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Congress Report from the American Diabetes Association66th Annual Scientific Sessions in Washington, USA
19 December 2006 (online)
“More than 73 million Americans, one-third of the adult population, now have diabetes or may be on their way to getting it. With this diabetes mellitus is the disease with the highest impact on the US economy” the president of the American Diabetes Association said while opening the American Diabetes Association 66th Annual Scientific Sessions in Washington. Therefore, the Diabetes and Its Co-Morbidities and Complications was a major topic at the congress and several sessions covered aspects of preventing and treating the complications of diabetes, particularly cardiovascular disease.
In the session “Identifying markers for cardiovascular disease risk in diabetic patients” Dr. Theodore Mazzone, University of Illinois at Chicago, Chicago, IL, USA reviewed the prognostic role of visceral abdominal fat and HDL for advanced coronary atherosclerosis in type 2 diabetic patients. He and his colleagues examined the relationship between traditional and emerging cardiac risk factors and coronary artery calcification (CAC). Dr. Mazzone reported that age, systolic blood pressure and gender were significant predictors of CAC (p<0.001). The visceral adipose tissue and HDL-C were significant predictors of coronary atherosclerosis (p=0.0008, both measures) in this analysis. He also noted that the impact of race/ethnicity on CAC was highly significant (p=0.006). Asian patients had a 26% higher CAC score than Caucasians, while African-American and Hispanic patients had a 63% and a 25% lower CAC score than Caucasians, respectively. It appears that while “traditional CV risk factors and race are predictors of CAC, visceral abdominal fat and HDL-C, as well as ApoB, are equally important pathophysiologic and clinical markers,” said Dr. Mazzone.
In the same symposium, Dr. Yamini Levitzky, Boston University School of Medicine, Boston, MA, USA reviewed the role of Impaired fasting glucose and cardiovascular disease risk. She stated that it remains unclear whether or not impaired fasting glucose (IFG) warrants broad public intervention. New data from the Framingham Heart Study suggest that the 2003 American Diabetes Association IFG definition (100/125 mg/dl) is associated with an increased coronary heart disease (CHD) risk in women but not in men. She added that until now, studies have failed to demonstrate a relationship between the 1997 (110 to 125 mg/dl) or 2003 IFG definitions and an increase in incidence of CV events. Dr. Levitzky and colleagues followed and categorized 4058 participants of the Framingham Offspring cohort free of CVD according to the 1997 and 2003 definitions for IFG. The study endpoints included CHD and CVD to compare the predictive value of the 1997 and 2003 IFG definitions for CHD and CVD risk. The results demonstrated that in men, neither the 1997 nor the 2003 IFG definition was associated with an increased risk for either CHD or CVD. In women, however, the 2003 IFG definition conferred an increased risk for CHD by 1.7 times. Furthermore, as the study was limited by both power and ability to generalize results to the population at large, confirmation of these data in other populations is needed.
Comment: An important question based on this session is whether or not there are different glycemic thresholds in women than in men that warrant attention. In clinical practice it would be easy to identify IFG but unfortunately until today it still remains not clear that prevalent clinical identification of IFG will ultimately drive therapeutic changes and if IFG improves the identification of candidates at risk for CHD.
Dr. R. Paul Wadwa, University of Colorado, Aurora, CO, USA spoke about Diabetes type and duration in young people and its association to increased arterial stiffness.
In the multicenter SEARCH for Diabetes in Youth substudy, Dr. Wadwa and colleagues examined the relationship between these parameters and glycemic control among 602 youths and young adults with Type 1 and Type 2 diabetes. Youths with Type 2 diabetes had significantly worse pulse wave velocities, augmentation index, and brachial distensibility than youths with Type 1 diabetes (p<0.01). He reported that multiple linear regression analyses showed a positive, significant association between Type 2 diabetes and brachial distensibility (p=0.02), augmentation index (p<0.01), and pulse wave velocity in the carotid to femoral segment (p<0.001) demonstrating that Type 2 diabetes and longer diabetes duration are independently associated with increased arterial stiffness in young adults with diabetes. The clinical question which needs an answer is: Can improved glycemic control lead to improvements in arterial stiffness and which role play insulin resistance and central adiposity in association with arterial stiffness:
The relation between polycystic ovary syndrome and cardiovascular risk was a topic in another session entitled: Polycystic ovary syndrome: Significant cardiovascular implications? During this session, Dr. David Ehrmann (University of Chicago, Chicago, IL, USA), Co-presenter Dr. Burton E. Sobel (University of Vermont, Burlington, VT, USA) as well as Dr. John E. Nestler (Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA) discussed this topic.
