Recent Diabetes and Cardiovascular Disease ConferencesOctober 2016
By Ben Best
The lifetime risk of type II diabetes is now estimated to be about 40% for an American.1
Type II diabetes (formerly called adult-onset diabetes) accounts for 95% of diabetes cases, distinct from type I (previously called juvenile-onset diabetes), which accounts for 5% of cases.2 Type II diabetes is usually caused by abdominal obesity, physical inactivity, or excess sugar consumption.3-5
The fact that high blood sugar may be more damaging to blood vessels than high blood lipids might be indicated by the fact that diabetes greatly increases risk of cardiovascular disease. Middle-aged diabetic men have triple the rate of cardiovascular deaths as nondiabetic men in the same age-group.6 About 80% of diabetics die of heart attack or stroke, while a substantial number of the remainder die of kidney failure.7 Blood vessel damage in diabetes includes damage to vessels in the kidneys.8,9
In healthy persons, elevated blood glucose from a meal causes pancreas cells to secrete insulin. Insulin causes muscle cells to absorb glucose, fat cells to store fat, and liver cells to store rather than produce glucose.
In a prediabetic condition (metabolic syndrome), the responsiveness to insulin by muscle, liver, fat, and other cells diminishes (insulin resistance), although not to the same degree in every tissue.10 Even though about 80% of obese persons have insulin resistance and symptoms of metabolic syndrome, nearly 40% of normal-weight people also have metabolic syndrome symptoms.11
Due to the close connection between diabetes and cardiovascular disease, both the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease held in Los Angeles and the Cardiovascular Disease Prevention Symposium held in Miami are very similar. The Miami conference is organized by Michael Ozner, MD, who is a member of the Life Extension® Scientific Advisory Board.
Both annual conferences are attended by physicians concerned with diabetes and cardiovascular disease. I have previously reported on these conferences in Life Extension Magazine® (July 2015 and July 2014). This report will provide updates based on the most recent conferences which were held in November 2015 and February 2016.
Can Food Be Addictive?
Nicole Avena, PhD, a research neuroscientist at New York Obesity Research Center, Columbia University, studies food addiction. Although food is required for survival, some people overconsume food, displaying symptoms comparable to what is seen with drug addiction, including compulsive bingeing, tolerance, withdrawal, and cross-sensitization to other addictive substances. Food is comparable to alcohol insofar as only a minority of consumers exhibit addictive symptoms.
Dr. Avena has observed that people do not binge on broccoli, but are most likely to binge on sugar or, to a lesser degree, on fat (especially when combined with sugar).12 Dr. Avena has shown that sugar-addicted rats demonstrate activation of the same regions of the brain as are activated by drug addiction.13 Sugar-addicted rats deprived of sugar will increase their intake of alcohol, thereby displaying cross-sensitization.14
Dr. Avena suggests that the sugar fructose contributes to obesity more than glucose because glucose (from starches and sucrose) releases insulin, which reduces appetite,15 whereas fructose does not cause insulin release.16 A survey of 175 countries showed that increased availability of sugar is associated with increased diabetes, an association not found with any other food type.11
Is Sitting a Health Hazard?
Ralph La Forge, MSc, CLS, a clinical lipid specialist at Duke Lipid Clinic, Durham, North Carolina, is concerned with the health hazards of sitting. More than half of the average person’s waking hours are spent sitting.17 Spending much time sitting has been associated with greater risk of dying from cancer and cardiovascular disease.18
The greatest health hazard is seen for those who are the least active.19 Obese and overweight individuals who were induced to walk for 2 minutes every 20 minutes showed reduced blood glucose and insulin.20 But a study of healthy individuals who get moderate exercise showed no mortality risk associated with the amount of time spent sitting.21 Treadmill workplace desks have been shown to reduce blood glucose and raise blood HDL, but standing desks did not show this benefit.22 Treadmill desks reduce work performance, whereas desks where it is possible to cycle while sitting do not interfere with work.23
Types of LDL Cholesterol
Ronald Krauss, MD, director of Atherosclerosis Research at California’s Children’s Hospital Oakland Research Institute, is concerned about the fact that low blood LDL cholesterol often is not a good predictor of low risk for coronary heart disease because the size of LDL particles is more important than the level of LDL cholesterol.
