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Slide 14. Medical Complications of Obesity Dr. Blackburn: Just before we came here, we got one of those emails from a patient that is trying to get started. It was sort of challenging because they have been at that starting point waiting for all the stars to line up. What have you thought about our strategy of not trying to push them on, but to not lose them in this area? This has been going on now for several weeks and we are finally getting all the travels over and all the weddings over with and so now everybody is together that our patient thinks they need to get started. What have you thought about our approach in keeping the person motivated, even though they are not doing the American Plate, they're not doing the portion control, they are not doing the physical activity? Ms. Day: We know that it takes small changes, and as we said, it is not going to happen overnight. What we have done with this particular patient is to just be there to support him. We know that we are not going to make him change: that needs to come from within. We are there to support him and kind of lead him in the right direction. Like you said, he is sort of getting himself all aligned with his exercise and his diet and he is taking it 1 step at a time. Again, it is going to be up to him to make those changes and we are clearly there to support him through that. Dr. Blackburn: Izzie, what would you think if you were to step in and give us a hand with this patient? He really has the need. He has a bad family history, his own medical condition, and he needs the weight loss, but we know in our Look AHEAD trial and our breast cancer weight reduction low fat trial that these are 4, 8, and 10 years. A few weeks [do] not bother us, but could you give us any clues about how we might get him to go beyond the talk and do the walk? Dr. Greenberg: I want to stress that when I talk about behavior change, it is not necessarily just food related or exercise related. When you want to talk about lifestyle change in getting people to integrate diet and exercise into their life, any change at all that you can start doing creates those ripples that make a difference. Somebody like that you could maybe just get them to do 5 or 10 minutes of relaxation at home a couple of times per week or some visualization work. Anything at all that gets them engaged -- it all counts, and you are beginning again to then make a difference in their lifestyle. Again it is something positive to talk about -- if they could start doing that, so that they want to come in and continue to see you.
Obesity and diabetes Obesity is on the increase globally, but particularly in western society. Globally, it is currently estimated that 1.1 billion people are overweight, with 320 million of these considered to be obese (IDF atlas). Being obese or overweight is associated with a number of negative events such as increased insulin resistance, hyperlipidaemia, hypertension and cardiovascular disease. For example, C VD mortality is 2–3 times greater when BMI > 35 kg/m 2 than when BMI is 18.5–24.9 kg/m 2 (Calle et al 1999), and CHD mortality increases by 30% for every 5-unit increment in BMI (Selmer & Tverdal 1995). Furthermore, obesity is the major risk factor for the development of type 2 diabetes. Globally, it is estimated that nearly 60% of diabetes cases can be attributed to a BMI > 21 kg/m 2 , and, in Western countries, it is suggested that nearly 90% of diabetes cases in people aged 30 years or older can be attributed to weight gain. These findings are supported by the observation that i n the USA, nearly 50% adults with type 2 diabetes have a BMI of 30 kg/m² or greater (Nelson et al 2002). Given this negative impact of weight, additional weight gain caused by diabetes treatment is a most undesirable consequence. References International Diabetes Federation. Diabetes Atlas 2 nd Edition. International Diabetes Federation 2003. Nelson et al. Diabetes Care 2002;25:1722-1728 Calle et al. N Engl J Med 1999;341:1097-1105. Selmer & Tverdal. J Epidemiol Community Health 1995;49:265-270.
The temporal relationship between insulin resistance, insulin secretion and the development of diabetes is shown in this slide. In the early stages, as insulin resistance increases (that is insulin sensitivity falls), there is a compensatory increase in insulin secretion and the individual remains normoglycemic. In the long term, as the -cells begin to fail, insulin secretion falls and abnormal glucose tolerance and hyperglycemia become apparent until frank type 2 diabetes develops. Slide 11
Cardiovascular Disease Mortality Increased in the Metabolic Syndrome One of the key issues that has not been dealt with by IDF and NCEP is how high is the risk of cardiovascular disease? I'm going to focus on just 2 observational pieces of data. And all of these data have their own limitations. The 2 papers I'm going to talk about look at cardiovascular mortality and nonfatal disease as well. This is a famous paper by Lakka; it's based on the Kuopio ischemic heart disease study, about 1200 men, 10-year follow-up, and a very, very high hazard ratio -- 3.55. That's sort of what the Framingham study shows for diabetes and coronary heart disease (CHD) in women, so if this sort of data is correct or generalizable, it suggests that you might treat these people as close to having CHD. These are Finnish data.
En France, la prévalence du syndrome métabolique, selon les critères du NCEP ATP III, montre un gradient nord-sud que l’on retrouve dans toutes les études de cohortes sur les maladies cardiovasculaires. Cette prévalence est plus importante à Lille qu’à Toulouse. En France, 22,5 % des hommes présentent un syndrome métabolique contre 18,5 % de femmes en moyenne.
On retrouve ces mêmes données, dans une étude japonaise, où l’on observe un risque multiplié par plus de 5 de développer un diabète en cas de présence d’un syndrome métabolique .