Dr. David Ehrmann said that while anovulation and hyperandrogenemia are the two central components comprising polycystic ovary syndrome (PCOS), PCOS is a syndrome with significant metabolic and cardiovascular derangements ranging from obesity, insulin resistance, beta cell dysfunction and a predisposition to diabetes, dyslipidemia, hypertension, and atherosclerosis. The predisposition to Type 2 diabetes reaches already a prevalence most commonly seen in Pima Indians, stated Dr. Ehrmann. Although body weight and/or body fat distribution is important, he said that data have shown that lean women with PCOS are often as insulin resistant as obese controls.
Co-presenter Dr. Burton E. Sobel (University of Vermont, Burlington, VT, USA) supported this contention, citing the strong interrelationship between insulin resistance and acceleration of atherosclerosis and stating that premature coronary disease is a relevant and troublesome feature in women with PCOS and that PAI-1 is the key to cardiovascular issues in women with PCOS. While many of the effects of Type 2 diabetes on the coagulation system are attributable to hyperglycemia, Dr. Sobel presented that plasminogen inhibitor activator-1 (PAI-1), a primary inhibitor of tPA and other plasminogen activators in the blood is the “bad actor in insulin disease, predisposing individuals to acute coronary syndrome and sudden death.” He explained that excessive levels of PAI-1 attenuate the protective effects conferred by fibrin, thereby predisposing an individual to thrombotic events. Additionally, in tissue, PAI-1 degrades the endothelial cell matrix, which attenuates normal migration of vascular smooth muscle cells. This results in unstable coronary artery plaque often seen in association with insulin resistance and Type 2 diabetes creating the cardiovascular morbidity in woman with PCOS.
The presentation by Dr. Nestler covered the question What are the therapeutic goals and new management strategies? He said 30-50% of obese women with PCOS will develop impaired glucose intolerance or type 2 diabetes. He commented that insulin resistance not only plays a critical role in the genesis of the disorder and a subsequent Type 2 diabetes progression, but also, influences the development of earlier cardiovascular disease that may include increased carotid artery intima-media thickness, increased coronary calcification, and coronary plaques at an extremely early age.
While traditional therapeutic goals for PCOS include the restoration of ovulation and decrease in testosterone levels, Dr. Nestler suggested that more novel goals also include the prevention of glucose intolerance and Type 2 diabetes as well as the prevention of atherosclerosis and acute coronary events. He stated that while oral contraceptives (OCs) may be effective in decreasing androgen levels, and possibly hirsutism, acne, and endometrial cancer risk, data suggest that OCs may also worsen insulin resistance, cause glucose intolerance, and increase triglyceride levels and overall cardiovascular risk even the second-generation of OCs. A new therapeutic strategy are the insulin sensitizers, which appear to perform better in all variables where OCs have performed worse, and may actually prevent Type 2 diabetes and cardiovascular disease in women with PCOS, while also improving ovulation. There is increasing evidence that this endocrine abnormality can be reversed by treatment with metformin (Glucophage® 500 or 850 mg three times per day or 1000 mg twice daily with meals) pioglitazone (15-30 mg once a day), rosiglitazone (4-8 mg once daily) or a combination of these medications. These medications have been shown to reverse the endocrine abnormalities seen with polycystic ovary syndrome within two or three months. The thiazolidinedione agent troglitazone has also been shown to normalize PAI-1 activity, improve glucose tolerance, and preserve beta cell dysfunction in PCOS. It is critical that women with this condition receive appropriate treatment aimed toward normalizing PAI-1 and ameliorating fibrinolytic abnormalities.
