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Reviews/Commentaries/ADA and TES Statement CONSENSUS REPORT

Obesity and Type 2 : What Can Be Unified and What Needs to Be Individualized?

1 5 ROBERT H. ECKEL, MD DAVID M. NATHAN, MD ost patients with 2 6 STEVEN E. KAHN, MB, CHB MICHAEL W. SCHWARTZ, MD 3 7 are obese, and the global epidemic ELE FERRANNINI, MD ROBERT J. SMITH, MD M 4 8 of largely explains the ALLISON B. GOLDFINE, MD STEVEN R. SMITH, MD dramatic increase in the incidence and prevalence of type 2 diabetes over the past 20 years. Currently, over a third (34%) of OBJECTIVE—This report examines what is known about the relationship between obesity fi U.S. adults are obese (defined as BMI .30 and type 2 diabetes and how future research in these areas might be directed to bene tpre- 2 vention, interventions, and overall patient care. kg/m ), and over 11% of people aged $20 years have diabetes (1), a prevalence RESEARCH DESIGN AND METHODS—An international working group of 32 experts projected to increase to 21% by 2050 (2). in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes – However, the precise mechanisms link- participated in a conference held on 6 7 January 2011 and cosponsored by The Endocrine ing the two conditions remain unclear, Society, the American Diabetes Association, and the European Association for the Study of Di- abetes. A writing group comprising eight participants subsequently prepared this summary and as does our understanding of interindi- recommendations. Participants reviewed and discussed published literature and their own un- vidual differences. Improved under- published data. standing will help advance identification and development of effective treatment RESULTS—The writing group unanimously supported the summary and recommendations as options. ’ representing the working group s majority or unanimous opinions. Excess weight is an established risk CONCLUSIONS—The major questions linking obesity to type 2 diabetes that need to be factor for type 2 diabetes, yet most obese addressed by combined basic, clinical, and population-based scientific approaches include the individuals do not develop type 2 diabe- following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what tes. Recent studies have identified “links” mechanisms do obesity and resistance contribute to b- decompensation, and if/when between obesity and type 2 diabetes in- obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3)How volving proinflammatory cytokines (tu- does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss mor necrosis factor and interleukin-6), drugs, and/or on b-cell function and glycemia? 4) What is necessary for regulatory , deranged me- approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients tabolism, and cellular processes such as with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance mitochondrial dysfunction and endoplas- effective and cost-effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent mic reticulum stress. These interactions conditions and innovative approaches to their pharmacological and surgical management. are complex, with the relative importance of each unclearly defined. Further genetic Diabetes Care 34:1424–1430, 2011 studies may elucidate additional common pathophysiological pathways for obesity and diabetes and identify promising new treatment targets. As physicians fre- quently prescribe -lowering med- ccccccccccccccccccccccccccccccccccccccccccccccccc ications associated with ,

1 trade-offs between glycemic control and From the Division of , and Diabetes and Division of Cardiology, Department of body weight with current therapeutic op- Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; the 2Division of Metab- olism, Endocrinology and , Department of Medicine, VA Puget Sound Health Care System and tions need more consideration. This issue University of Washington, Seattle, Washington; the 3Department of Internal Medicine, University of Pisa, is particularly pressing given accumulat- Pisa, Italy; the 4Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts; the 5Clinical ing evidence that even modest weight Research Center and Diabetes Center, Massachusetts General and Harvard Medical School, Boston, reduction—whether through lifestyle/ Massachusetts; the 6Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington; the 7Division of Endocrinology and the Hallett Center for behavioral interventions, obesity medica- Diabetes and Endocrinology, Alpert Medical School of Brown University, Providence, Rhode Island; and the tions, or