Diabesity: an overview of a rising epidemic...Medicine, Ain Shams University Hospital, Cairo, Egypt...

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Received for publication: 25.7.10; Accepted in revised form: 30.8.10

Nephrol Dial Transplant (2011) 26: 28–35doi: 10.1093/ndt/gfq576Advance Access publication 2 November 2010

Diabesity: an overview of a rising epidemic

Youssef M.K. Farag1 and Mahmoud R. Gaballa2

1Renal Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA and 2Department of InternalMedicine, Ain Shams University Hospital, Cairo, Egypt

Correspondence and offprint requests to: Youssef M. K. Farag; E-mail: [email protected]

Abstract‘Diabesity’ is the term for diabetes occurring in the con-text of obesity. In this review, we will overview the latestepidemiological data available describing the rising

prevalence, health impact and economic impact of dia-besity. We will also outline the measures required toslowdown this newly evolving epidemic. The globalprevalence of diabetes in 2010 was 284 million people

28 Nephrol Dial Transplant (2011): Editorial Reviews

© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: [email protected]

worldwide constituting around 6.4% of the world popula-tion, which is higher than was projected in earlier studies.Furthermore, the projections for 2030 show the preva-lence to reach 439 million individuals comprising~7.7% of the world population. The burden of diabeteson the world economy has been rising steadily in the lastdecade to reach $376 billion in 2010 and is expected toreach $490 billion in 2030. Diabesity represents a sub-stantial economic burden as reflected by diabetes andobesity consuming 14 and 5.7% of the USA’s total healthexpenditure, respectively, representing the highest knownexpenditure on diabesity worldwide. When costs asso-ciated with being overweight were also included, theupper limit of obesity expenditure rises to 9.1% of theUSA’s total healthcare expenditure. The highest recordedexpenditure on diabetes alone was in Saudi Arabia con-suming 21% of the country’s total health expenditure,with no data available about the health expenditure onobesity. The health impact of diabesity is substantial toinclude long-term diabetic complications, reduction inhealth-related functioning, reduction of quality of lifeand reduced overall life expectancy. Long-term complica-tions include myocardial infarction, cerebrovascularstroke and end-stage renal disease. Also recent advanceshave found that there is an association between chronicstress, depression and sleeping troubles to both diabetesand obesity. This century is the unprecedented diabeto-genic era in human history. It is thus urgent to take stepsincluding screening, prevention and early management inan attempt to control this evolving epidemic of diabesity.

Keywords: diabesity; diabetes mellitus; obesity

Introduction

Diabesity is a new term describing diabetes in the contextof obesity. Sometimes it is referred to as obesity-dependentdiabetes. Recently, it has been recognized as a major pub-lic health problem that is evolving to become an epidemic[1–3]. In this review, we will discuss the epidemiology andimpact of diabetes and obesity and how to combat this ris-ing epidemic. The prevalence of both type 2 diabetes andobesity has had a rapid increase worldwide during the lastcentury, mainly attributed to changes in human behaviour,especially sedentary lifestyle and dissemination of the west-ern diet [4], in addition to genetic susceptibility [5–10].Both diabetes and obesity are also integral components ofmetabolic syndrome [4,11,12].

Epidemiology of diabetes mellitus

The prevalence of diabetes has been persistently rising forthe last few decades and it is being recognized as a world-wide epidemic [13]. The magnitude of the problem is re-flected in Figures 1 and 2, which compare the estimates ofthe global prevalence of diabetes from the years 1995,2000, 2010 and projection for the year 2030. It shows that

the worldwide prevalence in the year 2010 is estimated tobe 6.4% [13]. Between 2010 and 2030, there will be a netincrease in the prevalence of diabetes among adults, as re-flected by the 73% increase in adult diabetes numbers indeveloping countries, compared to 20% increase in devel-oped countries [13]. Interestingly, these results show thatthe current prevalence of diabetes is much higher than thenumber projected before [13], which could also speculatea similar situation in the 2030s actual estimates.

