecture slides that you can download here (14MB!) or from the Leeds VLE. Please note a minor revision to slide 17. The website departs in places from the lecture sequence in an attempt to view the issues from different angles. When using it students should try to focus on the following overarching theme:

Once started, the pathology is self-perpetuating and further inflammatory changes affecting blood vessels, joints and muscles make it increasingly difficult for people to take the additional exercise which would greatly improve their condition.

Course Summary

Life assurance companies have known for many years that overweight or obese individuals, and people suffering from high blood pressure, all have a reduced life expectancy. In the 1970's researchers showed that elevated blood triglycerides and LDL cholesterol carried with them an increased risk of heart attacks and strokes. In recent years epidemiologists have recognised a clustering of symptoms or risk factors, whereby overweight people are also likely to develop insulin resistance (eventually progressing to type 2 diabetes), dislipidaemia, hypertension and a persistent, low-grade systemic inflammation that will probably lead to serious disability or a premature death from cardiovascular disease. This cluster is known as the "metabolic syndrome" [slides 1-11].

Many other serious and debilitating diseases (including Alzheimer's, arthritis, gallstones and several cancers) are also linked to obesity [slide 4], although the correlation may be less obvious than it is for heart attacks, aneurysms and strokes. The incidence of many of these conditions is rising throughout the world, although we do not fully understand the reasons for this. There are now more obese people than hungry people world wide. Costs of treatment could be enormous and governments in most countries view the rising levels of obesity, and especially child obesity, with considerable alarm.

Chronic inflammation [slides 12-18] is a common feature of many terminal or life-threatening conditions, but it is not the whole story. Tobacco smoking, lack of physical exercise, and low socioeconomic status also contribute to the ten-year gap in life expectancy between different areas of Leeds. There are substantial differences in the incidence of particular diseases between different racial groups [slides 19-21]. Throughout the world, people with a South Asian ancestry face a much higher risk of diabetes and cardiovascular disease [slides 20 & 189].

We discuss the pathophysiology of diabetes and cardiovascular disease [slides 22-24]. We distinguish between macrovascular [slides 32-39] and microvascular [slides 48-71] disease, and identify several causal mechanisms that link increased fat cell mass to insulin resistance and the inflammatory processes in the blood vessel wall. These include production of anti-insulin, pro-inflammatory cytokines (such as TNF-α and interleukin-1) from adipose tissue as the fat cell mass increases, coupled with a reduced output of the anti-inflammatory hormone adiponectin [see also slides 141-144]. Insulin resistance leads to dislipidaemia, hyperglycaemia, protein glycation and the accumulation of advanced glycation end products (AGEs) [slides 62-65] which exacerbate the inflammatory effects.

The receptor for AGE (RAGE) belongs to the immunoglobulin superfamily. Binding of AGE to RAGE ultimately results in the generation of reactive oxygen species (ROS) in the vascular wall [slides 17, 66-71], leading to reduced levels of nitric oxide, vasoconstriction and the activation of the redox-sensitive transcription factor NF-κB (nuclear factor kappa B) [slides 50-55]. Consequences include the transcription of atherosclerosis-related genes, such as ICAM, VCAM, MCP-1 and VEGF which favour macrophage recruitment and the development of atherosclerotic plaques.

We distinguish between type 1 and type 2 diabetes [slides 72-81], and discuss drugs that are used to treat these conditions, including sulphonylureas [slides 95-97], metformin, fibrates (for dislipidaemia), thiazolidinediones and digestive enzyme inhibitors. [See NICE guidelines below.] We study the systems that monitor blood glucose and control the release of insulin and glucagon from pancreatic islet cells [slides 86-94]. We note the action of the incretin hormones and the numerous secondary stimuli for insulin release [slides 98-100]. We also study the effect of insulin on target tissues [slides 101-132], including increased glucose entry, increased deposition of glycogen and fats, and changes in gene expression. We note that sulphonylureas are ineffective against type 1 diabetes, and study the links between metformin, AMPK and mTOR (mammalian target of rapamycin) [slides 126-127 & 133-136], between fibrates and PPAR-α and between thiazolidinediones and PPAR-γ [slides 59, 137-139]. We also note that many of these drugs have unwanted side effects, including weight gain and heart failure, and that rosiglitazone has recently been withdrawn.

Obese individuals are recommended to lose weight, and if they succeed in doing so their health is likely to improve. Unfortunately, such control is easier said than done [slides 145-150]. It is almost impossible to voluntarily lose more than 10% of one's body weight, and any weight lost is often regained over the next twelve months [slide 204]. It is difficult to lose weight because of the multiplicity of ancient and highly redundant sensing and signaling mechanisms, which conspire to increase hunger and reduce metabolic rate as the fat stores are reduced. We discuss the enteroendocrine cells within the gut that monitor the energy content of foods and help to determine the size and spacing of meals [slides 158-166]. Important signals include ghrelin, CCK, GIP, GLP1, oleylethanolamide and PYY, [slides 167-182] which are produced in an orderly sequence during the initiation, consumption and termination of a meal [slide 160]. We study the two way communication between enteroendocrine cells, the pancreatic islet cells and the central nervous system [slides 158 & 183].

Other inputs to the CNS include blood glucose, insulin, amylin and leptin which disclose our previous eating history and the size of our reserves. We note the permeability of the blood-brain barrier in the arcuate nucleus and in the solitary tract. We consider signaling within the central nervous system, including the anorexigenic POMC/CART neurons and the orexigenic AgRP/NPY pathways [slide 185 & 186]. Outputs from the CNS include thyroxin and catecholamines which help to determine spontaneous physical activity and basal metabolic rate, matching energy consumption to the available food supply. Non-shivering thermogenesis by brown fat [slide 210] is now recognised in adults as well as new-born infants.

Obese patients are advised to use a combination of diet and increased exercise, with a view to achieving a 10% reduction in body weight over a period of several months. Most of the sensors that control food intake respond best to energy-rich fats and proteins, with the result that high carbohydrate / low fat "slimming" meals are often deeply unsatisfying and must be calorie-controlled. In contrast to this, low-carbohydrate "Atkins" diets can be eaten ad lib. but are nevertheless associated with high drop-out rates [slides 193-205]. In practice there may be little to choose between low fat and low carbohydrate diets, and this may ultimately turn on personal preferences, although there may be some benefit in being a member of a self-help group.

There are few effective weight loss drugs [slide 211], and those that are approved often have significant side effects [slide 26]. These include heart valve defects, risk of addiction or abuse, or increased suicide risk. New drugs are continuously under development, but the multiplicity of redundant parallel signaling pathways between the brain and the gut is making progress painfully slow [summary slide 183]. We also study those drugs that are proving effective against the metabolic syndrome [slide 212], including the statins, which have both cholesterol-lowering and anti-inflammatory effects [slide 213], and the ACE-inhibitors, angiotensin receptor blockers and diuretics, which are effective against hypertension and heart failure. We cover the regulation of cholesterol biosynthesis [slides 214-217].

