A widely cited 2001 review by Atkinson and Eisenbarth set the agenda for diabetes care for the remainder of the decade with a prediction, since borne out, that genetically engineered insulins (particularly glargine, see Lepore et al 2000) and every more accurate and inexpensive glucose monitors would play a significant role in improving the lot of diabetics. Norris, Engelgau and Narayan in 2001 and Bodenheimer, Loring, Holman and Grumbach in 2002 pointed out that patients who had been given significant training in handling the fluctuations in their chronic disease on their own, at least in the short run, actually had better outcomes than those who were well-informed but instructed not to make any adjustments independent of their physician’s advice.
The Causes & Costs of Poor Patient Compliance with Diabetes Management Regimes
Making diabetic patients more self-confident in managing their diabetes may require overcoming some psychological barriers. A 2000 analysis by Ciechanowski, Katon and Russo and a 2001 study by Anderson, Freedland, Clouse and Lustman found that overall, diabetics were twice as likely as nondiabetics to suffer clinical depression. Rates among women and those whose diabetes was poorly controlled were even higher. Not surprisingly, these are the patients with the poorest diets and lowest medication adherence, the cost of whose emergency treatment disproportionately impacted the overall healthcare budget. Krinsley reported in a 2004 paper in the Mayo Clinic Proceedings that the use of protocol he designed and the set aside of a small number of beds for patients in diabetic crisis, helped mitigate those costs by reducing length of hospital stays in the ICU by 10% , decreased need (19%) for packed red blood cell transfusions, a 75% reduction in renal failure, and most important, 29% fewer deaths on the floor.
The Longer a Diabetic Lives, the More Important Cardiovascular Care Becomes
One mixed blessing of the extended lives of diabetics, however, is that according to major 2002 review by Beckman, Creager and Libby most of them now die of cardiovascular disease, and so as to stave off these for as long as possible, prescription diuretics, ACE inhibitors, statins and anticoagulants should be considered in virtually all cases of adult diabetes management. By 2007, Dahlof et al. reported a major refinement to the traditional mix of blood pressure medications for diabetics , favoring a combination of amlopidine with perindopril as needed over atenolol and bendroflumethiazide as needed.
Diabetes & Metabolic Syndrome
Diabetes research became inextricably linked focused on the tremendous rise in the numbers of patients with metabolic syndrome, a symptomatic cluster involving visceral fat deposits around the stomach, high blood pressure, often with a number of circulating markers of ongoing inflammatory processes. Patients with metabolic syndrome are extraordinarily prone to type 2 diabetes and heart disease. In 2003, Park, Zhu, Palaniappan et al reported that a six year survey disclosed that almost one in four adults in the United States now showed signs of metabolic syndrome, and in 2005 the American Heart Association and the National Heart, Lung, and Blood Institute issued comprehensive new guidelines for its diagnosis and management (See Grundy et al). In 2006, Nathan et al published a consensus algorithm for the initiation and adjustment of hyperglycemia for the many new cases of type 2 diabetes emerging.
Diabetes & Inflammatory Processes
A 2003 review by Fernandez-Real and Ricart provides additional support for an inflammatory basis for chronic diseases via their survey of the actions of two proinflammatory cytokines, TNF-alpha (Tumor Necrosis Factor alpha) and IL-6 (Interleukin 6). Both substances turn out to be heavily involved in both type 2 diabetes, and in atherosclerosis.
A further linkage of diabetes with inflammatory processes at the molecular and cellular level was found in a 2007 study by Lumeng, Bodzin and Saltiel. They discovered that cells designed to fight off infection in fat tissue, macrophages, undergo an unfavorable change in their surface polarization that increases with high-fat feeding. Instead of being protective, they become inflammatory and contribute to insulin resistance, a pattern seen time and again in metabolic syndrome.
The Boom in Genetic Studies of Type 2 Diabetes
While the genetics of type 1 diabetes have long been very well understood, the 2000s saw greater insights into type 2 susceptibility, and a contributing cofactor, high triglyceride levels. A vast team headed up by Saxena, Voight, Lyssenko et al analyzed 386,731 genetic variants found among 1464 patients with type 2 diabetes and matched them against an approximately equal number of normals. In a 2007 paper reported in Science, they uncovered significant six new variants, five related to the diabetes and one related to the triglyceriedes.