Now, this is a slide that is published in The Lancet, and I think it's one of the most influential papers. This is Dr. John Yudkin from London, who collaborates with Dr. Yajnik from India. They both have the same BMI. The percent body fat for the man on the left is 9%; for the person on the right, the body fat is 22%. Same BMI, 2.5 times more body fat. The gentleman on the left runs marathons; the highest level of physical activity for the gentleman on the right is when he runs to catch the elevator! And one of the fundamental problems of the metabolic syndrome and obesity is the large reduction in activity as we modernized, and we haven't compensated enough for it.
Circling back to the discussion of abdominal adiposity, data regarding waist circumference and diabetes illustrate its health impact. These are age-adjusted data from the Nurses’ Health Study, analyzing responses from 43,581 subjects who provided information on weight and body measurements in 1986. These subjects had no history of cancer, heart disease, stroke, or any type of diabetes. An 8-year follow-up in this population showed a strong positive association between waist circumference and the incidence of diabetes. At the far end of the spectrum, women with a waist circumference >96.3cm had a diabetes risk of 22.4, relative to women in the normal waist circumference range of <71 cm. Other obesity measures studied included body mass index and waist-to-hip ratio; both of these were also found to be independent determinants of type 2 diabetes in this population. The sharpest risk gradient was documented with waist circumference, indicating that it is a powerful independent predictor of type 2 diabetes in women. (WC was measured at the high point of the iliac crest at minimal respiration – to the nearest 0.1 cm.) Carey VJ, Walters EE, Colditz GA, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: the Nurses’ Health Study. Am J Epidemiol. 1997;145:614-619.
Upper body obesity, specifically visceral obesity, is associated with adverse health consequences and elevated plasma free fatty acid (FFA) concentrations. It has been proposed that excess release of FFA from visceral fat is a significant contributor to these adverse health consequences, because the FFA enter into the portal circulation to affect the liver and from there enter the systemic circulation via the hepatic vein. KW: obesity, fatty acids
Pour qu’un sujet puisse être défini comme ayant un syndrome métabolique, il faut : • qu’il soit porteur d’une obésité abdominale centrale, définie comme une circonférence abdominale > 94 cm chez l’homme, et > 80 cm chez la femme de type européen, avec quelques ajustements pour d’autres groupes ou spécificités ethniques ; • et qu’il ait au moins deux autres des facteurs prédisposant : - TG élevés >150 mg/dl ou un traitement spécifique de cette anomalie lipidique ; - un HDL C <40 mg/dl chez l’homme, ou < 50 mg/dl chez la femme, ou un traitement spécifique de cette anomalie lipidique ; - une élévation de la pression artérielle systolique > 130 mmHg ou une PAD > 85 mmHg, ou un traitement de cette hypertension ; - une élévation de la glycémie > 1 g/l ou un diagnostic de diabète de type II.
Adipose tissue was not previously viewed as an organ. It was regarded solely as an inert depot for energy storage. It is now known that adipose tissue secretes adipokines — bioactive peptides — that act locally and systemically. In other words, adipose tissue is an endocrine organ. It provides the metabolic communication mechanism with distant organs including the central nervous system. As an example of the systemic actions of these adipokines: TNF- represses the genes involved in the uptake and storage of glucose and nonesterified fatty acids. It also suppresses the genes in the liver that are involved in glucose uptake, metabolism, and fatty acid oxidation. Some of leptin’s effects are mediated through actions on peripheral tissues such as muscle and pancreatic beta cells. It is suggested that an enhanced understanding of adipose tissue’s endocrine function could lead to better approaches to metabolic conditions such as obesity. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab . 2004;89:2548-2556.
This slide illustrates the pathophysiology of atherosclerotic cardiovascular disease related to metabolic syndrome. Research suggests that innate immunity and inflammation are involved in the development of insulin resistance and that they are predictors of type 2 diabetes. Immunity and adiposity drive the development of insulin resistance, chronic inflammation, and other features of metabolic syndrome through the actions of adipokines (eg, leptin, adiponectin, resistin) and cytokines (eg, tumor necrosis factor-alpha [TNF- ], interleukin-6 [IL-6]) on the liver and skeletal muscle. In addition, factors derived from monocyte/macrophages and adipocytes lead to the development of cardiometabolic risk factors such as increased HDL-C, triglycerides, high blood pressure, and high waist circumference. This process leads to diabetes and/or atherosclerosis, atherothrombosis, and eventually cardiovascular events. Reilly MP, Rader DJ. The metabolic syndrome: more than the sum of its parts? Circulation . 2003;108:1546-1551.