The most successful treatment for obesity is gastric surgery, removing or bypassing much of the stomach and duodenum, and greatly reducing its capacity for food. Although effective, this is a serious, irreversible and expensive operation which caries a measurable risk. It is difficult to see how it could be rolled out to a significant fraction of the population, or what the voluntary uptake might be.

There is strong evidence that increased physical activity brings substantial health benefits over a period of about five years, and this should be part of any weight control program. It is important to offer these recreational opportunities to the entire population, including inner-city residents and minority ethnic groups. Increased physical activity can reverse or ameliorate most of the adverse features of the metabolic syndrome, and produces substantial improvements in life expectancy, psychological well-being and quality of life [slides 27-31, 81, 83, 209]. Increased physical exercise is far more effective than the currently available drugs.

Control of Food Intake

Mouse over the diagram below (no need to click) for interactive content.

hindbrain hypothalamus forebrain mouth salivary glands stomach small intestine large intestine anus liver gall bladder exocrine pancreas islet tissue pylorus vagus sympathetic chain cholecystokinin blood glucose local gut hormones peristalsis stretch taste smell vision insulin brain pathways autonomic autonomic autonomic autonomic autonomic

NICE Guidelines

It can be difficult to locate short descriptions of current clinical practice. The UK National Institute for Health and Clinical Excellence (NICE) is certainly authoritative, but their 2006 guidance on Obesity is 84 pages, their 2008 recommendations on Type 2 diabetes is 279 pages and their 2009 update on newer agents for Type 2 Diabetes is 102 pages long.

Fortunately, the NICE 2009 Quick Reference Guide is only 20 pages, but covers everything that you need to know about drug therapy for type 2 diabetes, and a lot more besides. Download a copy, and study the summary chart on pages 8 - 9. Please do not try to learn this publication by rote, but it will give a good feel for the sort of issues that arise.

Some oral hypoglycaemic drugs may be poorly tolerated by the patient, in which case another agent must be used. There is a tendency for the disease to intensify or for these drugs to lose their effectiveness over time, so type 2 diabetic patients gradually progress from monotherapy with metformin to combinations of drugs which may finally include insulin injections as their condition worsens. The treatment objective is keep glycosylated haemoglobin [HbA1c] close to target around 6.5%, but to avoid hypoglycaemia and to delay any deterioration for as long as possible.

The Establishment

Conventional wisdom still stresses the importance of a low-fat / high-carbohydrate calorie-controlled diet, exemplified by the image below. Visit the Food Standards Agency website to read their dietary recommendations in full.

The Heretics

Increasing numbers of scientists are challenging the established position, and pointing out that better weight loss results can be obtained by ignoring the conventional advice. They also argue that since diabetics have excess blood sugar, reducing their carbohydrate intake seems a logical first step. Small scale trials with type 2 diabetics have produced impressive results. Weight is certainly lost faster on low-carbohydrate diets, despite the fact that the subjects can eat as much as they like. The long term outcomes are still being studied, but it is already clear that high-fat / low-carbohydrate diets do not produce the adverse blood lipid profiles that were intially expected.

Both sides are defending their positions with an almost religious ferocity, which is reminiscent of previous scientific battles about the chemiosmotic theory or continental drift. Although the result still hangs in the balance, the smart money probably favours a major paradigm shift.

Drugs for obesity, diabetes and cardiovascular disease

Circulatory diseases are major killers, which ultimately affect over half the population. A correspondingly large number of drugs compete for this lucrative marketplace. Some examples are listed below. Try to focus on the major classes of drugs that are in use, and understand why they are prescribed, rather than trying to memorise the names of individual products.

Drugs primarily for hypertension

ramipril is an ACE (angiotensin converting enzyme) inhibitor, which blocks the proteolytic conversion of angiotensin I into angiotensin II. The fall in angiotensin II causes relaxation of arteriolar smooth muscle, and decreased aldosterone output.

valsartan is an angiotensin II receptor blocker, which also causes relaxation of arteriolar smooth muscle, and decreased aldosterone output. It may be preferred to ACE inhibitors because it does not interfere with bradykinin metabolism, so is less likely to cause a troublesome cough.

metoprolol is a β-blocker which acts mainly to reduce the contractility of cardiac muscle.

nifedipine is a Ca++ antagonist, which blocks calcium entry into cardiac & smooth muscle. This reduces cardiac contractility and relaxes vascular muscle.

Drugs for heart failure

frumil is a mixture of two diuretics: furosemide and amiloride. Furosemide inhibits the KNaCl carrier in the loop of Henle, while amiloride is a "potassium sparing" diuretic which blocks Na channels in the distal convoluted tubules. Used together they help to stabilise blood potassium in the normal range. Current draft guidance from NICE emphasises the use of ACE inhibitors and aldosterone antagonists such as spironolactone in heart failure, however other diuretics such as frumil are also used.

Drugs for angina

nitroglycerine (glyceryl trinitrate) is the high explosive used in dynamite. It is an organic nitrate which in small doses is metabolised to ntric oxide. Its principal effect is to cause relaxation of venous smooth muscle, thereby reducing cardiac preload and providing rapid pain relief in angina.

ACE inhibitors (such as ramipril) are also effective for angina. In this case the beneficial effects are achieved by reducing afterload.


aspirin is the oldest NSAID (non-steroidal anti-inflammatory drug) and is a non-specific inhibitor of the cyclooxygenase COX1 & COX2 isoenzymes involved in prostaglandin and thromboxane biosynthesis. This interferes with platelet aggregation, and reduces the risk of unwanted blood clots, while at the same time increasing. the risk of stomach bleeding and haemorrhagic strokes. Aspririn is slightly beneficial to patients suffering from ischaemic heart disease, but the benefits of mass-medication with aspirin to the general population are disputed.

clopidogrel (pronounced "cloh-pee-doh-grel" not "cloppy doggerel") binds to platelet ADP receptors and inhibits blood clotting. It is used to treat atherosclerosis.

heparin is a naturally occuring sulphated glycosaminoglycan found in mast cells. It is a speedy and effective anticoagulant that is purified commercially from slaughterhouse material. It is normally given by injection for its short-term effect, and subsequently replaced by slower acting drugs that can be given by mouth.

warfarin inhibits the carboxylation reaction in liver tissue that forms the γ-glutamyl residues that occur in many clotting factor proteins. It is economical in use, but slow to take effect. It is an enormous advantage that it is effective by mouth. The dose must be carefully controlled. In higher doses warfarin causes massive internal bleeding, so it is also used as a rat poison.

streptokinase is a purified bacterial protease that is used to dissolve blood clots during acute myocardial infarction. It should ideally be given by injection within one hour from the onset of symptoms. It is antigenic and therefore unsuitable for repeated use, so it is increasingly being replaced by recombinant tPA = tissue plasminogen activator.