Comment: We have learned that PCOS is a “cardiovascular disease”. The aim is that all women with PCOS should be screened for glucose intolerance, dyslipidemia, hypertension, and cardiovascular risk factors. The therapy should focus towards decreasing the risk for Type 2 diabetes, and early cardiovascular disease.
The role HDL-C plays for cardiovascular risk and how it can be influenced was covered in the session HDL-Mostly Good-Sometimes Bad?
Ala R. Tall MD, Columbia University School of Medicine, New York, NY, USA presented the overwhelming evidence that low plasma levels of high-density lipoprotein cholesterol (HDL-C) are an important and independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aiming at elevating HDL-C levels, within the context of reducing global cardiovascular risk, would benefit such patients. The latter is increasingly adopted by international treatment guidelines. Therapeutic options for patients with low HDL-C include treatment with statins, fibrates and nicotinic acid, either as monotherapy or in combination. Of these options, nicotinic acid is not only the most potent agent for raising HDL-C but is also effective in reducing key atherogenic lipid components.
Phillip Barter, MBBS, PhD, Heart Research Institute, Camperdown, Australia reviewed the subtypes of the HDL and showed the complexity of the HDL ApoA1, and HDL ApoA2, which are clinically the most important sybtypes and targets for modern treatment as well as HDL ApoB, HDL ApoC, HDL ApoD and HDL ApoJ.
HDL ApoA1 and HDL ApoA2 are the relevant HDL particles in humans for protecting from atherosclerosis. This is realized through an antiinflammatory, antioxidative and antithrombotic function of HDL. First line strategies to elevate HDL are lifestyle strategies, weight reduction, increase of physical activity and the stop of smoking and alcohol consumption.
The pharmacologic spectrum includes fibrates, statins, niacin and the new class of CETP inhibitors, whereas fibrates and statins have an low or secondary effect on HDL-C. The most efficient drug available today to elevate HDL-C is niacin which increases HDL-C by 25-35% - mostly HDL ApoA1, and HDL ApoA2. Niacin reduces directly lipolysis in fat tissue due to inhibition of triglyceride lipase and increases HDL-cholesterol and reduces LDL-cholesterol and triglycerides. Niacin also blocks the release of free fatty acids from the liver and decreases catabolism of HDL combined with a distinct LDL lowering effect. The in the past often described negative effect of worsening glucose tolerance is minimal or not existent with the today also available form of an extended release niacin (NIASPAN®). Nicotinic acid is today the most efficient drug to increases HDL cholesterol and a perfect assumption in the prevention of cardio vascular events in patients with diabetes mellitus and metabolic syndrome. Results of the ARBITER 2 study show that progression of atherosclerosis was halted or greatly slowed by combining Niaspan with statin therapy. High density lipoprotein cholesterol (HDL-C) levels were significantly increased (p=0.002). The benefit of increasing HDL-C levels in slowing down atherosclerosis progression is well known and nicotinic acid is a well-established treatment.
A new class of drugs are CETP-inhibitors (e.g. Torcetrapib), which will be introduced in the market soon. By blocking CETP Torcetrapib leads to incorporation of the cholesterin in the HDL-C particle and reduces in animal model significantly atherosclerosis. CETP inhibitors have a potential to increase HDL-C by 40-90%. In the currently running clinical trials Torcetrapib doubles HDL ApoA1a and HDL ApoA2.
In summary Barter stated that patients with diabetic dyslipidemia are commonly treated with triglyceride-lowering fibrates, but niacin appears more effective than the fibrates for raising HDL-C. Since most patients with diabetes will require lipid-lowering therapy, the use of statins to lower LDL cholesterol has become routine therapy for the majority of patients. The additional use of extended release low-dose niacin therapy could provide an additional improvement of HDL levels and lipoproteins in patients with diabetes.