Moreover, a recent study by Yang et al. was published in2010 estimating the prevalence of diabetes among theChinese population from June 2007 to May 2008 [14]. Itincluded a representative sample of 46 239 adults, aged20 years and older from 14 different providences [14].Identification of undiagnosed diabetes was based on an oralglucose tolerance test (OGTT) showing a fasting glucoselevel ≥7.0 mmol/L (126 mg/dL) and/or 2-h glucose level≥11.1 mmol/L (200 mg/dL), whereas those with previouslydiagnosed diabetes were identified based on self-report[14]. The age-standardized prevalence of diabetes was10.6% among men and 8.8% among women, accountingfor 92.4 million adults with diabetes (50.2 million menand 42.2 million women). In underdeveloped areas, theage-standardized prevalence of diabetes was higher amongurban residents (10.4%) versus rural residents (5.8%) [14].Moreover, the investigators showed a rising prevalencewith increasing age and with increasing body mass index(BMI), confirming the relationship between obesity anddiabetes in their cohort [14]. Other data showed that dur-ing the last 25 years, the prevalence of diabetes hasdoubled in the USA and multiplied by three to five timesin India, Indonesia, China, Korea and Thailand [15].Interestingly, regions with the highest comparative preva-lence rates are North America (10.2%), followed by the

Line Graph representing total number of people withdiabetes worldwide

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Fig. 1. Total number of people with diabetes worldwide in the years1995, 2000, 2010 and projections for 2030, as reported by King et al.[24], Rathmann and Giani [79] and Shaw et al. [13].

Nephrol Dial Transplant (2011): Editorial Reviews 29

Middle East and North Africa (9.3%) [16]. The Pacificisland nation of Nauru has 30.9% of its adult populationliving with diabetes, followed by the United Arab Emi-rates (18.7%), Saudi Arabia (16.8%), Mauritius (16.2%),Bahrain (15.4%), Reunion (15.3%), Kuwait (14.6%), Oman(13.4%), Tonga (13.4%) and Malaysia (11.6%) [16].

Health impact of diabetes mellitus

The major health impact of type 2 diabetes mellitus (DM) isdue to its long-term complications including retinopathy,nephropathy, neuropathy, cardiovascular diseases, periph-eral vascular diseases, stroke and periodontal pathologies[17]. Recent studies demonstrated that there is a reductionin health-related functioning associated with individualswith impaired fasting glucose, impaired glucose toleranceand type 2 DM when compared to those with normal glu-cose tolerance. This was in the form of increased bodilypain, reduced physical functioning, general health, mentalhealth and vitality at baseline [18].

Eliminating diabetes was observed to extend both theoverall life expectancy and the health-adjusted life expect-ancy for men by 1.3 and 1.4 years and for women by 2.0and 1.7 years, respectively. Moreover, patients with dia-betes had a significantly lower health-related quality of lifein contrast to those without diabetes [19].

Economic impact

The burden of diabetes on the world economy has beenincreasing lately to reach at least $376 billion in 2010and is expected to reach $490 billion in 2030. In 2010,it is estimated that ~12% of the health expenditures perperson worldwide are expected to be spent on diabetesto reach $1330 per person [20]. This represents a significanteconomic burden as reflected by its consumption of 21, 16,15 and 14% of the country’s total health expenditure inSaudi Arabia, Egypt, Mexico and USA, respectively (seeFigure 3). In contrast, hypertension and its main sequelae,stroke and myocardial infarction, cost ~10% of the world’s

overall health expenditure [21]. In the USA, the totalexpenditure on diabetes reached ~$41 billion in 2010, incontrast to $73 billion spent on all cancers combined,$96 billion on heart diseases, $63 billion on pulmonaryconditions, $48 billion on hypertension, $19 billion onstroke and $65 billion on mental disorders [22]. Althoughdeveloping countries are anticipated to have a 69% in-crease in prevalence by 2030 [13], 91% of the world totalhealth expenditure on diabetes will be in developed coun-tries while only 9% of the total will be in the developingcountries [20].

