 Take
as CME Activity
Sponsored by The College of Physicians & Surgeons of Columbia University.
Supported by an educational grant from sanofi - aventis US.
Method of Participation
This activity should take approximately
0.5
hours to complete. The participant should read the learning objectives, the content
of
Glucose Homeostasis–Clinical Data, answer the
posttest questions, and complete the evaluation at the end of the section. The posttest
questions do not appear at the end of the section, rather they are dispersed throughout
the text of
Glucose Homeostasis–Clinical Data. The evaluation
at the end of the section provides each participant with the opportunity to comment
on the quality of the instructional process, the perception of the enhanced professional
effectiveness, and the presence of commercial bias. To receive category
1
AMA PRA credit, participants must complete the registration information,
CME posttest (70% constitutes a passing score) and the participant evaluation. Credit
will be granted through May 1, 2008.
Needs Statement
The prevalence of overweight and obesity is reaching epidemic proportions.1
Between the late 1980s and 2000, the prevalence of obesity increased from 22.9%
to 30.5%.2 Obesity is associated with serious medical conditions, such
as type 2 diabetes and cardiovascular disease, which increase morbidity and mortality.3-5
The high prevalence of obesity has made understanding the biological mechanisms
involved in feeding behavior and metabolic regulation an important focus of biomedical
research. research.6 Understanding the biological mechanisms underlying
energy balance may lead to more effective treatments for diseases associated with
excessive energy intake and dysregulation of metabolism.
Obesity, particularly obesity with excess abdominal fat, is associated with an atherogenic
lipoprotein profile characterized by increased triglycerides, low levels of high-density
lipoprotein cholesterol, and alterations in low-density lipoprotein cholesterol
composition and concentration.3, 7-9 Abnormalities in serum lipids are
one of the most prevalent modifiable risk factors for atherosclerosis, and early
recognition and treatment of lipid abnormalities improve prognosis for cardiovascular
disease.10-12 Obesity is itself associated with increased risk for insulin
resistance, type 2 diabetes, and cardiovascular disease.3-5 In persons
with type 2 diabetes, the absolute risk of major coronary events may approach that
of nondiabetic persons with coronary heart disease.13
Perturbations of the endocannabinoid system may contribute to the etiology of obesity,
insulin resistance, type 2 diabetes, and dyslipidemia.14-17 The cannabinoid
(CB) receptor type 1 is expressed in a number of peripheral sites involved in the
control of energy balance and metabolic homeostasis, including the brain, liver,
adipose tissue, skeletal muscle, and gastrointestinal tract.16-19 There
is a need to provide an educational resource that increases awareness of the endocannabinoid
system and its potential role in diseases associated with obesity and the dysregulation
of metabolism.
References- Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among
US adults, 1999-2000. JAMA. 2002;288:1723-1727.
- Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of
overweight and obesity in the United States, 1999-2004. JAMA. 2006;295:1549-1555.
- Després JP. Health consequences of visceral obesity. Ann Med. 2001;33:534-541.
- Pouliot MC, Després JP, Nadeau A, et al. Visceral obesity in men. Associations with
glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 1992;41:826-834.
- Wang Y, Rimm EB, Stampfer MJ, Willett WC, Hu FB. Comparison of abdominal adiposity
and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr.
2005;81:555-563.
- Fricke O, Lehmkuhl G, Pfaff DW. Cybernetic principles in the systematic concept
of hypothalamic feeding control. Eur J Endocrinol. Feb 2006;154(2):167-173.
- Zamboni M, Armellini F, Cominacini L, et al. Obesity and regional body-fat distribution
in men: separate and joint relationships to glucose tolerance and plasma lipoproteins.
Am J Clin Nutr. Nov 1994;60(5):682-687.
- Cnop M, Havel PJ, Utzschneider KM, et al. Relationship of adiponectin to body fat
distribution, insulin sensitivity and plasma lipoproteins: evidence for independent
roles of age and sex. Diabetologia. Apr 2003;46(4):459-469.
- St-Pierre J, Miller-Felix I, Paradis ME, et al. Visceral obesity attenuates the
effect of the hepatic lipase -514C>T polymorphism on plasma HDL-cholesterol levels
in French-Canadian men. Mol Genet Metab. Jan 2003;78(1):31-36.
- Ballantyne C, O’Keefe J, Gotto A. Dyslipidemia Essentials. Royal Oak, Mich:
Physicians’ Press; 2005.
- Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in
Adults. Third Report of the National Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III). Circulation. Dec 17 2002;106(25):3143-3421.
- Grundy S, Cleeman J, Merz C, et al. Implications of recent clinical trials for the
National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation.
2004;110:227-239.
- Grundy S, Pasternak R, Greenland P, Smith S, Fuster V. AHA/ACC Scientific Statement
- Assessment of Cardiovascular Risk by Use of Multiple-Risk-Factor Assessment Equations--A
Statement for Healthcare Professionals from the American Heart Association and the
American College of Cardiology. J Am Coll Cardiol. 1999;34 (October 1999):1348-1359.
- Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance.
Nat Neurosci. 2005;8:585-589.
- Sipe JC, Waalen J, Gerber A, Beutler E. Overweight and obesity associated with a
missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes (Lond).
2005;29:755-759.
- Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid
system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73-100.
- Cota D, Woods S. The role of the endocannabinoid system in the regulation of energy
homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.
- Engeli S, Bohnke J, Feldpausch M, et al. Activation of the peripheral endocannabinoid
system in human obesity. Diabetes. 2005;54:2838-2843.
- Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation
of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and
hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171-3180.
Goal
The goal of the entire interactive activity (Endocannabinoid System Overview, Enery
Balance & Metabolic Regulation, Dislipidemia, Glucose Homeostasis) is to provide
physicians with an educational resource on the endocannabinoid system and its potential
role in diseases associated with obesity and the dysregulation of metabolism. Learning ObjectivesUpon completion of Module IV, the participant should be able to:
- Summarize the prevalence of obesity in the US
- Describe the evidence supporting a role for the endocannabinoid system in glucose metabolism
- Describe the evidence supporting a role for the endocannabinoid system in glycemic control
- Understand the relationship between adiponectin and insulin resistance
Target AudienceThis activity is intended for Cardiologists, Endocrinologists, Primary Care Physicians, and Basic Scientists. Accreditation StatementThe College of Physicians & Surgeons of Columbia University is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The College of Physicians and Surgeons designates this educational activity for a maximum of .5 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. This program has been planned and produced in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). DisclosuresThe College of Physicians & Surgeons must ensure balance, independence, objectivity, and scientific rigor in its educational activities. All faculty participating in this activity are required to disclose to the audience any significant financial interest and/or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in his/her presentation and/or the commercial contributor(s) of this activity. This activity does not include any discussion of commercial products.
Course DirectorHenry N. Ginsberg, MD
Dr. Ginsberg receives research support from Merck, Pfizer, Reliant, sanofi-aventis US and Takeda. He is a consultant for Abbot, Amylin, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck Schering Plough, Pfizer, Reliant, Roche, sanofi-aventis US and Takeda.
FacultySamuel Klein, MDDr. Klein has nothing to disclose. Timothy E. McGraw, PhDDr. McGraw receives research support from sanofi-aventis US. Distribution DateThis CME activity has been designated for CME credit from May 1, 2007 until May 1, 2008. © 2007 Trustees of Columbia University. All rights reserved.
ECSN FacultyHenry N. Ginsberg, MD
Irving Professor of Medicine
College of Physicians and Surgeons of Columbia University
Director, Irving Center for Clinical Research
New York–Presbyterian Hospital
New York, New York
Samuel Klein, MD
William H. Danforth Professor of Medicine and Nutritional Science
Director, Center for Human Nutrition
Washington University School of Medicine
St. Louis, Missouri
Timothy E. McGraw, PhD
Professor of Biochemistry
Weill Medical College of Cornell University
New York, New York Overview to Glucose Homeostasis
Overweight and obesity are reaching epidemic proportions in the United States.1 Data from the National Health and Nutrition Examination Survey (NHANES) indicated that the prevalence of overweight (body mass index [BMI] 25-29.9 kg/m2) and obesity (BMI ≥30 kg/m2) among adults increased from 55.9% to 64.5% between the late 1980s and 2000.2 The prevalence of obesity alone increased by almost 8 percentage points, from 22.9% to 30.5% during the same period.