The session “How Do We Know It's A Metabolic ‘Syndrome’? Epidemiological and Genetic Perspectives” addressed the ongoing discussion about the Metabolic Syndrome as constructed mystery or clinical paradigm presented by Edwin Gale, MB, BChir, FRCP, Cambridge, GB.
He reviewed the epidemic expansion of diabetes mellitus and the Metabolic syndrome world wide. Edwin Gale presented different views to the metabolic syndrome driven by the physician, pharmacologist, preventive physician, nurse and industry. The more prevalent sedentary lifestyle and the globalization of “fast” and overly rich nutrition promotes the development of risk factors for the metabolic syndrome and the development of diabetes he states. The risk factors are well-known: obesity, visceral adiposity, physical inactivity and unhealthy diet. Consequently, metabolic syndrome, a condition strongly associated with obesity, has become an epidemic problem. Today the Metabolic syndrome is the largest epidemic in the western world after the Spanish influenza and the disease with the highest impact on the western economy but the Metabolic Syndrome is currently undergoing vivid exciting debates between a mystery of medicine or a clinical paradigm. Also if the pathophysiology of the Metabolic Syndrome seems to be clear this syndrome needs to be further elucidated. The insulin resistance of fat, muscle and liver is the central pathophysiological event in the development of this disease. Genetic and environmental factors play a major role in this process, although the precise pathogenesis of insulin resistance and type 2 diabetes is still largely unknown. Edwin Gale presented that there is no doubt that it is useful to summarize the clinical spectrum under terms like insulin resistance syndrome, Metabolic vascular syndrome, Cardio Metabolic Syndrome, but different diagnostic and treatment recommendations or even different definitions and terms do not help to make preventive, diagnostic or treatment strategies easier.
Comment: In this session the Metabolic syndrome was presented in its endocrine, nutritional, cardiovascular, metabolic and behavioral syndrome indicating different views of this disease. In the discussion was clearly stated that the patient was missed in the concept. Despite the lack of a clear definition we should not forget to treat the cluster of metabolic risk factors and its complications caused by them in our patients. If we see the discussion with the patients' eyes the Metabolic Syndrome is a clinical paradigm even without the causal understanding of the condition.
Obesity is associated with low-grade chronic inflammation, and serum markers of inflammation are independent risk factors for cardiovascular disease. Increased cytokine secretion from adipose tissue and increased systemic proinflammatory cytokine activity seems to play a significant role in increasing the risk for metabolic syndrome and Diabetes Type 2. Based on the observation that obese subjects have increased leptin levels paralleled by an elevated risk of insulin resistance and potential leptin resistance, Zhao and coworkers described a mechanism by which circulating C-reactive protein (CRP) binds to plasma leptin and attenuates its physiological functions. When several serum leptin-interacting proteins (SLIPs) were isolated from human blood using leptin-affinity chromatography, one of the major SLIPs was CRP. By binding to leptin, CRP reduced leptin binding to the leptin receptor in physiologic concentration in cultured cells. In vivo, infusion of high concentrations of human CRP into ob/ob mice blocked the effects of leptin upon satiety and weight reduction and the anti-diabetic effects of leptin on blood glucose and reduced liver triglyceride levels.
In the session “Metabolic pathways of inflammation and obesity-genetic constructs and therapeutic opportunities”, Dr. Gökhan S. Hotamisligil (Harvard University School of Public Health, Boston MA, USA) said that despite substantial efforts to gain control over obesity and glucose intolerance, both problems have truly become global epidemics that are expected to double in incidence within the next 5 years. Both of these syndromes are associated with well-known diseases (e.g., Type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease) and less well appreciated pathologies (e.g., airway disease, musculoskeletal disease, and cancer) this presenting significant challenges for diagnostics, therapy and prevention. It is important to approach this cluster of pathologies and to explore the interface between metabolic and inflammatory responses Dr. Hotamisligil suggested. He explained that the complex signalling cascade between insulin and its receptor substrates 1 and 2 (IRS1, IRS2) is a critical modular component. In the presence of nutrient excess (e.g., lipids), negative signalling events result that mediate both insulin resistance and metabolic dysfunction. Three leading underlying molecular mechanisms have been implicated: c-Jun NH2 terminal kinase (JNK), I75 B kinase (IKK-NFß), and protein kinase C (PKC).