In 2007, it was estimated that the burden of pre-diabetesand diabetes on the US economy reached $218 billion,$153 billion for higher medical costs and $65 billion forreduced productivity [23]. Moreover, the World HealthOrganization (WHO) announced that by 2025 India andChina would have ~130 million diabetics consumingaround 40% of their country’s healthcare budget.

Diabetes and end-stage renal disease

Chronic kidney disease (CKD) is a major complication ofdiabetes. Diabetes remains the leading cause of end-stagerenal disease (ESRD) in most countries in the world, ac-counting for 40–50% of incident ESRD cases [24–26].Recent studies showed the prevalence of CKD to be ashigh as 39.6 and 41.7% in patients with diagnosed andundiagnosed diabetes, respectively [27]. In contrast, CKDprevalence in those without diabetes is 10.6% [27]. Joyceet al. compared the direct cost of care before and afteronset of ESRD for patients with and without diabetes[28] and concluded that the total adjusted annual costsper patient pre- and post-ESRD were significantly higherfor diabetes (P < 0.0001) [28]. Adjusted annual costs perpatient before and after diagnosis of ESRD were signifi-cantly higher for diabetics (P < 0.0001); annual costs were69% ($38 041 vs $22 538) and 79% ($96 014 vs $53 653)higher pre- and post-onset, respectively [28]. In 2007, themortality in the USA for patients with ESRD was 157.3deaths per 1000 patients [29]. Moreover, the cost for ESRDin the USA was $35.32 billion in 2007 [29]. This empha-

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Line Graph showing the increase in diabetes prevalence and the projectionfor the year 2030, emphasizing the magnitude of the problem

Fig. 2. Prevalence of diabetes worldwide in the years 1995, 2010 and projections for 2030, as reported by King et al. [24], Rathmann and Giani [79]and Shaw et al. [13].


sizes that diabetes and its closely related complicationESRD represent a huge economic and health problem.The high prevalence of ESRD among the diabetic popula-tion with its added substantial economic burden augmentsthe problem even further to reach alarming levels.

Epidemiology of obesity

The WHO reports in 2005 indicate that the global preva-lence of overweight adults (age 15+) (BMI 25–29.9 kg/m2) was ~1.6 billion and that of obese adults (BMI ≥30 kg/m2) was at least 400 million [11]. This accountsfor one quarter of the world’s total population being atincreased risk for developing cardiovascular disease, dia-betes and eventually CKD. The projections for the year2015 expect the prevalence of overweight adults to beas high as 2.3 billion and that of obese adults to be ~700million. In 2005, the prevalence of being overweight amongchildren younger than 5 years was estimated to be 20million globally [11].

In the USA, the prevalence values varied according toage, sex, race and ethnic groups (Table 1). However, theprevious trend of increasing obesity prevalence in theUSA does not seem to be continuing at the same rate overthe past 10 years, and this is more evident among womenthan men [30]. These values differ than those from otherparts of the world as reflected by a recent study by Gigante

et al. in 2009 on 49 395 individuals investigating theprevalence of obesity in Brazil, showing that the preva-lence of overweight was 47% among males and 39%among females and that of obesity being around 11% forboth genders [31].

The obesity epidemic is suggested to be due to the com-plex interaction of both environmental factors and genes[32]. It has been suggested that there are genes favouringstorage of fat, which became maladaptive in our modernenvironment minimizing physical activity and favouringhigh-energy intake [32]. It has been found that obesechildren and adolescents are more likely to become obesein adulthood [33], and the risk rises even more if theyhave an obese parent [34]. Also, many studies haveshown additive effects of genes on the body weight inthe years following birth [35–37]. The recent changesin physical activities and nutritional behaviour includingsmall snacks [38] and fast food (of the western diet) [39]are thought to be partly responsible for the increasingprevalence of obesity in children.