Persons with the highest concentration of small, dense LDL particles have triple the incidence of metabolic syndrome,24 and are more insulin resistant than persons with large, buoyant LDL.25 Small, dense LDL is not only more easily oxidized than the larger particles, it is more easily glycated (modified by sugar).
Even in healthy persons, the amount of glycated LDL is several times larger than the amount of oxidized LDL.26 Dr. Krauss has shown that diets low in fat and high in carbohydrate increase small, dense LDL in proportion to the amount of carbohydrate.27 Aside from dietary influences, Dr. Krauss has established that many people do not benefit from LDL-lowering statin drugs because of inherited genetic factors.28,29
Blood Lipids in Diabetes
James Underberg, MD, an internist at NYU Medical Center, New York City, is an expert in metabolic abnormalities most often found in diabetics (diabetic dyslipidemia), which are characterized by high blood triglycerides and lipoprotein composition that promotes atherosclerosis.30 The amount of triglycerides divided by the amount of HDL cholesterol is an excellent predictor of insulin resistance and cardiovascular disease risk when the ratio is high.31 A high carbohydrate diet has been shown to increase this ratio, indicating increased risk.32
Atherosclerosis is most strongly predicted by small, dense LDL, low HDL, and remnant cholesterol particles.33 Remnant cholesterol is calculated as non-fasting total cholesterol minus HDL cholesterol, minus LDL cholesterol.34,35 Remnant cholesterol is associated with chronic inflammation, whereas LDL cholesterol is not.36 Remnant cholesterol induces endothelial dysfunction through oxidative stress.37 According to one study, high remnant cholesterol is more predictive of myocardial infarction (heart attack) than any other lipid particle.38
Benefits of HDL Cholesterol
Eliot Brinton, MD, associate professor at University of Utah School of Medicine, Salt Lake City, spoke about the role of HDL cholesterol in protecting against cardiovascular disease. Unlike LDL cholesterol, which can contribute to atherosclerosis by its deposition in the walls of arteries, HDL can prevent atherosclerosis by removing cholesterol from arteries.39 HDL can also help to prevent or to correct endothelial dysfunction (the reduced ability of blood vessels to dilate), another condition that contributes to atherosclerosis.40 A third means by which HDL can protect against atherosclerosis is by its anti-inflammatory properties.40
Approximately 10% of patients given statin drugs to lower LDL cholesterol cannot tolerate those drugs. These patients can benefit from the increased HDL resulting from taking nicotinic acid (niacin, vitamin B3).41 But no benefit is seen for most patients attempting to combine statins with nicotinic acid.42
Insulin Secretion and Insulin Resistance
Ralph DeFronzo, MD, professor of medicine at the University of Texas Science Center, San Antonio, is a renowned diabetes expert who edited International Textbook of Diabetes Mellitus.
In the 1980s, Dr. DeFronzo showed that although muscle is the most important tissue associated with insulin resistance (resistance to glucose-uptake induced by insulin),43 insulin resistance of the liver prevents the liver from reducing its glucose production.44 More of the glucose produced by the liver comes from protein than from glucose that has been stored in the liver as glycogen.45 According to Dr. DeFronzo, obese type II diabetics tend to be insulin resistant in both their liver and muscle, whereas lean type II diabetics have defective insulin secretion in response to blood glucose.46 But as type II diabetes progresses, both lean and obese diabetics exhibit increasingly defective insulin secretion as well as defective insulin sensitivity.46
Dr. DeFronzo and his associates have shown that insulin sensitivity and glucose utilization decrease in proportion to increasing amounts of free fatty acids in the blood.47 But the ability of insulin to suppress free fatty acids is impaired in type II diabetes, creating a vicious cycle. 48,49 Dr. DeFronzo has shown that reducing free fatty acids in the blood of type II diabetics improves glucose utilization in mitochondria (energy producing parts of cells).50
Branched-Chain Amino Acids in a High Fat Diet?