Drugs for dislipidaemia

lovastatin is a natural product originally derived from oyster mushrooms which inhibits liver HMG-CoA reductase and is used to treat dislipidaemia (high LDL cholesterol). Statins also have important anti-inflammatory effects.

gemfibrozil is a fibrate which binds to PPAR-α in many tissues and is used to treat dislipidaemia.

Drugs for type 2 diabetes

metformin is a biguanide used for the treatment of type 2 diabetes. It is cheap, it has an excellent safety profile, and it is the most widely prescribed oral hypoglycaemic drug. It activates liver AMPK, probably by increasing cytosolic [AMP] and suppresses hepatic gluconeogenesis. Metformin does not cause weight gain in contrast to insulin and the sulphonylureas.

exenatide is an analogue of glugacon-like peptide1 (GLP-1) but with a much longer biological half life. It is an incretin hormone which stimulates insulin release from pancreatic β-cells and is used for the treament of type 2 diabetes. It was originally isolated from the saliva of the Gila monster (lizard) but is now made synthetically. It must be given by injection, since it is a protein, and it is not effective orally.

glipizide is a long-acting sulphonylurea that stimulates insulin secretion from pancreatic β-cells and is used for the treatment of type 2 diabetes. It binds to the sulphonylurea receptor and promotes the opening of an associated ATP-sensitive potassium channel.

pioglitazone is a thiazolidinedione which binds to PPAR-γ in many tissues, increasing insulin sensitivity and is used for the treatment of type 2 diabetes. Side effects include mild weight gain, and an expansion of blood volume whihc may increase the risk of heart failure. The related drugs troglitazone and rosiglitazone have been shown to increase the risk of adverse cardiovascular events and have been withdrawn for safety reasons.

acarbose is an α-glucosidase (amylase) inhibitor that delays carbohydrate digestion within the small intestine and is used for the treatment of type 2 diabetes. Side effects include flatulence and diarrhoea.

Drugs for weight control

orlistat is an inhibitor of gastric and pacreatic lipases that impedes lipid digestion within the small intestine. It is used in conjunction with a calorie-restricted diet for the treatment of obesity and to delay or prevent the onset of type 2 diabetes. Side effects include steatorrhea (smelly, oily faeces), anal leakage and diarrhoea.

sibutramine is a selective serotonin re-uptake inhibitor (SSRI) which acts on the central nervous system to suppress appetite and eating behaviour and thereby combats obesity. This drug has recently been withdrawn from the market because of safety concerns.


Bearing in mind that this is a large and diverse class, it would be unfair to set "nit-picking" questions that rely on detailed knowledge of one particular aspect. Such questions might unfairly favour one group of students over another. Therefore expect broadly-based questions that allow candidates to combine information from more than one lecture, and also to select which facts they will use to illustrate their answers.

Here is the question set in 2009 with its associated marking scheme:

"Explain why obese patients are normally urged to lose weight, and why they often find it very difficult to do so.".

Marking scheme:

Equal weighting for the two halves of the question.

The first half requires a description of the pathological consequences of obesity, stressing diabetes, hypertension, dislipidaemia and cardiovascular diseases, but also including other adverse effects such arthritis, dyspnoea, snoring, sleep apnoea, hiatus hernia and gastro-oesophageal reflux disease. Candidates could also mention self-image, psychological and reproductive problems but I was not expecting an exhaustive list. They should understand the differences between microvascular and macrovascular disease.

They should mention loss of life expectancy and quality of life, the cost of treatment for these conditions, and the observation that many of these adverse conditions improve if the subject succeeds in losing weight. Bonus marks for including details of the pathological mechanisms and processes, and in particular for stressing the importance of low-grade inflammation.

The second half of the question is about the numerous negative feedback loops regulating body weight, which cause metabolism to slow down and hunger to increase as the body falls below its “target” weight. Candidates should be aware of the multiplicity of parallel regulatory pathways, and the problems that this redundancy creates for rational drug design. They could mention the interactions between eating and mood, and fact that the most effective anorexic drugs cause unacceptable depression and suicide risk.

A good answer will include a discussion of diet regimes, including low fat and low carbohydrate diets, the problem of people abandoning their diet, and the need for high levels of physical exercise as part of an effective weight loss regime.

It was possible to get a good mark while recalling less than half of the potential material.

Self-assessment questions

These questions are all in the extended matching format. Your performance is NOT being recorded and you can attempt these questions as often as you like. You can adjust the feedback level to give either an overall mark, or a list of the questions that you got wrong, or full interactive feedback with a discussion of the merits of the various possible answers.

Theme: therapy for the metabolic syndrome, diabetes and related conditions.

Select from the following list of treatments the single therapy which best matches each of the situations described in statements A to F below. Each option may be used once, more than once or not at all.

treatment type 









diet + exercise






































organic nitrate




lipase inhibitor








ACE inhibitor








AR blocker





table 1patient Apatient Bpatient Cpatient Dpatient Epatient F











































venous pH







HDL cholesterol







LDL cholesterol




























Clinical observations

(To aid comparison, all the blood analyses are grouped together in table 1 above.)

1. Patient A: A 68 year old grandmother (height 1.6m, weight 90kg) attended her local GP clinic for a routine visit. She complained of increasing tiredness and joint pains, and said that she had been sleeping badly and recently had to rise several times each night to pass urine. She was out of breath after her short walk to the clinic. Her blood pressure was 140/90mm Hg, heart rate 100/min and her blood analysis is in table 1. The GP noted that although her heart rhythm was normal, there were basal crepitations in both lungs and her ankles were slightly swollen. She said that she had been trying to lose weight, and had joined weight-watchers, but so far with little success. She had also joined a gym, but found most of the exercises painful. "With all those fit people running round, Doctor, I just felt like a big floppy lump of lard."

2. Patient B: A 45 year old businessman (height 1.8m, weight 95kg) suddenly felt unwell while visiting clients and was immediately brought to the Accident and Emergency Department by taxi. On examination he was pale, breathless, sweating and extremely anxious. His blood pressure was 130/95mm Hg, heart rate 120/min. He complained of severe retrosternal chest pain, radiating to the jaw and neck, which had started in the last 45 minutes. An emergency ECG showed marked ST segment elevation in leads V2 and V3 without other obvious changes. He said that he had missed breakfast and had not eaten since the previous evening. His blood analysis is listed in table 1 and all blood enzymes tested were within the normal range.

3. Patient C: A 19 year old university student (height 1.95m, weight 70kg) left a birthday party feeling unwell and was discovered by his friends the following morning in a very poor condition. He was breathing heavily and unable to stand up, although his consciousness improved slightly when lying flat. His breath smelled "beery" and at first they thought he might be drunk, but alarmed by his worsening symptoms they called the emergency services. On examination he was barely conscious, his tongue was dry and furrowed, all accessible mucous surfaces and armpits were also dry, blood pressure 80/50 mm Hg, heart rate 150/min. His blood analysis is listed in table 1.