bariatric surgery—can improve 8Translational Research Institute for Metabolism and Diabetes, Florida Hospital–Sanford/Burnham Re- glycemic control and reduce diabetes risk. search Institute, Orlando, Florida. These intriguing, but still largely un- Corresponding authors: Robert H. Eckel, [email protected], and Steven E. Kahn, [email protected]. explored, connections between obesity edu. DOI: 10.2337/dc11-0447 and type 2 diabetes suggested the timely This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/ need to convene a group of scientificex- dc11-0447/-/DC1. perts in the fields to more closely examine R.H.E. and S.E.K. contributed equally to this report. © 2011 by the American Diabetes Association and The Endocrine Society. Readers may use this article as long underlying pathophysiology and treatment as the work is properly cited, the use is educational and not for profit, and the work is not altered. See options for patients with type 2 diabetes http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. addressing issues of excess weight and

1424 DIABETES CARE, VOLUME 34, JUNE 2011 care.diabetesjournals.org Eckel and Associates glycemic control simultaneously. Partic- of (6); 2)ectopicfatdeposi- involved in pathways related to insulin re- ipants in the January 2011 conference tion, particularly in the and perhaps sistance independent of obesity (19,20). (Supplementary Data) were tasked with also in skeletal muscle, and the dysmeta- Not surprisingly, many obesity var- examining what is known about the re- bolic sequelae (7); and 3) mitochondrial iants appear to be involved in pathways lationship between obesity and type 2 dysfunction, evident by decreased mito- affecting energy homeostasis. Although diabetes and the heterogeneity of these chondrial mass and/or function (8). Mito- numerous diabetes- and obesity-associated conditions, what needs to be learned, and chondrial dysfunction could be one of have been identified, the known how to direct future research in these many important underlying defects linking genes are estimated to predict only 15% areas to advance effective interventions obesity to diabetes, both by decreasing in- of type 2 diabetes and 5% of obesity risk and improve patient care. What follows sulin sensitivity and by compromising (21). Although additional genes with im- summarizes the major issues addressed b-cell function. portant roles will undoubtedly be discov- and the outcomes of the discussion. ered, this low predictive power may reflect Mechanisms of progressive b-cell the importance of environmental factors, Mechanisms of obesity-associated dysfunction in obese individuals less frequent genetic variants with stron- insulin resistance The link between obesity and hyperinsu- ger effects, or gene-environment, gene- The influence of obesity on type 2 di- linemia, first identified ;50 years ago (9), gene, and epigenetic interactions that are abetes risk is determined not only by the reflects compensation by insulin-secreting not readily identified through methods degree of obesity but also by where b-cells to systemic insulin resistance. Al- basedonpopulationgenetics.Methods accumulates. Increased upper body fat though mechanisms underlying this for detecting gene-gene interactions exist, including visceral adiposity, as reflected coupling (e.g., mild and but the population size needed to detect in increased abdominal girth or waist-to- raised levels of circulating free fatty acids) them is substantially greater than is re- hip ratio, is associated with the metabolic remain elusive, obese normoglycemic in- quired for detection of single genes of rel- syndrome, type 2 diabetes, and cardio- dividuals have both increased b-cell mass atively small effect. Alternatively, pathway vascular (3), although underlying and function (9–12). Obesity-induced glu- analyses or a systems biology approach mechanisms remain uncertain. Whether cose intolerance reflects failure to mount combining information from DNA varia- subcutaneous fat lacks the pathological one or more of these compensatory re- tions with transcript, protein, and metab- effects of visceral fat or is simply a more sponses (13). olite profiles may better capture the neutral storage location, for example, re- Factors predisposing to b-cell de- genetic influences on metabolism than quires further study. Beyond differences compensation could also be primarily ge- studying single genes. One should also in body fat distribution, emerging evi- netic or epigenetic. A clear, mechanistic keep in mind that the missing dence