Programmed Cell Death & Diabetes
In 2003, a proposal by Butler, Janson, Bonner-Weir et al to start targeting the type 2 diabetic’s shortfall in beta cells in pancreatic tissue, by reducing the premature and excessive apoptosis (natural cell death) gained traction as a pro-active measure, since stopping their death seemed a better strategy than just trying to compensate for it after the fact.
Obesity: An Increased Emphasis on Childhood & Adolescence
A 2005 review in The Lancet by Haslam and James set the stage for the rest of the decade: Adult and childhood obesity had now become the sixth most common disease worldwide. A 2006 analysis by Wang and Lobstein reported that after reviewing results from 25 countries, that obesity among school-aged children increased between 1980 to 2010 in 23 of 25 countries, the exceptions being Russia and to some extent Poland, during the collapse of state socialism and the current market economies. A contrarian view was reported in a 2008 study by Ogden, Carroll & Flegal. The increase in the prevalence of high BMI for age among US children that was previously seen in large-scale US surveys between 1988-2004 was not observed between 2003-2004 and 2005-2006. Even at the highest BMI for age level, no change in prevalence was found between 2003-2004 and 2005-2006, either overall or by racial/ethnic group. In other words, we have a lot of fat kids, but their numbers are not growing as fast as earlier professional and popular media reports suggest.
In 2007, an expert committee of specialists in childhood obesity, headed by Sarah Barlow, substantially revised their guidelines for the diagnosis and management of the condition in children and adolescents, devising a four step program with the hopes of arresting the condition before it carried over into adulthood.
Weight-Loss Surgery
A 2007 analysis in the New England Journal of Medicine (Adams, Gress, Smith et al) demonstrated that patients who had undergone gastric bypass surgery dramatically decreased their risk of dying from diabetes, heart disease and cancer, relative to matching groups of obese persons not having the surgery and against normals who had surgeries other than bypass. Also in 2007, a Swedish study in the New England Journal of Medicine (Sjostrom, Narbro, Sjostrom et al) compared roughly 4,000 obese patients, half of whom had weight loss surgery while the other half had treatment involving counseling, dieting and exercise. Patients who had gastric bypass, vertical-banded gastroplasty, or banding did significantly better in the ensuing years. While 13 would go on to die of heart disease, and 29 fell to cancer, those treated with more conventional methods had a greater number of deaths from both heart disease (25) and cancer (47). The researchers highlight the fact that those nutritionally counseled, who dieted and exercised ultimately weighed plus or minus two percent of their original obese level weight.
Fat-Bypass Drugs
Nonetheless, there is still a ray of hope for patients (typically women) who would prefer to try one of the fat-bypass drugs, such as orlistat (beter known by its trademarked names of prescription strength= Xenical, over-the-counter = Alli ) on the market as well as a reduced calorie diet, as opposed to by-pass surgery. A 2009 Turkish study by Ulusoy et al shows a clear cut improvement in cardiovascular risk factors and cardiac function.
Obesity as a Social Contagion
An intriguing hypothesis was put forward in 2007 by Christakis and Fowler: That obesity was a kind of contagious social disease. Their observation of 12,067 members of the Framingham Heart Study showed that not only did non-obese siblings subsequently increase their chances of becoming obese (+40% ) if a sibling subsequently became obese, but also if they married (+37%) or befriended (+57%) a person who became obese. While the data that supports this conclusion is unassailable, implementation of its practical preventive follow-up, viz. ostracizing fat people, seems unlikely to gain widespread support.
The Genetics of Obesity
A more conventional insight into the roots of obesity was found in the 2007 papers of Dina, Meyre, Galina et al, Frayling, and Frayling, Timpson, Weedon et al. They reported that variations in FTO (fat mass and obesity associated) genes not only predict 22% of the increased of obesity in children and adults of European ancestry but also tie in with conditions leading to type 2 diabetes. An even more extensive analysis, also in 2007, by Scuteri, Sanna, Chen et al found genetic markers that tied in with BMI (body-mass index) numbers, hip circumference, and overall body weight.