4. Patient D: A 58 year old diabetic woman (height 1.7m, weight 68kg) was already receiving treatment with glipizide and lovastatin plus ramipril for hypertension. Although her symptoms were reasonably well controlled (blood pressure 135/95mm Hg, resting heart rate 75/min and blood analysis in table 1) she was troubled by a persistent cough. What changes to her existing therapy might best relieve this symptom?

5. Patient E: A 28 year old man (height 1.8m, weight 88kg) was arrested after a night club brawl. He appeared to have fared badly during the altercation and scarcely knew where he was. Despite the cold weather he was sweating profusely, still belligerent and bleeding from his mouth and lip. "We don’t want this bugger messing up the cells", said the sergeant, "Is that blood or is it all the red wine he’s been drinking? Take him down to A&E and get him sorted out. Ask if they’ve got anything to calm him down." On examination his skin was warm and moist, and he had only superficial injuries, blood pressure 130/80mm Hg, heart rate 160/min and the blood analysis in table 1. Blood ethanol was 7.2mM.

6. Patient F: A 34 year old mother (height 1.75m, weight 85kg) consulted her GP. She had gained weight while pregnant and wanted to return to her original size. "I’ve been to this health farm where they fed us all a lobster and cranberry diet and had us jumping into cold water but it hasn’t done me a right lot of good. I’ve been so busy answering the phone and driving the kids around in my 4x4 and visiting friends that I never have time to eat properly. I have tried starvation diets for a couple of days but as soon as I start eating I seem to put it straight back on again. I wish I was like Victoria Beckham." The GP took a blood sample for analysis (table 1) and recorded blood pressure 126/82 mm Hg, heart rate 73/min.


feedback:  please remember to re-submit if you change the feedback setting

Reading List

I have struggled to compile this list. There are numerous recent reviews, but these are often much too detailed for undergraduate use, and there is considerable overlap between them. I suggest that you focus mainly on the summary, introduction, diagrams and discussion in the following papers. Try to identify the most important factors and avoid getting bogged down in the minutiae. You should only study the detailed explanation if the summary seems unclear.

Try to understand the underlying pathological mechanisms, and the mode of action of drugs that are used to treat these very common conditions.

Most of these references have clickable links on the authors names to navigate to the published paper. In a few cases I have provided a path using the digital obejct identifier (DOI) system, where this is more convenient for Leeds users than the journal URL. Most of these links should work both on and off campus. Please let me know of any that don't. Sometimes you may need to click on the "institutional login" and quote your University of Leeds password.

Benigni et al (2010) Angiotensin II revisited: new roles in inflammation, immunology and aging EMBO molecular medicine 2, 247–257. DOI

Brasier et al (2010) The nuclear factor-kB–interleukin-6 signalling pathway mediating vascular inflammation Cardiovascular Research 86, 211–218. DOI

Giacco & Brownlee (2010) Oxidative Stress and Diabetic Complications Circ. Res. 107, 1058-1070. DOI

Hummasti & Hotamisligil (2010) Endoplasmic Reticulum Stress and Inflammation in Obesity and Diabetes Circ. Res. 107, 579–591. DOI

Koh et al (2010) Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle PNAS 107, 15541–15546. DOI

Lim et al (2010) AMPK as a mediator of hormonal signalling Journal of Molecular Endocrinology 44, 87-97. DOI

Olefsky & Glass (2010) Macrophages, Inflammation, and Insulin Resistance Ann Rev Physiol 72, 219–246. DOI

Steckelings (2009) The evolving story of the RAAS in hypertension, diabetes and CV disease – moving from macrovascular to microvascular targets Fundamental & Clinical Pharmacology 23, 693–703. DOI

Tabas et al (2010) The Impact of Macrophage Insulin Resistance on Advanced Atherosclerotic Plaque Progression. Circ. Res. 106, 58-67.

Wang & Nakayama (2010) Inflammation, a Link between Obesity and Cardiovascular Disease. Mediators of Inflammation 2010, ID 535918. doi:10.1155/2010/535918

Wong et al (2010) Endothelial Dysfunction: The Common Consequence in Diabetes and Hypertension J Cardiovasc Pharmacol 55, 300–3007. DOI

Yan et al (2010) The RAGE Axis: A Fundamental Mechanism Signaling Danger to the Vulnerable Vasculature Circulation Research 106, 842–853. DOI

Zhang & Zhang (2010) Adipose “Talks” to Distant Organs to Regulate Insulin Sensitivity and Vascular Function Obesity 18, 2071–2076. DOI

In addition to reading scientific papers, it might also be beneficial to study the sections on atherosclerosis and cardiovascular disease in a recent pathology text book from the Health Sciences Library. There are any number of these, generally available in multiple copies from library shelves QZ 4 and thereabouts. Choose a recent edition, because ideas about atherosclerosis are changing rapidly at present.

Full list of papers

Here are about 220 papers that I consulted when preparing these lectures. There is is no need to read them all, this list is mainly for the use of teaching staff who are maintaining this website. There should be links to all the papers that are mentioned on the slides. They are provided so that people can follow up ideas that they find interesting, and also to illuminate areas where I was particularly obscure. The links from the authors' names (or sometimes from the DOI) will often take you to the abstract, at which point you can opt to either read the full text HTML report, or alternatively download the PDF version.


Abramson & Wright (2007) Are lipid-lowering guidelines evidence-based? The Lancet 369, 168–169.

Adams et al (2006) Overweight, Obesity, and Mortality in a Large Prospective Cohort of Persons 50 to 71 Years Old. N Engl J Med 355, 763–778.

Adan et al (2008) Anti-obesity drugs and neural circuits of feeding. Trends in Pharmacological Sciences 29, 208-217.

Ahmed (2005) Advanced glycation endproducts — role in pathology of diabetic complications. Diabetes Research and Clinical Practice 67, 3-21.

Ait-Oufella et al (2009) Cytokine network and T cell immunity in atherosclerosis. Semin Immunopathol 31, 23–33.

Andrews et al (2008) UCP2 mediates ghrelin’s action on NPY / AgRP neurons by lowering free radicals. Nature 454, 846–851.

Aragones et al (2008) Oxygen Sensors at the Crossroad of Metabolism. Cell Metabolism 9, 11–22.

Ashall et al (2009) Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription. Science 324, 242–246.

Ashcroft (2006) K-ATP channels and insulin secretion: a key role in health and disease. Biochem. Soc. Trans. 34, 243-246.

Avruch et al (2009) Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 296, 592–602.


Balakumar et al (2009) Emerging role of PPAR ligands in the management of diabetic nephropathy. Pharmacological Research 60, 170–173.