suggests that different subtypes of basis for this decompensation has re- could be an illusion of inferring additive may be functionally dis- mained elusive. Genetic studies have genetic effects from epidemiological data tinct and affect glucose homeostasis dif- helpedidentifytheroleofsomekeymol- (22). ferentially. Adult humans have limited ecules in b-cell biology that may be im- and variable numbers of brown fat cells portant in this regard. For example, Does a shared pathogenesis (4), which play a role in thermogenesis recent rodent studies have demonstrated underlie both obesity and and potentially influence energy expendi- diabetogenic effects of reduced pancre- type 2 diabetes? ture and obesity susceptibility (5). Im- atic expression of the Pdx1 gene (14,15). Although the link between obesity and proved understanding of the function of While these animal studies have demon- type 2 diabetes is widely held to involve different fat cell types and depots and strated that PDX1 deficiency relates mech- two discrete lesions—obesity-induced in- their roles in metabolic homeostasis is a anistically to diabetes through b-cell sulin resistance and b-cell failure—both priority for investigation into the patho- apoptosis, and PDX1 deficiency is linked disorders may share an underlying defect. genesis and complications of obesity. toMODY4(16),itisnotclearyetthat This “unified field theory” raises ques- Likewise, adipose tissue is composed of PDX1 deficiency has a role in common tions about whether defects favoring heterogeneous cell types. Immune cells forms of type 2 diabetes in humans. This progressive weight gain and metabolic within adipose tissue also likely contrib- example illustrates how a growing under- impairment also contribute to b-cell de- ute to systemic metabolic processes. As standing of genetics and cellular function of compensation. the study of adipose biology progresses, the b-cell can identify potential mediators One potential link could be sustained it will be important to consider whether predisposing obese individuals to type 2 cell exposure to nutrient concentrations additional subtypes of or other diabetes and further may provide insights exceeding energy requirements. Deleteri- cell types can be identified to refine for the development of new therapeutic ous cellular effects of nutrient excess can our understanding of obesity complica- agents. include impaired inflammatory signaling, tions and generate novel approaches to endoplasmic reticulum stress, excess pro- prevention. Genetic factors linking obesity duction of reactive oxygen species, mito- At least three distinct mechanisms and diabetes chondrial dysfunction, accumulation of have been proposed to link obesity to Genome-wide association scans (GWAS) triglycerides and/or fatty acyl interme- insulin resistance and predispose to type and approaches now have diates, and activation of serine-threonine 2diabetes:1) increased production of identified ;40genesassociatedwithtype kinases (23). These responses are not mu- adipokines/cytokines, including tumor 2 diabetes (17,18) and a similar number, tually exclusive, and induction of one necrosis factor-a, , and retinol- albeit largely different, with obesity. Most may trigger another, leading to a cascade binding protein 4, that contribute to type 2 diabetes genes appear to be related of damage. Obesity-associated cellular insulin resistance as well as reduced levels to b-cell dysfunction, with many fewer injury can in turn recruit and activate care.diabetesjournals.org DIABETES CARE, VOLUME 34, JUNE 2011 1425 Consensus Report macrophages and other immune cells that insulin action, obesity-induced insulin caloric intake in obese adults and over- exacerbate tissue inflammation (23,24). resistance may arise not only as a direct weight children (30,31). Collectively, these responses contribute consequence of excessive adipose mass Medications have been used to assist to the pathogenesis of insulin resistance but via neuronal mechanisms as well. in for almost 80 years, but in the liver, skeletal muscle, and adipose Whether disturbed neurocircuits also con- adverse effects frequently restrict utility. tissue, and some (e.g., acquired mito- tribute to deteriorating b-cell dysfunction Medications have been developed based chondrial dysfunction and inflammation) as obesity and its sequelae progress is an on physiological insights, more recently may occur in b-cells as well via mecha- active area of investigation (27). targeting control nisms discussed above. In susceptible in- of appetite