Health impact of obesity

Obesity is associated with increased risk for numerouschronic diseases including diabetes, hypertension, heartdisease and stroke [40]. Obesity is also associated withvarious diseases including gastroesophageal reflux dis-ease, colorectal polyps, colon cancer and liver diseasessuch as non-alcoholic fatty liver disease, cirrhosis and he-patocellular carcinoma [41]. Moreover, obesity and highBMI are associated with significantly reduced quality oflife. The diabetes and coronary artery disease associatedwith obesity are also factors that contribute to the reduc-tion of the quality of life [42]. Adams et al. reported thatthe risk of death is increased by 20–40% in overweight in-

Table 1. The age-adjusted prevalence of obesity and overweight in theUSA in 2007–2008

Obesity Obesity and overweight (BMI ≥25)

Men 32.2% 68.0%Women 35.5% 72.3%Both sexes 33.8% 64.1%

Fig. 3. Graphic representation of expenditure on diabesity in relation to the total countries’ health expenditure in developed and developing countries,with data about obesity lacking in developing countries. Data are based on the following references: Zhang et al. [20], Withrow and Alter [47], Seidelland Deerenberg [80], Barrett et al. [45], Muller-Riemenschneider et al. [81], Zhao et al. [82] and Colditz [83].


dividuals and by 2–3-fold in obese individuals comparedto normal weight individuals [43].

Economic impact

The health expenditure attributed to obesity alone in rela-tion to a country’s total health expenditure varies globallyreaching 0.7–2% [44,45] in France and 2.8–5.7% [45,46] inthe USA, respectively [47] (Figure 3). When costs asso-ciated with being overweight were also included, the upperlimit of this range rises to reach 9.1% of a country’s totalhealthcare expenditure [48]. Moreover, healthcare expendi-tures for morbidly obese individuals (BMI ≥40 kg/m2) are81% higher than normal weight individuals (BMI = 18.5–24.9 kg/m2), 65% higher than overweight individuals (BMI25–29.9 kg/m2) and 47% higher than individuals with classI obesity (BMI = 30–34.9 kg/m2). This higher expenditurewas attributed to more frequent office-based visits, out-patient hospital care, inpatient care and prescription drugs[49]. In the USA, it is estimated that the total economic costof obesity was close to $147 billion per year by 2008 [50].The total indirect cost in the USA for 1999 was estimated tobe ~$66 billion [51]. However, since the prevalence ofobesity has increased substantially since 1999, the currentcosts are expected to be much higher. The annual medicalspending because of overweight and obesity in the USAwas ~$93 billion in 2002, constituting around 9% of thetotal health expenditure [52]. Furthermore, the USA totalhealth expenditure on atherothrombosis including myo-cardial infarction, ischaemic stroke and peripheral arterialdisease was $300 billion in 2004 [53].

Recent advances

Chronic stress

Recent studies by Gastaldi et al. in 2009 showed a signifi-cant contribution of chronic stress to the development ofdiabesity, through activation of the autonomic, neuroen-docrine, inflammatory and immunologic systems [54]. Itis thought that chronic psychological stress which charac-terizes the modern western daily life can in fact activatethe hypothalamic-pituitary-adrenal axis to disturb thephysiologic anabolic–catabolic hormonal balance, withdownstream effect of increased visceral fat and insulinresistance [54]. Chronic stress is suggested to result inheightened neuroendocrine response with ensuing riskof developing pre-diabetes and cardiovascular diseases.Thus, targeting modifiable risk factors including stressmanagement should be a cornerstone in therapy [54].