Barnes & Karin (1997) Nuclear Factor-κB — a pivotal transcription factor in chronic inflammatory diseases. New Engl J Med 336, 1066-1071.

Benigni et al (2010) Angiotensin II revisited: new roles in inflammation, immunology and aging EMBO molecular medicine 2, 247–257. DOI

Berner-Hansen & Witte (2008) The role of serotonin in intestinal luminal sensing and secretion. Acta Physiologica 193, 311-323.

Bhatwadekar et al (2008) A new advanced glycation inhibitor, LR-90, prevents experimental diabetic retinopathy in rats. Brit J Ophthalm 92, 545-547.

Bishop-Bailey & Bystrom (2009) Emerging roles of peroxisome proliferator-activated receptor-β/δ in inflammation. Pharmacology & Therapeutics 124, 141–150.

Blum & Shamburek (2009) The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. Atherosclerosis 203, 325–330.

Booth & Lees (2007) Fundamental questions about genes, inactivity, and chronic diseases. Physiol Genomics 28, 146–157.

Borer et al (2009) Appetite Responds to Changes in Meal Content, Whereas Ghrelin, Leptin, and Insulin Track Changes in Energy Availability. J Clin Endocr & Metab 94, 2290-2298.

Bosi (2009) Metformin – the gold standard in type 2 diabetes: what does the evidence tell us?. Diabetes, Obesity and Metabolism 11(S2), 3 - 8.

Brasier et al (2010) The nuclear factor-kB–interleukin-6 signalling pathway mediating vascular inflammation Cardiovascular Research 86, 211–218. DOI

Brown & Griendling (2009) Nox proteins in signal transduction Free Radical Biology and Medicine 47, 1239-1253. DOI

Byberg et al (2009) Total mortality after changes in leisure time physical activity in 50 year old men: 35 year follow-up of population based cohort. BMJ 338, b688.


Cai et al (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB Nature Medicine 11, 183–190.

Cameron et al (2010) Cut-points for Waist Circumference in Europids and South Asians Obesity 18, 2039–2046. DOI

Carey & Kingwell (2009) Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with ‘exercise mimetics’. Diabetologia 52, 2015–2026.

Celi (2009) Brown Adipose Tissue — When It Pays to Be Inefficient. N Engl J Med 360, 1553–1556.

Chao & Cheing (2009) Microvascular dysfunction in diabetic foot disease and ulceration Diabetes Metab Res Rev 25, 604–614. DOI

Chaudhri et al (2008) Gastrointestinal Satiety Signals. Annu. Rev. Physiol. 70, 239–55.

Chen et al (2009) NOD-Like Receptors: Role in Innate Immunity and Inflammatory Disease. Annu. Rev. Pathol. Mech. Dis. 4, 365–98.

Chen et al (2009) C-reactive Protein Upregulates Receptor for Advanced Glycation End Products Expression and Alters Antioxidant Defenses in Rat Endothelial Progenitor Cells. J Cardiovasc Pharmacol 53, 359-367. DOI

Chen et al (2010) Fitness, fatness, and systolic blood pressure: Data from the Cooper Center Longitudinal Study Am Heart J 160, 166–170. DOI

Cheng et al (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Reviews Drug Discovery 8, 627–644.

Cheong et al (2010) Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by Kv1.3 channel blockers Cardiovascular Research [in press]. DOI

Chobanian (2009) The Hypertension Paradox — More Uncontrolled Disease despite Improved Therapy. N Engl J Med 361, 878–87.

Clifton (2008) Dietary treatment for obesity. Nature Clinical Practice: Gastroenterology & Hepatology 5, 672–681.

Cotti et al (2010) Can a chronic dental infection be considered a cause of cardiovascular disease? A review of the literature Int J Cardiol [in press]. DOI

Coughlan et al (2009) RAGE-Induced Cytosolic ROS Promote Mitochondrial Superoxide Generation in Diabetes. J Am Soc Nephrol 20, 742–752.

Cummings & Overduin (2007) Gastrointestinal regulation of food intake. J Clin Invest 117, 13-23.

Cunningham et al (2009) mTOR controls mitochondrial oxidative function through a YY1–PGC-1a transcriptional complex. Nature 450, 736–741.

Curfman et al (2010) Sibutramine — Another Flawed Diet Pill N Engl J Med 363, 972–974.

Cypess et al (2009) Identification and Importance of Brown Adipose Tissue in Adult Humans. N Engl J Med 360, 1509–1517.


Dauchet et al (2009) Fruits, vegetables and coronary heart disease. Nat. Rev. Cardiol. 6, 599–608.

Davis et al (2009) Comparative Study of the Effects of a 1-Year Dietary Intervention of a Low-Carbohydrate Diet Versus a Low-Fat Diet on Weight and Glycemic Control in Type 2 Diabetes. Diabetes Care 32, 1147–1152.

DeBose-Boyd (2008) Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Research 18, 609–621.

Delahoy et al (2009) The Relationship Between Reduction in Low-Density Lipoprotein Cholesterol by Statins and Reduction in Risk of Cardiovascular Outcomes: An Updated Meta-Analysis. Clinical Therapeutics 31, 236–244.

Ding et al (2009) Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Women and Men. N Engl J Med 361, 1152-63.

D'Souza et al (2009) Pathogenesis and pathophysiology of accelerated atherosclerosis in the diabetic heart Mol Cell Biochem 331, 89–116. DOI

Duan et al (2009) PPARs: the vasculature, inflammation and hypertension. Curr. Opin. Nephrol. Hypertens. 18, 128–133. DOI

Dunlop & Tee (2009) Mammalian target of rapamycin complex 1: Signalling inputs, substrates and feedback mechanisms. Cellular Signalling 21, 827–835.


Ehrenberg & Krook (2009) Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ. Pharmacol Rev 61, 373–393.

Eicher et al (2010) The additive blood pressure lowering effects of exercise intensity on post-exercise hypotension Am Heart J 160, 513–520. DOI

Ernst & Moser (2009) Use of Diuretics in Patients with Hypertension. N Engl J Med 361, 2153-2164.

Espenshade & Hughes (2007) Regulation of Sterol Synthesis in Eukaryotes. Annu. Rev. Genet. 41, 401–27.

Etgen et al (2010) Physical Activity and Incident Cognitive Impairment in Elderly Persons Arch Intern Med 170, 186–193.


Fearon & Faux (2009) Oxidative stress and cardiovascular disease: Novel tools give (free) radical insight. J Mol Cell Cardiol 47, 372–381.

Ferrannini & Mingrone (2009) Impact of Different Bariatric Surgical Procedures on Insulin Action and β-Cell Function in Type 2 Diabetes. Diabetes Care 32, 514-520.

Figarola et al (2007) Anti-inflammatory effects of the advanced glycation end product inhibitor LR-90 in human monocytes. Diabetes 56, 647-655.