Obesity compromises glucose homeostasis, particularly when it is associated with fat accumulation in the abdominal cavity, liver, or skeletal muscle compartment.3 The induction of insulin resistance is the primary mechanism of altered glucose homeostasis in obese patients, and it may be partially related to increased levels of free fatty acids (FFAs) delivered to those sites.3,4 Obesity is associated with an increased risk for insulin resistance, type 2 diabetes, and cardiovascular disease.5,6 In persons with type 2 diabetes without known coronary heart disease, the absolute risk of major coronary events may approach that of nondiabetic persons with coronary heart disease.7
Insulin is a major regulator of whole-body energy homeostasis. Insulin inhibits hepatic gluconeogenesis, and it stimulates glucose uptake into adipose tissue and muscle. These effects result in postprandial blood glucose lowering. Insulin also regulates fatty-acid metabolism by inhibiting lipolysis and stimulating lipogenesis in adipose tissue.
Insulin target tissues do not properly respond to insulin in insulin-resistant conditions such as obesity and type 2 diabetes mellitus, resulting in a dysregulation of energy metabolism. Evidence indicates that alterations in fatty-acid metabolism contribute to the higher risk of insulin resistance in obesity, although the exact mechanism linking obesity to insulin resistance is unknown.
A consistent, inverse relationship has been observed between adiponectin levels and both obesity and insulin resistance.8 Epidemiologic data indicate that plasma adiponectin levels fall before the onset of obesity and insulin resistance. However, adiponectin levels rise in situations where insulin sensitivity improves, such as after weight loss or treatment with insulin-sensitizing drugs.9 Adiponectin facilitates the actions of insulin on muscle and liver, and it also acts in the central nervous system to facilitate glucose disposal and increase total energy oxidation.9,10 Polymorphisms in the gene coding for adiponectin are associated with obesity and insulin resistance.9
Perturbations of the endocannabinoid system (ECS) may contribute to the development of insulin resistance and type 2 diabetes. The cannabinoid receptor type 1 (CB1) is expressed in a number of peripheral sites involved in the control of glucose homeostasis, including the pancreas, liver, adipose tissue, skeletal muscle, and gastrointestinal tract.11-14 Increased plasma endocannabinoid levels have been demonstrated in people with type 2 diabetes. In addition, insulin appears to decrease endocannabinoid levels in normoglycemic patients.14 The potential modulation of glucose homeostasis by the ECS in peripheral tissues is explored in the following sections.
Clinical DataDr. Mackie’s video clip on the ECS and Glycemic Control.
Click play for Dr. Mackie’s comments on the ECS and Glycemic Control.
In the RIO-Lipids study, obese subjects treated with a CB1 receptor antagonist (rimonabant, 20 mg/day for 1 year) had a significant increase in the plasma adiponectin level compared with placebo-treated obese subjects (P <0.001, last observation carried forward in patient subgroups).15 A retrospective analysis of these data suggested that the increase in adiponectin could not be attributed to weight loss alone, and it was associated with significant reductions in the plasma glucose and insulin responses to an oral glucose challenge (baseline vs 1 year).15 This statistically based finding will need to be confirmed in experiments where weight is maintained and the independent effects of rimonabant on adiponectin levels can be investigated.
In overweight and obese persons with mild hyperglycemia, visceral fat contains significantly higher levels of the endocannabinoid 2-arachidonoyl-glycerol than subcutaneous fat.14 Additional studies are needed to determine if the higher visceral fat endocannabinoid levels are related to FFA-induced insulin resistance in peripheral tissues.
Dr. Ginsberg’s video clip on future research.
Click play for Dr. Ginsberg’s comments on future research.
Overweight subjects with type 2 diabetes and hyperglycemia exhibited blood endocannabinoid levels significantly higher than those of age- and BMI-matched normoglycemic subjects (Figure 1).14 Thus, normal regulation of blood endocannabinoid levels may be disrupted in persons with hyperglycemia.14 The RIO-Diabetes trial treated 1045 overweight and obese subjects with type 2 diabetes. Subjects were required to have taken metformin or a sulfonylurea monotherapy for at least 6 months, with fasting plasma glucose between 100 and 271 mg/dL and hemoglobin A1c (HbA1c) between 6.5% and 10%. Results from this trial indicate that rimonabant treatment (20 mg/day for 1 year, intent-to-treat population) in overweight and obese subjects with type 2 diabetes leads to significant decreases in body weight and improvements in glycemic control compared with placebo (Figure 2).16 The favorable change in mean HbA1c was observed in subjects receiving metformin or sulfonylureas. This observation suggests that rimonabant may have additive effects to standard, background oral antidiabetic therapy. Additional studies are needed to determine if favorable changes in glycemic control during treatment with a CB1 receptor antagonist are independent of weight loss.