and metabolism, or opportu- dividuals, therefore, obesity-induced Managing body weight by nistically when weight loss was noted as metabolic impairment can favor insulin behavioral change and medications a side effect of approved medications. resistance on the one hand and progres- The dramatic increase in incidence and Table 1 lists medications that have been sive b-cell dysfunction on the other. Re- prevalence of obesity over the past 50 available and others under development. duced insulin secretion can in turn years, associated in part with major In general, weight loss achieved with worsen the nutrient excess problem by worldwide changes in caloric intake and these medications ranges from 2 to 8% raising circulating concentrations of glu- dietary composition, has focused atten- greater than placebo, with some sugges- cose, free fatty acids, and other nutrients. tion on lifestyle intervention to reverse or tion that combination therapy may either In this way, a vicious cycle arises whereby ameliorate caloric imbalance. In general, increase weight loss or ameliorate side ef- obesity-induced nutrient excess triggers programs including individual or group fects and increase tolerability. However, inflammatory responses that cause insu- counseling to modify behavior result in most drug trials last only 6–12 months, lin resistance, placing a greater demand 5–10% weight loss and are effective for 6– and thus there are few long-term data that on the b-cell, and as b-cell function de- 12 months, after which weight regain is weight loss can be sustained. Moreover, clines the cellular toll taken by nutrient the rule. Some longer-term lifestyle inter- high drop-out rates, which approach 50%, excess increases. Since not all obese indi- vention studies with sustained interven- are characteristic of many weight-loss trials viduals develop hyperglycemia, however, tions demonstrate more durable weight and result in survivor effects in efficacy anal- an underlying abnormality of the b-cell loss (28,29), with extent of weight loss yses, thereby potentially amplifying drug must coexist with nutrient excess to pro- in the first 3–6 months generally predict- benefits and limiting generalizability. Fur- mote type 2 diabetes (13). ing longer-term success. Successful life- thermore, concern regarding adverse ef- Brain neurocircuits governing energy style intervention programs typically fects, including risk homeostasis also affect insulin sensitivity involve self- of weight, dietary and central effects (e.g., depression) in in the liver and perhaps other peripheral intake, and activity; behavioral modifica- drugs crossing the blood-brain barrier, con- tissues (25), and inflammation similar to tion; frequent contact; and caloric balance tinue to limit approval and application. that induced by obesity in peripheral through , with or without . insulin-sensitive tissues also occurs in For example, short-term intervention Managing body weight by these areas of the brain (26). If obesity is studies suggest that dietary changes, bariatric surgery associated with impairment of neurocir- which emphasize less fat and refined car- Health benefits of bariatric surgery, de- cuits regulating both energy balance and bohydrates, make it easier to reduce total termined largely from nonrandomized

Table 1—Weight-loss medications: past, current, and future

Medication Availability Serious adverse effects Withdrawn Fenfluramine 1973–1997 Cardiac valvular insufficiency and pulmonary Dexfenfluramine 1996–1997 Cardiac valvular insufficiency and pulmonary hypertension Phenylpropanolamine* 1960–2000 Hemorrhagic Rimonabant 2006–2009 Depression and suicidal ideation Sibutramine* 1997–2010 Nonfatal myocardial infarction and nonfatal stroke (in subjects with preexisting cardiovascular conditions) Current Phentermine# 1959–present Palpitations and elevated 1999–present Liver injury

Phase 3 trials and current applications to FDA/EMA Lorcaserin Potential valvular heart disease and psychiatric and cognitive disorders Bupropion/naltrexone Seizures, palpitations, and transient blood pressure elevations Topiramate/phentermine Depression, suicidal ideation, cardiovascular events, memory loss, and birth defects GLP-1 analogs EMA, European Medicines Agency; FDA, U.S. and Drug Administration; GLP-1, -like peptide 1. *Phenylpropanolamine is still available in some European countries and sibutramine in some South American countries. #Phentermine is one of a class of sympathomimetic drugs that also includes benzphetamine, diethylpropion, and phendimetrazine.