Are Your Gut Microbes Making You Fat? Or Is Your Being Fat, Making Better Microbes Leave Your Colonic Neighborhood?
A 2006 theory published in two papers by Nature by Ley, Turnbaugh, Klein and Gordon, and Ley, Turnbaugh, Mahowald et al, that sounded absurd, but which gained a great deal of evidence to support it is that obese people have intestinal microflora -----notably a higher ratio of firmicutes----- that promotes obesity, while thin individuals have intestinal microflora -------notably a higher ratio of bacteroidetes------that actually promotes leaness. The mechanism by which bacteria alter the body’s intake of nutrients is not unlike that of the cow with its abundance of microbes in its four-chambered stomach, excepting that instead of having the bacteria primarily processing cellulose from grass, hay or grains so as to make it a bioavailable energy source with trace amounts of protein and fat, bacteria in the human intestines like the firmicutes excel in extracting fats from the passing food stream for deposition in the human body. Turnbaugh, Hamady, Yatsunenko et al would subsequently provide a 2009 refinement of the theory: The difference between lean and obese individuals in terms of their gut microflora is that the obese have a far less diverse array of bacteria, rendering the earlier observation of an imbalance in favor of firmicutes, accurate but incomplete because the remaining population of non-firmincutes which are not bacteroides, is also sparse, and symptomatic of a genuine lack of species richness.
Other Issues in Metabolism: Fasting Blood Tests & Tests of Body Fluids in General
A cardinal practice, the use of a fasting period before measurement of blood chemistry, particularly of triglycerides, came under close scrutiny. Based on the observation that postprandial triglycerides are typically elevated relative to fasting levels, and that it is exactly this elevation that might contribute the most to heart disease, Bansal, Buring, Rifai et al studied a group of approximately 27,000 women, who had triglyceride tests of either type, with some of either type of test takers subsequently having had heart attacks. Those whose triglyceride tests were taken after meals, and who showed a high triglyceride level, were, in retrospect, by far more likely to have a subsequent heart attack, making postprandial tests a superior prognostic indicator. The heart attacks of fasting-triglyceride-test- taking women were not predicted any way nearly as often because these tests essentially gave a false-negative results that did not show that tell-tale spike in triglycerides.
In 2007 Wishart, Tzur, Eisner et al announced the construction of the HMDB, the Human Metabolome Database, a searchable online resource, reporting on the properties and range of concentrations in bodily fluids of over 2000 human metabolites derived from scans of the existing scientific literature. The collection includes a great many linkages to genetic data, related enzymes, disease associations, and spectroscopic profiles.
Does Red Wine Really Help Your Obesity, Cholesterol, Triglycerides?
A 2006 laboratory animal study in Cell by Lagouge, Argmann, Gerhart-Hines et al, provided a significant ray of hope for the ingestion of resveratrol, a compound widely associated with red wines and the French advantage in longevity and lower cardiovascular disease, despite a diet rich in saturated fats and cholesterol. While claims that its efficacy in humans is clear cut and that it extends the life of all creatures are still unproven, it does have a high degree of potential in delaying the onset of Metabolic Syndrome, and has been shown to reduce the development of beta-amyloid plaques found in Alzheimer’s Disease
Post-Menopausal Bone-Loss Breakthroughs
Treatment for post menopausal bone loss saw its greatest advance in a 2007 paper in the New England Journal of Medicine by Black, Delmas, Eastell et al. Zoledronic acid, an IV-administered medicine to fight the loss of bone in certain cancers and in Paget’s Disease (and for those purposes marketed under the trade name Zometa) was approved for the more common condition of the prevention of limb or joint breakage owing to bone thinning and weakening in women in their 50s and above. While it was later shown to be strongly counterindicated in patients with kidney disease and certain jaw bone or dental problems, its once-a-year administration under the trademarked brand name Reclast, has proven to be of significant benefit, even for women who have already had a fracture.
Tony Stankus, FSLA tstankus@uark.edu Life Sciences Librarian, Science Coordinator & Professor
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