Adiponectin is the hormone expressed by adipocytes; this circulating plays a key role in the regulation of fat and in glucose metabolism. Adiponectin levels have been shown to be reduced in adults with obesity and type 2 diabetes In a study of obese Japanese subjects with type 2 diabetes and CVD, conditions commonly associated with insulin resistance and hyperinsulinaemia, plasma levels of adiponectin were found to be decreased. In a study of 352 nondiabetic women, Matsubara and colleagues found hypertriglyceridaemia and reduced HDL-C to be associated with low plasma adiponectin concentrations. In mice consuming a high-fat/high-sucrose diet, Fruebis and colleagues showed that administration of globular adiponectin resulted in weight loss and a decrease in plasma glucose, free fatty acids (FFAs) and triglycerides. Increased adiponectin levels were determined by Chandran and colleagues to be associated with improved insulin sensitivity. Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation byactivating AMP-activated kinase. Nat Med . 2002;8:1288-1295. Weyer C, Funahashi T, Tanaka S, et al. Hypoadiponectinemia in Obesity and Type 2 Diabetes: Close Association with Insulin Resistance and Hyperinsulinemia. J Clin Endocrinol Metab . 2001;86:1930-1935. Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia. J ClinEndocrinol Metab . 2002;87:2764-2769. Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related proteinincreases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci. 2001;98:2005-2010. Chandran M, Ciaraldi T, Phillips SA, Henry RR. Adiponectin: More Than Just Another Fat Cell Hormone? Diabetes Care. 2003;26:2442-2450.
Cette figure illustre la densité énergétique d’un déjeuner copieux en regard de 3 petits morceaux de fromage… Pour un apport énergétique comparable de 600 kcal. Nom de Poids de Energie Glucides Lipides Protides % de l ’apport l’aliment la portion (kcal) (g) (g) (g) énergétique (g) total Tomates 107,25 84 3,5 7,54 0,8 14,3 + 1 c. à soupe d’huile Filet de cabillaud 100 97 0 1 22 16,5 Sauce crème fraîche 30 49 0,9 4,5 0,6 8,4 (15% MG)+ ciboulette Riz blanc 150 178,5 39,5 0,3 3,5 30,5 Haricots verts 150 36 7 0,3 3,5 6,2 1 cuillère à soupe 7,25 65 0 7,24 0 11,1 de matière grasse Salade de fruits frais 150 77,2 16 0,8 1,5 13 Total 694,5 586,7 66,9 21,7 31,9 100 &quot;J’ai bien mangé …&quot; Nom de Poids de Energie Glucides Lipides Protides % de l ’apport l’aliment la portion (kcal) (g) (g) (g) énergétique (g) total Pain blanc 50 135 28 0,5 4 21,6 (2 tartines) Emmenthal 30 113 0 8,5 9 18 Roquefort 30 111 0 10 5,5 17,8 Camembert 30 85 0 6,5 6,5 13,6 Crème au chocolat 125 181 26 6 6 29 Total 265 625 54 31,5 31 100 &quot;Je n’ai pas beaucoup mangé …&quot; 11
באמצעות הפחתה של 10 אחוז מהשמקל אנו מצליחים לשפר במידה משמעותית את הפרמטרים הגליקמיים , , מפחיתים את הסיכון להתפתחות של יתר לחץ דם עורקי , ומשפרים במידה משמעותית את פרופיל הליפידים של המטופל . מהי התרומה הבריאותית לשיפור בגורמי הסיכון הנובע מהפחתת משקל של 10 אחוז .? כיצד הפחתת משקל של חמישה או עשרה אחוז בעזרת רדוקטיל משפרת את גורמי הסיכון הקרדיומטבוליים ? בנתוני המחקרים שאציג בפניכם אדגים את השיפור בגורמי הסיכון הקרדיומטבוליים בקרב מטופלים ברדוקטיל שהפחיתו במשקלם .
Gary – Added baseline HbA1c for sib
DISCUSSION By decreasing β -cell workload and improving β -cell response, GLP-1 is an important regulator of glucose homeostasis. Upon food ingestion, GLP-1 is secreted into the circulation. GLP-1 increases β -cell response by enhancing glucose-dependent insulin secretion. BACKGROUND GLP-1 is secreted from L cells of the small intestine. GLP-1 decreases β -cell workload, hence the demand for insulin secretion, by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand ( β -cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β -cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake Effect on Beta cell: Drucker DJ. Diabetes . 1998;47:159-169. Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand . 1997;160:413-422. Effects on Liver: Larsson H, et al. Acta Physiol Scand . 1997;160:413-422. Effects on Stomach: Nauck MA, et al. Diabetologia . 1996;39:1546-1553. Effects on CNS: Flint A, et al. J Clin Invest . 1998;101:515-520.
The effect of GLP-1 on weight: GLP-1 affects the gastrointestinal system and delays absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al. 1993). Combined, these gastrointestinal effects reduce the meal-related increase in glucose. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce energy intake by inducing satiety. Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing energy intake.
Patients treated with insulin had a slight weight gain, those with insulin and placebo . Those patients treated with pramlintide and insulin had a significant weight drop during this 16 weeks of therapy .
Even things like smoking -- which is not included in the definition of the metabolic syndrome, although smoking increases the risk of the metabolic syndrome incidentally -- you can see even small amounts of smoking, like 1 to 5 cigarettes a day, increases the risk 1.5-fold and there's a linear line. And incidentally, that 1.5-fold is stronger than the so-called fancy risk factor C-reactive protein. This is stronger than any inflammatory marker, yet nobody has held a symposium called &quot;What Do Low Levels of Smoking Do to You&quot; because it's so boring, so simple.