1426 DIABETES CARE, VOLUME 34, JUNE 2011 care.diabetesjournals.org Eckel and Associates studies, are being increasingly recog- of surgical procedure. However, many the duration of their glucose intolerance. nized. These benefits include substantial questions remain, including the follow- Further, interventions are typically started and sustained weight loss (32), resolution ing: How much weight loss is required for late in the disease, with minimal preven- of comorbidities such as diabetes, hyper- health benefits? What is the effect of tive efforts. In addition, as initial weight tension, and dyslipidemia (33,34), and different interventional methods on loss is the main determinant of longer- reduced myocardial infarction, , long-term outcomes? What mechanisms term weight loss, the typical initial goal and associated mortality (35). For ex- underlie the heterogeneous responses? of ;5–10% weight loss may be inade- treme obesity, surgery is now the pre- Further, regarding diabetes, Is the optimal quate to produce glycemic control (42). ferred and currently only effective timing for treatment the same or different Furthermore, although controlling body treatment modality. Acute morbidity from obesity? Are b-cells preserved or do weight (either by reduction or by preven- and mortality of surgical approaches they even grow? Why do not we see the tion of further rise) improves glycemic have been dramatically reduced, enabling same efficacy and durability of response control by ameliorating both insulin resis- widespread use of these procedures. Fur- for other obesity-related pathologies (e.g., tance and b-cell dysfunction, the impact of thermore, over the long term, bariatric hypertension) as for glycemic control? On- pharmacologically induced improved gly- surgery might reduce aggregate health going randomized clinical trials (40) prom- cemic control on body weight varies by care expenditures (36). There is also a ise to answer many questions regarding individual drug. Glucose-lowering medi- growing movement toward using surgery patient selection, optimal procedure, cations can be broadly categorized into to control diabetes, independent of severe when to intervene, and where initial and thoseassociatedwithweightgainand excess weight, but there are currently few chronic care should be delivered. those essentially weight neutral or pro- scientifically valid data to support this moting weight loss (Table 2). Whether clinical path. Barriers to effective management weight gain offsets any benefit of reduced Bariatric surgery falls into two general A vast array of barriers—ranging from glycemia on cardiovascular risk needs to categories: purely restrictive procedures deficits in basic research to socioeco- be determined. Further, weight changes such as the laparoscopic adjustable gastric nomic and individual psychological factors do not necessarily predict changes in gly- band devices, which appear to improve beyond the scope of the conference— cemic control (43), and while specific diabetes via weight loss, and procedures undermines current efforts to manage therapies may work in certain diabetes bypassing the proximal gut, such as the obesity, particularly in individuals with subtypes, the response to glucose-lowering Roux-en-Y gastric bypass (RYGB) or type 2 diabetes. Lessons learned from medications varies considerably. This latter newer gastric sleeve procedures. The efforts such as those applied to tobacco topic was the focus of a similar workshop latter approaches (“metabolic” surgery) cessation may be quite relevant (41). in 2009 on individualizing therapies in appear to produce unique effects on Lifestyle programs (especially long- type 2 diabetes (44). enteroendocrine hormones and neuronal term) are often plagued by inadequate Equally challenging is the problem of signaling pathways and produce more reimbursement. Further, there is a lack of weight regain, which usually follows any weight loss and diabetes remission than evidence-based individualized goals and degree of weight loss, however achieved banding alone (34,37). Metabolic surger- strategies combining lifestyle and medi- (Fig. 1). Well studied and viewed as a nor- ies are associated with increases in an- cations, or appreciation of sequential mal response in lean individuals, this phe- orexigenic and decreases in orexigenic (stepped) therapy. As mechanisms lead- nomenon is equally robust among the hormones, changes largely absent in ing to obesity and its maintenance are not obese. It involves complex, highly inte- band or restrictive procedures, and may fully understood, questions remain about grated physiological responses that are explain the differential outcomes (38). Al- which interventions, be they lifestyle or similar to those invoked in weight- though mechanisms leading to weight pharmacological, might be most effective reduced, nonobese individuals. The bio- loss and diabetes remission are only be- during various stages of weight gain, loss, logic basis appears to be the tendency to