Sun Kim, MD, assistant professor of medicine at Stanford University, has attempted to understand research by Duke University’s Dr. Chris Newgard indicating that adding branched-chain amino acids to a high-fat diet increased insulin resistance above that seen with a high-fat diet alone.51
In healthy people a test drink of branched-chain amino acids has been shown to increase blood insulin even more than a pure glucose drink.52 Another test on healthy humans showed that combining branched-chain or aromatic amino acids with carbohydrates doubled the insulin increase of carbohydrates alone.53 Unlike other amino acids, which are oxidized primarily in the liver, branched-chain amino acids are primarily oxidized in skeletal muscle.54 Although Dr. Kim has confirmed the association between certain amino acids and insulin resistance, she has questions about what causal relationships exist.55 Dr. Newgard has not yet published data confirming a causal relationship, but he cautions persons at risk of type II diabetes from eating foods high in fat and branched-chain amino acids such as meat and some milk products.
Heart Failure and High Blood Pressure
Mariell Jessup, MD, professor of medicine at the University of Pennsylvania, discussed treatment and prevention of heart failure. In heart failure the heart is unable to pump enough blood to meet the needs of the body. One American in five over the age of 40 will develop heart failure.56 Heart failure is the leading cause of hospitalization for people over age 65, with up to half of the victims dying within one year.57
A heart failure victim has shortness of breath, is easily tired, and can accumulate fluid in tissues. Fluid retention (congestive heart failure) in the lungs causes breathing difficulties and a hacking cough, whereas peripheral fluid retention (edema) is associated with swollen limbs. Poor kidney function is the best predictor that a heart failure victim will die.58
High blood pressure is the greatest modifiable risk factor for heart failure,59 along with diabetes and being overweight.60 Losing weight is an effective way to reduce blood pressure. Every increased unit of body mass index (BMI) is associated with a 5% increased risk of heart failure in men, and a 7% increased risk in women.61 Cardiovascular disease risk increases in direct proportion to all blood pressure readings above 115/75 mmHg.62
Insofar as these conferences were mainly concerned with preventing cardiovascular disease risk, they did not acknowledge the fact that type II diabetes greatly increases the risk of getting cancer.63
Excess weight and lack of exercise are obvious contributors to type II diabetes and death by cardiovascular disease or cancer.
Metformin is the most commonly used drug to lower blood glucose for prevention and treatment of type II diabetes.64
Most attempts to lose weight by dieting fail in almost all cases, nearly all the weight is regained within five years, with a third of dieters gaining more weight than they lost.65 Bariatric surgery, by contrast, is usually a successful way for the very obese to lose weight.66
Rather than reducing food consumption, changing to a vegetarian diet can be an effective way of losing weight without regaining it. Vegetarians have lower body weight,67,68 and a lower risk of metabolic syndrome.69 Dr. Michael Ozner (who organized the Miami conference) recommends a Mediterranean diet.
Reducing carbohydrates can also be a way of losing weight. In many cases a low carbohydrate diet has led to reduction or elimination of medications being used to treat type II diabetes.70
Lower risk of cancer, diabetes, and cardiovascular disease by dietary changes that don’t require restricting food intake can be the simplest way to better health. This lifestyle change can often be achieved without a protracted or difficult period of adjustment.
If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.
- Gregg EW, Zhuo X, Cheng YJ, et al. Trends in lifetime risk and years of life lost due to diabetes in the USA, 1985-2011: a modelling study. Lancet Diabetes Endocrinol. 2014;2(11):867-74.
- Available at: https://cvp.ucsf.edu/diseases/diabetes.html. Accessed July 19, 2016.
- Telford RD. Low physical activity and obesity: causes of chronic disease or simply predictors? Med Sci Sports Exerc. 2007;39(8):1233-40.
- Hardy OT, Czech MP, Corvera S. What causes the insulin resistance underlying obesity? Curr Opin Endocrinol Diabetes Obes. 2012;19(2):81-7.