SafetyThe overall withdrawal rate in the RIO studies was high,16-19 but was not different from the overall withdrawal rates observed in other obesity studies.20 Compared with placebo, subjects treated with rimonabant 20 mg/day reported a greater rate of discontinuation due to adverse events in the 12 months of active treatment.16 Adverse events leading to discontinuation were not different for the rimonabant 20 mg and placebo groups during the second year of treatment in the RIO-North America and RIO-Europe 2-year studies.18,19 In RIO-Diabetes, adverse events leading to study discontinuation over 1 year of treatment that were reported more commonly in subjects treated with rimonabant 20 mg included depressive disorders, nausea, anxiety, and dizziness. Reported depressive disorders were usually mild or moderate in severity. Approximately 8% of subjects in both rimonabant groups (5 mg/day and 20 mg/day) reported serious adverse effects compared with 4% of subjects in the placebo group 16 No serious adverse events linked to psychiatric disorders were recorded in either rimonabant group. Individuals with a history of significant depression or other psychiatric disorders, or who had prior use of antidepressant medications, were excluded from all of the RIO studies. Data from preclinical and human postmortem studies are equivocal with regard to the effect of CB1 receptor blockade and emotional responses to stress (reviewed in Gadde and Allison).21 Additional studies are needed to determine the potential effects of rimonabant treatment on psychiatric events in different patient populations.
FiguresFigure 1. Dysregulation of blood endocannabinoid levels in hyperglycemia. Panel shows serum endocannabinoid levels in overweight type 2 diabetes vs healthy volunteers. The experiment was designed uniquely to assess whether a noncorrected hyperglycemia, due to a pathological condition, results in increased serum endocannabinoid levels. For this reason, the experiments included male and female subjects with type 2 diabetes receiving randomized pharmacological treatments and whose only common clinical features were hyperglycemia (approximately 1.85 g/L), age (approximately 65 years), and BMI (approximately 30 kg/m2). 2-AG, 2-arachidonoyl-glycerol. **P <0.01, ***P = 0.005 vs controls, as assessed by the Kuskal-Wallis nonparametric test. From Matias et al.14 
Figure 2. Changes in hemoglobin A1c (HbA1c) levels. Mean (SE) change from baseline in HbA1c levels over 1 year. HbA1c levels were lower with both doses of rimonabant than with placebo (P = 0.03 for 5 mg/day and P <0.0001 for 20 mg/day) with a sustained decline in the rimonabant 20 mg group. Consistent with potential direct peripheral metabolic effects of CB1 receptor blockade, the observed effects of rimonabant 20 mg were approximately twice that attributable to concurrent weight loss alone after adjustment with analysis of covariance (ANCOVA, data not shown). This statistically based finding will need to be confirmed in experiments where weight is maintained and the independent effects of rimonabant on glucose metabolism can be investigated. From Scheen et al.16 Permission pending.
References- Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:1723-1727.
- Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA. 2006;295:1549-1555.
- Bergman RN. Pathogenesis and prediction of diabetes mellitus: lessons from integrative physiology. Mt Sinai J Med. 2002;69:280-290.
- Kovacs P, Stumvoll M. Fatty acids and insulin resistance in muscle and liver. Best Pract Res Clin Endocrinol Metab. 2005;19:625-635.
- Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care. 2000;23:1278-1283.
- Expert Panel on the Identification, Evaluation and Treatment of Overweight in Adults. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults-The Evidence Report. National Institutes of Health. Obes Res. 1998;6(suppl 2):51S-209S.
- Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1999;100:1134-1146.
- Trujillo ME, Scherer PE. Adiponectin-journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med. 2005;257:167-175.
- Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89:2548-2556.
- Qi Y, Takahashi N, Hileman SM, et al. Adiponectin acts in the brain to decrease body weight. Nat Med. 2004;10:524-529.
- Cota D, Woods S. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.
- Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27:73-100.
- Juan-Picó P, Fuentes E, Javier Bermúdez-Silva F, et al. Cannabinoid receptors regulate Ca(2+) signals and insulin secretion in pancreatic beta-cell. Cell Calcium. 2006;39:155-162.
- Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171-3180.
- Després JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134.
- Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368:1660-1672.
- Després JP, Golay A, Sjöström L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134.
- Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365:1389-1397.
- Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295:761-775.
- Douketis JD, Macie C, Thabane L, Williamson DF. Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice. Int J Obes (Lond). 2005;29:1153-1167.
- Gadde KM, Allison DB. Cannabinoid-1 receptor antagonist, rimonabant, for management of obesity and related risks. Circulation. 2006;114:974-984.
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