ginning to be understood, the above en- and regain. In addition, medications under defend attained weight, whether normal docrine, peptide, and neural effects may development may carry indeterminate risk. or excessive, which seems to be wired in mediate these benefits because of struc- Likewise, surgery is an imperfect remedy tural changes including isolation of the due in part to perceived risks and high cost. gastric cardia; exclusion of the distal With laparoscopic banding now approved Table 2—Weight effects of glucose-lowering 2 stomach, duodenum, and proximal jeju- for BMI .30 kg/m with a comorbidity medications num; exposure of the distal intestine to such as diabetes or hypertension, 27 mil- undigested nutrients; and partial vagot- lion Americans would be eligible for sur- omy. Longer duration of diabetes and in- gery. However, the large-scale feasibility of Medication class Weight effects sulin use, both typically associated with such an approach is uncertain and com- GLP-1 analogs ↓ decreased b-cell function and possibly pounded by issues related to reimburse- Pramlintide ↓ surrogates for reduced b-cell mass, are as- ment. Thus, the search must continue for 6 or ↓ sociated with reduced postsurgical remis- how to implement optimal lifestyle inter- a-Glucosidase inhibitors 6 sion rates, thus suggesting that residual ventions and to find effective drugs and/or DPP-4 inhibitors 6 b-cell function may be a critical factor minimally invasive devices. Insulin ↑ for metabolic benefits (39). These barriers are further compli- ↑ Known differences in mechanism and cated in the context of type 2 diabetes. Glinides ↑ efficacy, along with risks and patient Obese patients with hyperglycemia are ↑ priorities (e.g., weight loss vs. metabolic/ often poorly characterized not only in DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon- diabetes goals) already inform the choice terms of their history of obesity but also in like peptide 1. care.diabetesjournals.org DIABETES CARE, VOLUME 34, JUNE 2011 1427 Consensus Report

cell–derived b-cells. Moreover, longitudi- nal studies of b-cell dysfunction in hu- mans should address differences in the amount of weight loss required to durably improve b-cell function. Finally, research to elucidate the intrauterine environ- ment’s impact on b-cell development and function may provide further strate- gic approaches to protecting progressive b-cell dysfunction. Develop innovative approaches to phar- macological and surgical management. Innovative approaches to managing obe- sity may lower certain barriers under- mining treatment of both obesity and type 2 diabetes. For example, modulating the axis may benefitbothenergy balance and glycemia. Novel pharmaco- Figure 1—Schematic representation of the natural history of obesity. Primary (excess) weight logical development may depend on in- gain occurs usually over years against the typical background of mild age-related increase in formation gained from more efficient use weight in the general population. Intentional weight loss frequently is at least partially successful, of genomic, proteomic, and metabolomic but in the vast majority of cases, is followed by weight regain. Weight loss and its maintenance is approaches and from information learned the therapeutic goal; prevention of primary weight gain is a societal endeavor. from studying weight-loss mechanisms in bariatric surgery. In addition, co-opting multiple central nervous system defenses individuals, a multifactorial, synergistic less traditional organs such as the brain against weight loss. Current models of explanation seems more compatible and gut into the core pathophysiology energy homeostasis predict genetic or with current knowledge. Multiple mech- of type 2 diabetes may reveal new bio- acquired defects in key neurocircuits anisms may link b-cell dysfunction to markers and/or targets for therapeutic that undermine the normal response to systemic insulin resistance, including intervention. Finally, safe and effective cen- adiposity-related humoral signals. Much differing cellular responses to nutrient trally acting drugs that decrease appetite of the basic science in this area has been excess and impaired brain neurocircuits or increase satiety are urgently needed. performed in animal models of obesity governing energy homeostasis. One However, as regulatory agencies increase (genetic or overfeeding); extrapolation way to approach this complex patho- the need for safety testing, fewer new to the pathophysiology of human obesity physiology is to examine glucose-tolerant and innovative approaches for weight remains uncertain. obese patients and study the association loss are being developed because of the The panoply of potential mechanisms with and progression to b-cell decom- prolonged time and immense expense defending body weight helps explain why pensation. involved. the field is moving toward targeting mul- Expand research on heterogeneity. So Emphasize primary prevention of obe- tiple pathways by harnessing