JNK, IRS1 in inflammation, obesity, and related pathologies
Dr. Hotamisligil noted that JNK is spontaneously activated in the presence of obesity and is mediated by the JKN1 isoform. He added that hyperactivation of JNK1 leads to serine phosphorylation of IRS-1. Experimental data suggest that suppression of JNK activation in turns leads to suppression of adipose and liver tissue inflammation, thereby enabling recovery of insulin action in a profound fashion. A potential therapeutic option using this pathway could be by suppressing obesity-related activation of JNK, which might be able to control inflammatory and insulin responses that promote obesity, Type 2 diabetes, hepatosteosis, and atherosclerosis. Furthermore it appears that the endoplasmic reticulum (ER) also plays an important role in triggering inflammatory stress. When demand or capacity increases, the ER mounts a stress response that entails such factors as increased secretory demand, protein synthesis and lipid load, altered nutrient status, calcium flux, and critical structural alterations. The ER stress response is also linked to activation of JNK activity in the cells, and hence an increase in IRS-1 and insulin activity. Current research provides data that chemical modification of ER function can produce profound therapeutic effects that include normal glycemic levels, completely rescued insulin receptor signalling, and improved hepatosteosis.
Dr. Daniela M. L. Tsukumo, State University of Campinas, Campinas, SP, Brazil spoke about toll-like receptor 4 (TLR4) a potential therapeutic target? TLR4 may play a critical role in activation of the immune response in mammals, and may be integral to diet-induced obesity and the development of insulin resistance said Dr. Daniela Tsukomo. TLR-4 is a subclass of toll-like receptors activated by lipopolysaccharides and nonbacterial agonists, e.g., saturated fatty acids. Mice with a loss of function mutation in TLR4 had lower weight gain, decreased adiposity, improved insulin sensitivity, and improved glucose tolerance compared to control mice. Dr. Tsukomo reported that a high-fat-diet-induced increase in Ser307 phosphorylation was observed in the issues of control mice but not mice with loss of TLR4 function; this was accompanied by a reduction in IRS-1 expression in muscle and adipose tissue. Explaining the association between activation of TLR4 signalling and upregulation of intracellular inflammation (e.g., JNK, IKKβ/lκβ/F-κβ) and its relation to insulin resistance, she stated that mice fed with a high-fat diet also demonstrated an increase in IKK and JNK activity as well as iNOS expression (compared to none in control mice). She concluded that TLR4 appears to be a key mediator in the cross-talk between the inflammatory and metabolic pathways and therefore, a potential target for therapy.
Dr. Bankim A. Bhatt, University of Pittsburgh, Pittsburgh, PA, USA discussed the Pro-inflammatory NF-κβ pathway, weight gain, and insulin resistance.
Interventions that affect the activity of the pro-inflammatory NF-κβ pathway also directly affect insulin sensitivity. Dr. Bhatt explained that the specific role of the five different subunits of the NF-κB-family (p50, p65, p52. RelB, and cRel) is still not entirely clear, in particular, since studies have mainly focused on the importance of NF-κB p50 in activating the inflammatory response.
Dr. Bhatt said that while all mice placed on a high-fat diet developed obesity, p50 deficient male mice (KO) animals gained significantly less weight compared to high-fat wildtype (WT) mice (p<0.01). WT mice fed high-fat diets also had significantly greater epididymal fat weights compared to KO animals (p<0.05). Conversely, KO and WT controls gained equal amounts of weight. However, KO mice fed a high-fat diet developed similar degrees of glucose intolerance and insulin resistance compared to WT mice also fed a high-fat diet. In conclusion, Dr. Bhatt said, deletion of just one subunit of NF-κB, namely NF-κBp50, has a protective effect on body weight gain but not insulin action on high fat diets. Moreover, whole body lipid homeostasis is significantly improved in p50 KO mice. Further study will elucidate the mechanism underlying this effect, which the researchers believe includes depressed fatty acid oxidation and an increase in PPAR activity.