Figarola et al (2008) LR-90 prevents dyslipidaemia and diabetic nephropathy in the Zucker diabetic fatty rat. Diabetologia 51, 882-891.

Finley & Haigis (2009) The coordination of nuclear and mitochondrial communication during aging and calorie restriction. Ageing Research Reviews 8, 173–188.

Flaa et al (2008) Does sympathoadrenal activity predict changes in body fat? An 18-y follow-up study. Am J Clin Nutr 87, 1596–601.

Folmes & Lopaschuk (2007) Role of malonyl-CoA in heart disease and the hypothalamic control of obesity. Cardiovascular Research 73, 278–287.

Foresight Programme (2007) Tackling Obesities: Future Choices. Department of Innovation Universities and Skills DIUS/PUB 8654/2K/12/07/AR


Foster et al (2010) Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet Ann Intern Med 153, 147–157.

Fraisl et al (2009) Regulation of Angiogenesis by Oxygen and Metabolism. Developmental Cell 16, 167–179.

Fruchart (2009) Peroxisome proliferator-activated receptor-alpha (PPARα): At the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 205, 1–8.

Fu et al (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α Nature 425, 90–93.


Galkina & Ley (2009) Immune and Inflammatory Mechanisms of Atherosclerosis. Annu. Rev. Immunol. 27, 165–97.

Gao & Mann (2009) Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. Cardiovascular Research 82, 9–20.

Giacco & Brownlee (2010) Oxidative Stress and Diabetic Complications Circ. Res. 107, 1058-1070. DOI

Goh & Cooper (2008) The role of advanced glycation end products in progression and complications of diabetes. J. Clin. Endocr. & Metab. 93, 1143-1152.

Goldberg (2009) Cytokine and Cytokine-Like Inflammation Markers, Endothelial Dysfunction, and Imbalanced Coagulation in Development of Diabetes and Its Complications. J Clin Endocrinol Metab 94, 3171–3182.

Goodarzi & Psaty (2010) Glucose Lowering to Control Macrovascular Disease in Type 2 Diabetes: Treating the Wrong Surrogate End Point? JAMA 300, 2051–2053. DOI

Grun & Blumberg (2009) Minireview: The Case for Obesogens. Molecular Endocrinology 23, 1127–1134.

Guo et al (2009) ERM protein moesin is phosphorylated by advanced glycation end products and modulates endothelial permeability. Am J Physiol Heart Circ Physiol 297, H238–H246.


Haimoto et al (2009) Effects of a low-carbohydrate diet on glycemic control in outpatients with severe type 2 diabetes. Nutrition & Metabolism 6, 21.

Hansen & Diep (2009) N-acylethanolamines, anandamide and food intake. Biochemical Pharmacology 78, 553–560.

Hardie (2008) Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Letters 582, 81–89.

Hassing et al (2009) Overweight in midlife and risk of dementia: a 40-year follow-up study. Intl J Obesity 33, 893–898.

Hawley & Holloszy (2009) Exercise: it's the real thing! Nutrition Reviews 67, 172–178.

Heroux et al (2010) Dietary patterns and the risk of mortality: impact of cardiorespiratory fitness Int J Epidemiology 39, 197–209. DOI

Hession et al (2010) Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities Obesity Reviews 10, 36–50. DOI

Holst (2007) The physiology of glucagon-like peptide 1. Physiol. Rev. 87, 1409-1439.

Huang (2009) eNOS, metabolic syndrome and cardiovascular disease. Trends in Endocrinology and Metabolism 20, 295–302.

Hummasti & Hotamisligil (2010) Endoplasmic Reticulum Stress and Inflammation in Obesity and Diabetes Circ. Res. 107, 579–591. DOI

Huwiler & Pfeilschifter (2009) Lipids as targets for novel anti-inflammatory therapies. Pharmacology & Therapeutics 124, 96–112.


Idelevich et al (2009) Current pharmacotherapeutic concepts for the treatment of obesity in adults. Ther Adv Cardiovasc Dis 3, 75–90.

Im et al (2009) Sterol Regulatory Element Binding Protein 1a Regulates Hepatic Fatty Acid Partitioning by Activating Acetyl Coenzyme A Carboxylase 2. Molecular & Cellular Biology 29, 4864–4872.

Inoue et al (2008) Daily Total Physical Activity Level and Premature Death in Men and Women: Results From a Large-Scale Population-Based Cohort Study in Japan (JPHC Study). Ann Epidemiol 18, 522–530.


Jacobs et al (2010) Waist Circumference and All-Cause Mortality in a Large US Cohort Arch Intern Med 170, 1293–1301.

Jacovina et al (2009) Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2–dependent fibrinolysis. J Clin Invest 119, 3384–3394.

Jones (2009) Novel pharmacotherapies for obesity poised to enter market. Nature Reviews Drug Discovery 8, 833-834.

Jugdutt (2009) Limiting Fibrosis after Myocardial Infarction. N Engl J Med 360, 1567–1569.


Karra et al (2009) The role of peptide YY in appetite regulation and obesity. J. Physiol 587, 19-25.

Katakami et al (2009) Serum endogenous secretory RAGE level is an independent risk factor for the progression of carotid atherosclerosis in type 1 diabetes. Atherosclerosis 204, 288–292.

Katzmarzyk (2003) Physical inactivity, excess adiposity and premature mortality. Obesity Reviews 4, 257–290.

Knip et al (2010) Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity. New Engl J Med 363, 1900-1908.

Koh et al (2010) Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle PNAS 107, 15541–15546. DOI

Kokkinos et al (2009) Exercise Capacity and All-Cause Mortality in Prehypertensive Men. Am J Hypertens 22, 735–741.

Kokkinos et al (2010) Exercise Capacity and Mortality in Older Men: A 20-Year Follow-Up Study Circulation 122, 790–797. DOI

Kopf et al (2010) Averting inflammation by targeting the cytokine environment Nature Reviews Drug Discovery 9, 703–718. DOI

Korn et al (2009) IL-17 and Th17 Cells. Annu. Rev. Immunol. 27, 485–517.

Ku et al (2009) Rheumatoid Arthritis A Model of Systemic Inflammation Driving Atherosclerosis. Circ J 73, 977–985.


Lastra & Whaley-Connell (2009) Diabetes: Aspirin and prevention of diabetes still a topic of debate. Nature Reviews Endocrinology 5, 365-366.

Lefebvre et al (2009) Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation. Physiol Rev 89, 147–191.

Lefterova & Lazar (2009) New developments in adipogenesis. Trends in Endocrinology and Metabolism 20, 107–114.

Lim et al (2010) AMPK as a mediator of hormonal signalling Journal of Molecular Endocrinology 44, 87-97. DOI

Lira et al (2010) PGC-1a regulation by exercise training and its influences on muscle function and insulin sensitivity Am J Physiol Endocrinol Metab 299, 145–161. DOI

Lomenick (2009) Effects of Meals High in Carbohydrate, Protein, and Fat on Ghrelin and Peptide YY Secretion in Prepubertal Children. J Clin Endoc & Metab 94, 4463-4471.