Depression

A recent case–control study conducted in 2010 on 296newly diagnosed type 2 diabetes patients, who werematched on age and sex with 296 controls, investigatedthe association of depression with diabetes [55]. It con-sisted of 592 subjects with 432 (73%) men and 160(27%) women aged between 25 and 60 years. The oddsof mild depression among diabetic patients were 3.86

times the odds among controls [95% confidence interval(95% CI): 2.22–6.71], while the odds of moderate to se-vere depression among diabetic patients were 3.41 timesthe odds among controls (95% CI: 2.22–6.71) [55]. Thisindicates that there would be a higher incidence of variousdegrees of depression in those with type 2 DM. Depressionwas also associated with those with high BMI to includeoverweight and obese people [55]. Thus, it is suggestedto begin screening for depression at an early stage withnewly diagnosed diabetics [55]. This is further supportedby previous literature showing up to three times higher riskof developing depression among diabetics in contrast tonon-diabetics [56].

Another meta-analysis for over 15 longitudinal studies(n = 58 745) identified a direct reciprocal link betweenobesity and depression that is most evident in clinicallydiagnosed depression. It also demonstrated that this rela-tionship is more evident in the American population, espe-cially among adults. Obesity also increased the risk ofdeveloping depression in the future and vice versa; havingclinically diagnosed depression was predictive of develop-ing obesity and overweight [57].

Challenges and opportunities

The best way contain this epidemic is to screen for earlydetection, prevention and early management of obesity, es-pecially in younger individuals, before the development oftype 2 DM. It was suggested that supplementation with mi-cronutrients such as vitamin D and vitamin E could attenu-ate the innate immunity [58]. This could be achieved byfortifying the food with these micronutrients besides in-cluding high vitamin D and vitamin E diet in the dailymeals of the school children, which needs a national plan,especially in developing countries. It is thus recommendedthat all individuals 30 years of age or older with risk factorsshould be screened annually for type 2DM and obesity [59].Risk factors include family history, hypertension, obesity,sedentary lifestyle, cardiovascular disease and hyperlipid-aemia [59]. Screening should be done for high risk indivi-duals using fasting plasma glucose (FPG). A patient withFPG ≥126 mg/dL (7.0 mmol/L) should be retested on adifferent day to confirm the diagnosis. An FPG <126 mg/dL (7.0 mmol/L) in an individual with a high suspicion fordiabetes should be followed by a 75 g OGTT, where a 2-hpost-load value ≥200 mg/dL (11.1 mmol/L) confirms dia-betes [60]. This is further supported by the fact that at thetime of diagnosis, 50% of patients have microvascular com-plications (retinopathy, neuropathy or nephropathy) andtwice the risk of macrovascular complications when con-trasted to the general population [61]. As for obesity, thereis mounting evidence that the BMI (weight in kilogram/height in meter squared) is reliable and valid for detectingobese and overweight individuals with increased risk formorbidity and mortality [62]. Moreover, counselling obeseindividuals about diet, exercise and behavioural interven-tions (skill development, motivation and support strat-egies) produces modest sustained weight loss (3–5 kgfor ≥1 year) [62]. A recent study by Lu et al. suggested thatHbA1C can aid in the screening for DM in addition to its


traditional use of long-term monitoring of blood glucose le-vels. It concluded that HbA1C ≤5.5 and ≥7.0% predict theabsence or presence of type 2 DM, respectively, whileHbA1C 6.5–6.9% is highly probable of DM [63]. Re-search institutions, non-governmental organizations alongwith the policy makers in the countries’ governmentsshould collaborate in setting these standards. Moreover,most guidelines agree that those with hypertension andhyperlipidaemia should be screened for diabetes [64].Diabetes risk calculators have a high negative predictivevalue (a value representing the likelihood that a patientwho has a negative test is free of the disease). The followingtests are also promising in differentiating the type ofdiabetes: C peptide, anti-islet cell antibodies and insulinlevels [65].