Comments: Several ways how obesity and associated systemic inflammation develop were discussed. Some interesting targets for new therapeutic strategies were presented. The interface between inflammatory and metabolic pathways represents a encouraging area for thinking about novel therapeutic approaches, particularly for patients in the pre-clinical state. Inhibition of JNK, chemical modification of ER, inhibition of certain subunits of function TLR4 and deletion of a specific NF-kB subunits seem to have a beneficial effect on inflammation, body weight gain and in certain cases on glucose homeostasis. These targets may offer the opportunity to develop new therapies against chronic metabolic disease.
Adding to the previous session on the Congress in the session entitled “Insights into obesity and novel therapeutic targets” GI hormone signalling pathways and a focus on the endocannabinoid system provoked an interesting dialogue regarding their potential as targets to optimize therapy in obese diabetic patients.
Gut hormones: focus on GIP and adipocytes was the title of a presentation held by Dr. David A. D'Allessio, University of Cincinnati, Cincinnati, OH, USA. Several gut hormones, namely GIP, GLP-1 and PYY, have been implicated broadly in the regulation of metabolism, and recent evidence has emerged for them in regulation of body weight said Dr. D'Allessio. He added that the question remains as to how their exogenous signals interact with exogenous pathways. GIP and GIPr: a weight gain break? Gut hormones are released in proportion to nutrient load and are responsible for regulating both pancreatic and endocrine functions. GIP in particular has been implicated in satiety and appears to play a role in important behavioral processes including food intake and body weight regulation via its receptor, GIPr, which is expressed in the brain as well as the central nervous system. Dr. D'Allesio stated that GIPr deletion reduces fat accretion in response to caloric over-consumption, and promotes enhanced energy expenditure suggestive of fatty acid oxidation. He said that these data raise the possibility that GIPr signalling at adipocyte cells could be a target for mitigating weight gain. However, he cautioned there are a paucity of data in humans, which prevents any broad conclusions from being made with regards to its potential for treating obesity.
GLP-1 and GLPr: more promising? In contrast to GIP, GLP-1 and its receptor GLPr, which are both expressed in the brain, look promising in terms of their potential for suppressing food intake and promoting weight loss. Experimental data suggest that the possible mechanisms for GLP-1 and GLPr's action on food intake includes delayed gastric emptying and increased capacity of the stomach, although these two actions have not yet been distinguished. Nevertheless, data from a recent study in which subjects received infused GLP-1 demonstrated a favorable 35% reduction in food intake. Additionally, preliminary data suggest that long-acting exenatide, a novel agent that works through the GLP-1 receptor, may promote substantial weight loss. GLP-1 and the GLP receptor have proven to be potent targets in humans but several questions remain, including specific mechanisms, if associated gastric and nausea effects can be mitigated, long-term effects, and their role in combination therapy said Dr. D'Allesio.
PYY - a new candidate? PYY is a member of the PPY/NPY family and is secreted after meals. It has been shown to act on the Y1, Y2, and Y3 receptors, and acts as a “gastric brake” before food intake. All three peptides are similarly metabolized by dipeptidyl peptidase-4 (DPP-IV). Dr. D'Allesio reported that novel experimental data show that working through the Y2, receptor, PYY3-36 suppresses food intake. In non-human primates, it has been demonstrated to delay gastric emptying and also suppress immediate and cumulative food intake over time. Moreover, he said that in humans, graded PYY3-36 infusions have resulted in a decline in food quantity, meal duration and caloric intake. Noting that phase I trials are currently examining the potential of synthetic PYY3-36, Dr. D'Allesio cautioned that long-term data are needed to more clearly elucidate its mechanism(s) (including anorexic effects), and that similar to GLP-1, PYY3-36-related nausea and gastric side effects are the most obvious concern.