Long et al (2010) Short-term exercise training prevents micro- and macrovascular disease following coronary stenting J Appl Physiol 108, 1766–1774. DOI

Ludman et al (2009) Statins and cardioprotection — More than just lipid lowering? Pharmacology & Therapeutics 122, 30–43.

Lundberg et al (2010) Roles of dietary inorganic nitrate in cardiovascular health and disease Cardiovascular Research [in press]. DOI


Ma & Blenis (2009) Molecular mechanisms of mTOR-mediated translational control. Nature Reviews Mol Cell Biol 10, 307-318.

Maas et al (2009) Morbidity is related to a green living environment. J Epidemiol Community Health [online only - not yet printed].

Magkos et al (2009) Management of the Metabolic Syndrome and Type 2 Diabetes Through Lifestyle Modification. Annu. Rev. Nutr. 29, 223–56.

Mann & Nye (2009) Fad diets in Sweden, of all places. Lancet 374, 767-769.

Marcovecchio et al (2010) Prevention and treatment of microvascular disease in childhood type 1 diabetes British Medical Bulletin 94, 145–164. DOI

Marion-Letellier et al (2009) Dietary modulation of peroxisome proliferator-activated receptor gamma. Gut 58, 586–593.

Mathur & Pedersen (2008) Exercise as a Mean to Control Low-Grade Systemic Inflammation. Mediators of Inflammation 2008, Article ID 109502.

Mckellar et al (2009) Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nature Reviews Cardiology 6, 410–417.

McLaren & Ramji (2009) Interferon gamma: A master regulator of atherosclerosis. Cytokine & Growth Factor Reviews 20, 125–135.

Mietus-Snyder & Lustig (2008) Childhood Obesity: Adrift in the "Limbic Triangle". Annu. Rev. Med. 59, 147–62.

Misra et al (2009) Increased Carbohydrate Induced Ghrelin Secretion in Obese vs. Normal-weight Adolescent Girls. Obesity 17, 1689–1695.

Montecucco & Mach (2009) Update on statin-mediated anti-inflammatory activities in atherosclerosis. Semin Immunopathol 31, 127–142.

Montecucco et al (2009) The Renin-Angiotensin System Modulates Inflammatory Processes in Atherosclerosis: Evidence from Basic Research and Clinical Studies. Mediators of Inflammation. Article ID 752406, doi:10.1155/2009/752406..

Mukhopadhyay et al (2009) The GAIT system: a gatekeeper of inflammatory gene expression. Trends in Biochemical Sciences 34, 324–331.

Myers et al (2008) Mechanisms of Leptin Action and Leptin Resistance. Annu. Rev. Physiol. 70, 537–56.


Nagaya et al (2010) Resting heart rate and blood pressure, independent of each other, proportionally raise the risk for type-2 diabetes mellitus Int J Epidemiology 39, 215–222. DOI

Ness et al (2007) Objectively Measured Physical Activity and Fat Mass in a Large Cohort of Children. PLoS Medicine 4, e97.

Nielsen & Joensson (2008) Low-carbohydrate diet in type 2 diabetes: stable improvement of bodyweight and glycemic control during 44 months follow-up. Nutrition & Metabolism 5, 14.

Nohara et al (2009) Retinoid X receptor heterodimer variants and cardiovascular risk factors. J. Atherosclerosis & Thrombosis 16, 303–318.

Norata et al (2009) Circulating soluble receptor for advanced glycation end products is inversely associated with body mass index and waist/hip ratio in the general population. Nutrition, Metabolism & Cardiovascular Diseases 19, 129–134.


Olefsky & Glass (2010) Macrophages, Inflammation, and Insulin Resistance Ann Rev Physiol 72, 219–246. DOI

Orasanu & Plutzky (2009) The Pathologic Continuum of Diabetic Vascular Disease. J Am Coll Cardiol 53, S35–42.

Owen & McCarthy (2007) Genetics of type 2 diabetes. Curr. Opin. Genet. Dev. 17, 239-244.


Pereira & Oakley (2008) Nuclear factor-κB1: Regulation and function. Int. J. Biochem & Cell Biol 40, 1425–1430.

Petry (2010) Gestational diabetes: risk factors and recent advances in its genetics and treatment British Journal of Nutrition 104, 775–787. DOI

Plaisance & Grandjean (2006) Physical Activity and High-Sensitivity C-Reactive Protein. Sports Med 36, 443–458.

Poli et al (2009) Cholesterol oxidation products in the vascular remodeling due to atherosclerosis. Molecular Aspects of Medicine 30, 180–189.

Popkin et al (2006) Measuring the full economic costs of diet, physical activity and obesity-related chronic diseases. Obesity Reviews 7, 271–293.

Praet & van Loon (2009) Exercise therapy in Type 2 diabetes Acta Diabetol 46, 263–278. DOI



Ramaswamy et al (2009) RAGE: therapeutic target and biomarker of the inflammatory response—the evidence mounts. J. Leukoc. Biol. 86, 505–512.

Ray et al (2009) A stress-responsive RNA switch regulates VEGFA expression. Nature 457, 916–920.

Reidelberger et al (2008) Effects of different intermittent peptide YY (3-36) dosing strategies on food intake, body weight, and adiposity in diet-induced obese rats. Am J Physiol Regul Integr Comp Physiol 295, R449-R458.

Riehl et al (2009) The receptor RAGE: Bridging inflammation and cancer. Cell Communication and Signaling 7, 12.

Rocha & Libby (2009) Obesity, inflammation, and atherosclerosis. Nat. Rev. Cardiol. 6, 399–409.

Ross & Bradshaw (2009) The future of obesity reduction: beyond weight loss. Nat. Rev. Endocrinol. 5, 319–326.

Roth & Breaker (2009) The Structural and Functional Diversity of Metabolite-Binding Riboswitches. Annu. Rev. Biochem. 78, 305–34.

Ruderman et al (2010) AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab 298, E751-E760.

Rutter & Leclerc (2009) The AMP-regulated kinase family: Enigmatic targets for diabetes therapy. Molecular and Cellular Endocrinology 297, 41–49.


Saha et al (2009) The monocyte/macrophage as a therapeutic target in atherosclerosis. Current Opinion in Pharmacology 9, 109–118.

Sakamoto & Holman (2008) Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Amer. J. Physiol. 295, E29-E37.

Sandoval et al (2008) The Integrative Role of CNS Fuel-Sensing Mechanisms in Energy Balance and Glucose Regulation. Annu. Rev. Physiol. 70, 513–35.

Sato (2009) SREBPs: protein interaction and SREBPs. FEBS Journal 276, 622–627.