additive ef- far, genetic studies have been limited by a sity and type 2 diabetes. Current clinical fects of current drugs, which individually lack of accurate assessments of pheno- approaches to obesity continue to focus produce ;5% weight loss (45). A number type. Additional large-scale population- on secondary and tertiary intervention. of compounds, old and new, alone or in based analyses addressing more complex Physicians often introduce secondary in- combination, are being developed. It is disease determinants of obesity and di- terventions when patients surpass some hoped that they may safely achieve the abetes (beyond single genetic polymor- dichotomous BMI threshold or when magnitude of change in body weight, as phisms) might improve understanding of patients self-identify, for cosmetic or health well as other beneficial effects such as glu- the relative impact of genetic and envi- reasons. They introduce tertiary inter- cose control, that has been obtained with ronmental factors linking them. Other vention when obesity-related complica- some of the surgical approaches. priorities include clarifying the genetic tions responsive to weight loss, such as basis for differences in fat distribution diabetes, hypertension, or sleep apnea, Recommendations across ethnic groups (46); identifying develop. Because weight problems develop Elucidate the pathogenesis linking obe- factors that control homing of adipose over the entire life span, however, empha- sity and type 2 diabetes. A better under- tissue to the different—visceral versus sizing obesity prevention is urgent and standing of mechanisms linking obesity, subcutaneous—fat depots (47) and adi- must include cooperation of insulin resistance, and type 2 diabetes may pose tissue angiogenesis (48); and under- institutions, the school systems, and the ultimately facilitate more individualized standingthetimecourseandextentof private (e.g., food industry) sector. The treatment. One future research priority transdifferentiation of brown and white likelihood of sustained benefits of weight is to clarify how identified gene variants adipocytes in humans (5). reduction on b-cell function and glycemia affect glucose, fatty acid, and energy me- Human b-cells, including those from in patients with early-onset versus more tabolism at both cellular and whole-body patients with type 2 diabetes, need to be prolonged durations of type 2 diabetes levels. Rather than searching for a single made more widely available for investiga- needs to be determined. factor or theory explaining the predispo- tional use. An additional approach would Although intensive lifestyle mod- sition to b-cell decompensation in obese be the creation of patient-specificstem ifications and medications have been

1428 DIABETES CARE, VOLUME 34, JUNE 2011 care.diabetesjournals.org Eckel and Associates conclusively demonstrated to slow the de- we have reached a point when we can be- Squibb/AstraZeneca, sanofi-aventis, , velopment of type 2 diabetes in those with gin to consider innovative and potentially GlaxoSmithKline, and Daiichi Sankyo and impaired glucose metabolism (28,49), reg- more effective approaches to managing grant support from Merck and Eli Lilly. A.B.G. ulatory authorities have still not approved both obesity and type 2 diabetes. In- acted as Site Principal Investigator for a clinical medications for preventing type 2 diabetes, creased understanding of the pathogene- trial funded by Eli Lilly that is now complete with results published. M.W.S. received con- nor have they provided a regulatory frame- sis of obesity and type 2 diabetes, for sulting fees from Merck, Pfizer, and Orexigen. work to do so. Guidance on what would be example, should not only help differenti- R.J.S. received consulting fees from GI Dy- required to approve medications for treat- ate responders from nonresponders but namics and royalties from Baxter and Fresenius ing high-risk individuals would foster more also make tailored therapy a reality. Kabi. S.R.S. received consulting fees from scientific investment in this area and sub- Equally beneficial will be incorporating , Bristol-Myers Squibb, Eli Lilly, and sequent availability of additional preventive these ideas into a chronic disease model Novartis and consulting fees as an advisory options. of care linking obesity management to di- board member for Arena. No other potential Adopt a chronic disease model linking abetes care systems, including multidisci- conflicts of interest relevant to this article were obesity to diabetes care. Current un- plinary approaches to patient care designed reported. derstanding of both pathophysiology and to prevent weight regain that is almost uni- The authors are grateful for the con- tributions of the speakers and participants in management suggests the need to adopt versal when therapy is stopped. the January 2011 conference, who are listed, a chronic disease model of care linking Presently, some of the major ques- together with affiliations, in the Supplementary obesity