Dr. F. Xavier Pi-Sunyer, Columbia University College of Physicians and Surgeons, New York, NY, USA spoke about A potential for endocannabinoids?
There have been interesting data examining the association between cannabis and food intake, Dr. Pi-Sunyer said that delta-9 tetrahydrocannabidiol (THC, the major psychoactive cannabinoid compound in marijuana) has been shown to induce appetite and food intake in animals and humans. He explained that the endocannabinoid system is a physiological system that integrates nutrient intake, transport, metabolism, and storage in the brain, gut, liver, and adipose and skeletal tissue. Blocking the endocannabinoid system, in particular the CB1 receptor (which is present throughout the CNS, including adicopyte cells), metabolic effects, (i.e. weight, homeostasis, and dyslipidemia and other cardiovascular abnormalities) are ameliorated.
The two recognized endocannabinoids are anandamide and 2 arachidonyl-glycerol and they work directly at the limbic forebrain (where there is motivation for palatable food) and hypothalamus (which regulates visceral processes including food intake, thermal regulation, and anterior pituitary secretion) Dr. Pi-Sunyer said. Experimental data have shown that when the CB1 receptors are blocked, appetite and food intake is suppressed. Dr. Pi-Sunyer reported that a promising new therapeutic strategy utilizing rimonabant, a selective CB1 antagonist agent, has been shown to reduce endocannabinoid-stimulated food intake, inhibit endocannabinoid-induced lipogenesis, and reverse diet-induced obesity. The mechanisms for these actions include stimulation of adiponectin expression and production in adipocytes, and amelioration of glycemic abnormalities to enhance glucose homeostasis. In the multi-country RIO trials, rimonabant therapy (20 mg/day) in obese subjects has been associated with significant reductions in weight and waist circumference and favorable changes in cardiometabolic risk factors, including the metabolic syndrome.
Comments: Currently rimonabant, a selective CB1 antagonist agent was approved in Europe. The study data allowed postulating, that treatment with rimonabant leads to sustained, clinically meaningful weight loss and reduction in waist circumference. Furthermore the CB-1 receptor antagonism achieved clinically significant improvements in HbA1c, lipid profile, and blood pressure. Rimonabant offers an additional new approach to the management of multiple cardiometabolic risk factors commonly observed in Type 2 diabetes.
Diabetes mellitus and its Co-Morbidities-what kind of a disease and how to treat?
During the meeting, type 2 diabetes was discussed with co-morbidities and complications. Several sessions discussed how to address the epidemic problem of obesity and glucose intolerance and how to gain control over both problems. Both of these syndromes are associated with a well-known cluster of metabolic diseases like Type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease and systemic inflammation. Several presenters focused on the fact that only treatment of all risk factors aiming for metabolic “normality” will have a sustained effect, especially cardiovascular survival. In particular, the systemic inflammation and novel therapeutic targets but also new therapeutic agents were intensively discussed. The insulin resistance was discussed controversary and seems not enough to explain the development of obesity and glucose intolerance. Visceral fat, metabolic pathways of inflammation and obesity, the interplay between gut hormones and adipocytes and the importance to treat patients to “lipid-normality”-especially HDL-levels-will be from fast growing relevance. This insight will have implications in the understanding, treatment and much more the prevention of these syndromes. Summarizing this, diabetes mellitus was presented as a condition characterized by several metabolic traits finding its pathophysiological origin in a tight association between inflammation, dyslipidaemia, hormone secretion from fat cells and weight gain opening new ways to treat and prevent this disease.
1 The ADA-meeting observer group included Drs. A. Bierhaus, PhD, Heidelberg; M. Blüher, MD, Leipzig; S. Boehncke, MD, Frankfurt; A. Hennige, MD, Tübingen; M. Lankisch, MD, Düsseldorf; M. Möhlig, MD, Berlin; H. Schatz, MD, Bochum; P. Schwarz, MD, Dresden; A. Stirban, MD, Bad Oeynhausen; D. T. Winter, MD, Giessen
Dr. med. Peter E. H. Schwarz
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