Recent therapeutic approaches are directed against theprincipal pathophysiology of diabesity, which includes theinnate immune system, the incretin system, inflammatorymediators, oxidative stress, mediators of insulin resistanceand the balance between energy intake and expenditure[66–68]. Therapeutic options that were suggested lately in-clude strategies aimed at glycaemic control and weight loss.Recent studies suggested a role for incretin-based anti-diabetic therapies; however, this remains controversialand more data are still needed to investigate their efficacy[69–71]. Glycaemic control using dipeptidyl peptidase-4inhibitor therapies (sitagliptin, vildagliptin and saxagliptin)[72–74] and glucagon-like peptide receptor agonist therapy(exenatide and liraglutide) [75,76] in addition to the trad-itional therapies are also recommended. In addition, anti-obesity strategies including behavioural modification andanti-obesity drugs such as orlistat, sibutramine and rimona-bant are still considered an alternative line of therapy, withrisk monitoring from the long-term use [77]. Moreover,laparoscopic surgical procedures such as banding of thestomach and Roux-en-Y gastric bypass could play a roleand have been reported to produce remission rates of typeII DM of up to 73% [78].

Conclusion

It is quite evident that diabesity has already become aworld-wide epidemic with a significant health and economic bur-den affecting both developed and developing countries.Numerous studies have examined the situation, however,further data are still needed to evaluate the economicburden, particularly of obesity, in developing countriesin different parts of the world including the Middle East,Africa, parts of Asia and parts of South America, wheredata are still scarce. Research studies are highly encouragedin developing countries in order to identify the epidemi-ology of diabesity, its economic and health burden and itsassociated risk factors. This will help better the allocationof each country’s resources to contain this evolving epi-demic. Genetic studies and drug targets for the treatmentof diabesity should have the utmost attention. We have alot to do.

We can conclude with what Hamlet said to his motherafter he killed Polonius:

‘I must be cruel only to be kind;

Thus bad begins, and worse remains behind.’

The Tragedy of Hamlet, Prince of Denmark,by William Shakespeare, Act 3; Scene 4

Conflict of interest statement. The authors declare no conflict of interest.

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Received for publication: 18.7.10; Accepted in revised form: 30.8.10

Nephrol Dial Transplant (2011) 26: 35–41doi: 10.1093/ndt/gfq574Advance Access publication 15 September 2010

Glomerular diseases and transplantation: similarities in pathogeneticmechanisms and treatment options

Claudio Ponticelli1, Rosanna Coppo2 and Maurizio Salvadori3

1Nephrology and Dialysis, Istituto Scientifico Humanitas Rozzano (Milano) Italy, 2Nephrology, Dialysis and Transplantation, ReginaMargherita University Hospital, Turin, Italy and 3Nephrology, Dialysis and Transplantation, Careggi University Hospital, Florence,Italy

Correspondence and offprint requests to: Rosanna Coppo; E-mail:[email protected]

AbstractGlomerular diseases and renal transplantation have alwaysbeen considered as independent fields of nephrology, dueto the supposed prevalent role of antibody production andimmune complex formation in glomerulonephritis versus adirect reaction of immune cell towards the grafted kidney.However, both conditions share common pathogeneticalpathways, and possible new therapeutic approaches arebeing envisaged. Innate immunity, particularly Toll-like re-ceptors, dendritic cells and complement pathways, B cellsand antibody networks are involved in the development ofglomerular damage as well as graft injury. Consequently,new treatments targeting previously not considered im-mune pathways, like nuclear factor-κB or the proteasomeand B-cell activation with antibody production, are beingtested in glomerular diseases and in transplanted kidneys.

Keywords: B cells; glomerulonephritis; innate immunity; renaltransplantation; treatment

Introduction

Glomerular diseases and renal transplantation have alwaysbeen considered as independent fields of nephrology. Thisconcept has been supported by the prevalent role of anti-body production and immune complex formation in glom-erulonephritis (GN) versus being due to the direct reactionof immune cells towards the grafted kidney. However, re-cent investigations have shown that the pathogenetic me-chanisms operating in both conditions share commonpathways offering some new therapeutic approaches iden-


© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: [email protected]

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