and diabetes care management sys- tions linking obesity to type 2 diabetes Data. In addition, the authors acknowledge tems. Besides including stepped-care ap- that need to be urgently addressed in- the editorial assistance of Dr. Terra Ziporyn, proaches similar to those used for other clude the following: medical editor, in writing the manuscript. chronic , this model involves bas- ing interventional (pharmacological and 1. Why do not all patients with obesity surgical) approaches on severity, dura- develop type 2 diabetes? References tion, and individual risk/benefit. The com- 2. Through what mechanisms do obesity 1. Centers for Disease Control and Pre- mon perception that the obesity problem and insulin resistance contribute to vention. National diabetes fact sheet: na- is insurmountable leads to some degree of b-cell decompensation, and if/when tional estimates and general information clinical inertia. What is needed is similar to obesity prevention ensues, how much on diabetes and in the United — States, 2011. Atlanta, GA, U.S. Depart- what occurred with tobacco a compre- reduction in type 2 diabetes incidence ment of Health and Human Services, hensive social, economic, and workplace will follow? Centers for Disease Control and Pre- approach to prevention and intervention. 3. How does the duration of type 2 di- vention, 2011 In addition, community-setting approaches abetes relate to the benefits of weight 2. Boyle JP, Thompson TJ, Gregg EW, supplemented by physician involvement reduction by lifestyle, weight-loss drugs, Barker LE, Williamson DF. Projection of can work when combining treatment and/or bariatric surgery on b-cell func- the year 2050 burden of diabetes in the modalities (50). Furthermore, multidis- tion and glycemia? US adult population: dynamic modeling ciplinary teams including nutritionists, 4. What is necessary for regulatory ap- of incidence, mortality, and prediabetes exercise physiologists, and behavioral/ proval of medications and possibly prevalence. Popul Health Metr 2010;8:29 mental health professionals can achieve surgical approaches for preventing 3. Björntorp P. Metabolic implications of body fat distribution. Diabetes Care 1991; both initial and sustained weight man- type 2 diabetes in patients with obesity? 14:1132–1143 agement and glucose control (28,29). 4. Cypess AM, Lehman S, Williams G, et al. This approach to attaining and maintaining Acknowledgments—This article is based on a Identification and importance of brown weight reduction is critically important conference jointly sponsored by The Endo- adipose tissue in adult humans. N Engl J both in alleviating the intensive defense crine Society, the American Diabetes Associa- Med 2009;360:1509–1517 of body weight by multiple biological tion, and the European Association for the 5. Frontini A, Cinti S. Distribution and de- systems and in reducing risk of b-cell de- Study of Diabetes, with the financial support velopment of brown adipocytes in the compensation and, over the long term, of an unrestricted educational grant from murine and human adipose organ. Cell – diabetes complications. Novo Nordisk. Metab 2010;11:253 256 R.H.E. received grant/research support from 6. Deng Y, Scherer PE. Adipokines as novel Sanofi Research Grant (fellowship educational biomarkers and regulators of the meta- Summary and conclusions ’ grant), diaDexus, and GlaxoSmithKline; com- bolic syndrome. Ann N Y Acad Sci 2010; Improved understanding of obesity s pensation for working as a consultant for 1212:E1–E19 heterogeneity, including interindividual Amylin, GTC Nutrition, Genfit, Eli Lilly, Pfizer, 7. Larson-Meyer DE, Newcomer BR, Ravussin differences in pathogenesis, propensity Johnson & Johnson, and Esperion; financial or E, et al. Intrahepatic and intramyocellular to regain lost weight, development of material support from Cardiometabolic Health are determinants of insulin resistance obesity-related complications including Congress and Institute; in prepubertal children. Diabetologia 2011; diabetes, and response to therapy, is crit- and honoraria from Vindico, CME Incite, and 54:869–875 ical to advance the development of effec- Voxmedia. S.E.K. received consulting fees from 8. Bournat JC, Brown CW. Mitochondrial Eli Lilly, GlaxoSmithKline, Intarcia Therapeu- dysfunction in obesity. Curr Opin Endo- tive and cost-effective interventions. The – insights that improve obesity prevention tics, and Novo Nordisk for acting as an advi- crinol Diabetes Obes 2010;17:446 452 sory board member; consulting fees and 9. Bagdade JD, Bierman EL, Porte D Jr. The and treatment will almost certainly bene- fi fi honoraria from and signi cance of basal insulin levels in t the incidence and care of type 2 diabe- Merck for acting as an advisory board member the evaluation of the insulin response tes. The converse may not be true since and speaker; and grant support from Daiichi to glucose in diabetic and nondiabetic current treatments of diabetes can have Sankyo. 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