Seale et al (2009) Transcriptional control of brown adipocyte development and physiological function—of mice and men. Genes & Development 23, 788–797.

Shackelford & Shaw (2009) The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nature Reviews Cancer 9, 563 – 575.

Shai et al (2008) Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet. N Engl J Med 359, 229-241.

Shaw (2009) LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol 196, 65–80.

Shelton & Miller (2010) Eating ourselves to death (and despair): The contribution of adiposity and inflammation to depression Progress in Neurobiology 91, 275–299. DOI

Shepherd et al (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. The Lancet 360, 1623–1630.

Shin et al (2008) Inputs to the Ventrolateral Bed Nucleus of the Stria Terminalis. J. Comp. Neurology 511, 628–657.

Skaug et al (2009) The Role of Ubiquitin in NF-κB Regulatory Pathways. Annu. Rev. Biochem. 78, 769–96.

Soro-Paavonen et al (2008) Receptor for Advanced Glycation End Products (RAGE) Deficiency Attenuates the Development of Atherosclerosis in Diabetes. Diabetes 57, 2461 – 2469.

Spinetti et al (2009) Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies. Cardiovascular Research 78, 265-273.

Stafylas et al (2009) The controversial effects of thiazolidinediones on cardiovascular morbidity and mortality. Int J Cardiology 131, 298–304.

Steckelings (2009) The evolving story of the RAAS in hypertension, diabetes and CV disease – moving from macrovascular to microvascular targets Fundamental & Clinical Pharmacology 23, 693–703. DOI

Sun et al (2009) RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice. Cardiovascular Research 82, 371–381.

Sun et al (2010) Physical Activity at Midlife in Relation to Successful Survival in Women at Age 70 Years or Older Arch Intern Med 170, 194–201.

Szabo (2009) Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. British Journal of Pharmacology 156, 713–727.


Tabas et al (2010) The Impact of Macrophage Insulin Resistance on Advanced Atherosclerotic Plaque Progression Circ. Res. 106, 58-67. DOI

Takano & Komuro (2009) Peroxisome Proliferator-Activated Receptor γ and Cardiovascular Diseases. Circ J 73, 214 – 220.

Thaler & Schwartz (2010) Inflammation and Obesity Pathogenesis: The Hypothalamus Heats Up Endocrinology 151, 4109–4115. DOI

Thomson et al (2009) Immunoregulatory functions of mTOR inhibition. Nature Reviews Immunology 9, 324–337.

Tontonoz & Spiegelman (2008) Fat and Beyond: The Diverse Biology of PPARγ. Annu. Rev. Biochem. 77, 289–312.

Towler & Hardie (2007) AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling. Circ. Res. 100, 328-341.



Vallabhapurapu & Karin (2009) Regulation and Function of NF-κB Transcription Factors in the Immune System. Annu. Rev. Immunol. 27, 693–733.

van Beekum et al (2009) Posttranslational Modifications of PPAR-γ: Fine-tuning the Metabolic Master Regulator. Obesity 17, 213–219.

van Haehling et al (2009) Cardiac cachexia: A systematic overview. Pharmacology & Therapeutics 121, 227–252.

van Marken Lichtenbelt et al (2009) Cold-Activated Brown Adipose Tissue in Healthy Men. N Engl J Med 360, 1500–1508.

Venkatachalam & Montell (2007) TRP Channels. Ann. Rev. Biochemistry 76, 387-417.

Verspohl (2009) Novel therapeutics for type 2 diabetes: Incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacology & Therapeutics 124, 113-138. [The first 8 pages are sufficient: students do not need the detailed pharmacology.].

Virtanen et al (2009) Functional Brown Adipose Tissue in Healthy Adults. N Engl J Med 360, 1518–1525.


Wallcher & Marx (2009) Advanced glycation end products and C-peptide—modulators in diabetic vasculopathy and atherogenesis. Semin Immunopathol 31, 103–111.

Wang & Nakayama (2010) Inflammation, a Link between Obesity and Cardiovascular Disease Mediators of Inflammation 2010, ID 535918. DOI

Weichart & Saemann (2009) The multiple facets of mTOR in immunity. Trends in Immunology 30, 218–226.

Weintraub (2009) Understanding Abdominal Aortic Aneurysm. N Engl J Med 361, 1114–1116.

West et al (2010) Insulin Signaling to the Glomerular Podocyte Is Critical for Normal Kidney Function Cell Metabolism 12, 329–340. DOI

Westerterp-Plantenga et al (2009) Dietary Protein, Weight Loss, and Weight Maintenance. Annu. Rev. Nutr. 29, 21–41.

Wideman & Kieffer (2009) Mining incretin hormone pathways for novel therapies. Trends in Endocrinology & Metabolism 20, 280-286.

Wijndaele et al (2010) Television viewing time independently predicts all-cause and cardiovascular mortality: the EPIC Norfolk Study Int J Epidemiol 2010, 1–10. DOI

Willet et al (1999) Guidelines for Healthy Weight. N Engl J Med 341, 427 - 433.

Williamson & Pahor (2010) Evidence Regarding the Benefits of Physical Exercise Arch Intern Med 170, 124–125.

Wong et al (2010) Endothelial Dysfunction: The Common Consequence in Diabetes and Hypertension J Cardiovasc Pharmacol 55, 300–3007. DOI

Woods et al (2008) Regulation of Food Intake Through Hypothalamic Signaling Networks Involving mTOR. Annu. Rev. Nutr. 28, 295–311.

Wren & Bloom (2007) Gut Hormones and Appetite Control. Gastroenterology 132, 2116-2130.

Wullschlegger et al (2006) TOR Signaling in Growth and Metabolism. Cell 124, 471–484.



Yamagishi et al (2009) Regulation of advanced glycation end product (AGE)-receptor (RAGE) system by PPAR-gamma agonists and its implication in cardiovascular disease. Pharmacological Research 60, 174–178.

Yan et al (2009) Receptor for AGE (RAGE) and its ligands—cast into leading roles in diabetes and the inflammatory response. J Mol Med 87, 235–247.

Yan et al (2010) The RAGE Axis: A Fundamental Mechanism Signaling Danger to the Vulnerable Vasculature Circulation Research 106, 842–853. DOI

Young et al (2009) Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes. Gut 58, 337-346.


Zeiser et al (2009) Regulation of different inflammatory diseases by impacting the mevalonate pathway. Immunology 127, 18–25.

Zhang & Zhang (2010) Adipose “Talks” to Distant Organs to Regulate Insulin Sensitivity and Vascular Function Obesity 18, 2071–2076. DOI

Zhang et al (2010) NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis PNAS 107, 18121-18126.

Zhao et al (2009) Advanced Glycation End Products Inhibit Glucose-Stimulated Insulin Secretion through Nitric Oxide-Dependent Inhibition of Cytochrome c Oxidase and Adenosine Triphosphate Synthesis. Endocrinology 150, 2569–2576.