- Johnson RJ, Perez-Pozo SE, Sautin YY, et al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev. 2009;30(1):96-116.
- Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16(2):434-44.
- Morrish NJ, Wang SL, Stevens LK, et al. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44 Suppl 2:S14-21.
- Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813-20.
- Gordin D, Groop PH. Aspects of Hyperglycemia Contribution to Arterial Stiffness and Cardiovascular Complications in Patients With Type 1 Diabetes. J Diabetes Sci Technol. 2016.
- Semple RK. EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons. Eur J Endocrinol. 2016;174(5):R209-23.
- Basu S, Yoffe P, Hills N, et al. The relationship of sugar to population-level diabetes prevalence: an econometric analysis of repeated cross-sectional data. PLoS One. 2013;8(2):e57873.
- Avena NM, Rada P, Hoebel BG. Sugar and fat bingeing have notable differences in addictive-like behavior. J Nutr. 2009;139(3):623-8.
- Rada P, Avena NM, Hoebel BG. Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience. 2005;134(3):737-44.
- Avena NM, Carrillo CA, Needham L, et al. Sugar-dependent rats show enhanced intake of unsweetened ethanol. Alcohol. 2004;34(2-3):203-9.
- Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006;116(7):1761-6.
- Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 2008;32(1):20-39.
- Available at: https://www.washingtonpost.com/news/wonk/wp/2015/06/02/medical-researchers-have-figured-out-how-much-time-is-okay-to-spend-sitting-each-day/. Accessed July 19, 2016.
- Biswas A, Oh PI, Faulkner GE, et al. Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis. Ann Intern Med. 2015;162(2):123-32.
- Ekelund U, Ward HA, Norat T, et al. Physical activity and all-cause mortality across levels of overall and abdominal adiposity in European men and women: the European Prospective Investigation into Cancer and Nutrition Study (EPIC). Am J Clin Nutr. 2015;101(3):613-21.
- Dunstan DW, Kingwell BA, Larsen R, et al. Breaking up prolonged sitting reduces postprandial glucose and insulin responses. Diabetes Care. 2012;35(5):976-83.
- Pulsford RM, Stamatakis E, Britton AR, et al. Associations of sitting behaviours with all-cause mortality over a 16-year follow-up: the Whitehall II study. Int J Epidemiol. 2015;44(6):1909-16.
- MacEwen BT, MacDonald DJ, Burr JF. A systematic review of standing and treadmill desks in the workplace. Prev Med. 2015;70:50-8.
- Koren K, Pisot R, Simunic B. Active workstation allows office workers to work efficiently while sitting and exercising moderately. Appl Ergon. 2016;54:83-9.
- Hoogeveen RC, Gaubatz JW, Sun W, et al. Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study. Arterioscler Thromb Vasc Biol. 2014;34(5):1069-77.
- Reaven GM, Chen YD, Jeppesen J, et al. Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest. 1993;92(1):141-6.
- Soran H, Durrington PN. Susceptibility of LDL and its subfractions to glycation. Curr Opin Lipidol. 2011;22(4):254-61.
- Krauss RM, Blanche PJ, Rawlings RS, et al. Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Am J Clin Nutr. 2006;83(5):1025-31; quiz 205.
- Strong A, Ding Q, Edmondson AC, et al. Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012;122(8):2807-16.
- Postmus I, Trompet S, Deshmukh HA, et al. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. Nat Commun. 2014;5:5068.
- Goldberg IJ. Clinical review 124: Diabetic dyslipidemia: causes and consequences. J Clin Endocrinol Metab. 2001;86(3):965-71.
- McLaughlin T, Reaven G, Abbasi F, et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol. 2005;96(3):399-404.
- Ma Y, Chiriboga DE, Olendzki BC, et al. Association between Carbohydrate Intake and Serum Lipids. Journal of the American College of Nutrition. 2006;25(2):155-63.
- Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia. 2003;46(6):733-49.
- Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384(9943):626-35.
- Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther. 2014;141(3):358-67.
- Varbo A, Nordestgaard BG. Remnant cholesterol and ischemic heart disease. Curr Opin Lipidol. 2014;25(4):266-73.
- Liu L, Wen T, Zheng XY, et al. Remnant-like particles accelerate endothelial progenitor cells senescence and induce cellular dysfunction via an oxidative mechanism. Atherosclerosis. 2009;202(2):405-14.
- Goliasch G, Wiesbauer F, Blessberger H, et al. Premature myocardial infarction is strongly associated with increased levels of remnant cholesterol. J Clin Lipidol. 2015;9(6):801-6.e1.
- Calabresi L, Gomaraschi M, Franceschini G. Endothelial protection by high-density lipoproteins: from bench to bedside. Arterioscler Thromb Vasc Biol. 2003;23(10):1724-31.
- Camont L, Lhomme M, Rached F, et al. Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities. Arterioscler Thromb Vasc Biol. 2013;33(12):2715-23.
- Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis. 2010;210(2):353-61.
- Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1580-4.
- DeFronzo RA, Gunnarsson R, Bjorkman O, et al. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76(1):149-55.
- Ferrannini E, Simonson DC, Katz LD, et al. The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism. 1988;37(1):79-85.
- Petersen KF, Price T, Cline GW, et al. Contribution of net hepatic glycogenolysis to glucose production during the early postprandial period. Am J Physiol. 1996;270(1 Pt 1):E186-91.
- DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37(6): 667-87.
- Belfort R, Mandarino L, Kashyap S, et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes. 2005;54(6):1640-8.
- Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians. 1999;111(3):241-8.
- Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-95.
- Daniele G, Eldor R, Merovci A, et al. Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals. Diabetes. 2014;63(8):2812-20.
- Newgard CB, An J, Bain JR, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9(4):311-26.
- Nilsson M, Holst JJ, Bjorck IM. Metabolic effects of amino acid mixtures and whey protein in healthy subjects: studies using glucose-equivalent drinks. Am J Clin Nutr. 2007;85(4):996-1004.
- van Loon LJ, Saris WH, Verhagen H, et al. Plasma insulin responses after ingestion of different amino acid or protein mixtures with carbohydrate. Am J Clin Nutr. 2000;72(1):96-105.
- Shimomura Y, Honda T, Shiraki M, et al. Branched-chain amino acid catabolism in exercise and liver disease. J Nutr. 2006;136(1 Suppl):250s-3s.
- Seibert R, Abbasi F, Hantash FM, et al. Relationship between insulin resistance and amino acids in women and men. Physiol Rep. 2015;3(5).
- Djousse L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime risk of heart failure. Jama. 2009;302(4):394-400.
- Davis BR, Piller LB, Cutler JA, et al. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006;113(18):2201-10.
- Hillege HL, Girbes AR, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102(2):203-10.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327.
- Schocken DD, Benjamin EJ, Fonarow GC, et al. Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation. 2008;117(19):2544-65.
- Hubert HB, Feinleib M, McNamara PM, et al. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983;67(5):968-77.
- Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957-67.
- Gallagher EJ, LeRoith D. Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. Physiol Rev. 2015;95(3):727-48.
- An H, He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol. 2016;228(3):R97-106.
- Dulloo AG, Montani JP. Pathways from dieting to weight regain, to obesity and to the metabolic syndrome: an overview. Obes Rev. 2015;16 Suppl 1:1-6.
- Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357(8):741-52.
- Key TJ, Davey GK, Appleby PN. Health benefits of a vegetarian diet. Proc Nutr Soc. 1999;58(2):271-5.
- Berkow SE, Barnard N. Vegetarian diets and weight status. Nutr Rev. 2006;64(4):175-88.
- Sabate J, Wien M. A perspective on vegetarian dietary patterns and risk of metabolic syndrome. Br J Nutr. 2015;113 Suppl 2:S136-43.
- Westman EC, Yancy WS, Jr., Mavropoulos JC, et al. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008;5:36.