Volume 10, Number 1, 2007
Mary Ann Liebert, Inc.
DOI: 10.1089/dis.2006.628

A Conceptual Framework for Targeting Prediabetes with Lifestyle, Clinical, and Behavioral Management Interventions THOMAS J. BIUSO, M.D., M.B.A.,1 SUSAN BUTTERWORTH, Ph.D., M.S.,2 and ARIEL LINDEN, Dr.P.H., M.S.3,4 Prediabetes is a condition that does not fall squarely into the primary or secondary preven-
tion domain, and therefore tends to be inadequately addressed by interventions in either
health promotion or disease management. Prediabetes is defined as having an impaired fast-
ing glucose (fasting glucose of 100–125 mg/dL), impaired glucose tolerance (two-hour post-
prandial glucose of 140–199 mg/dL), or both. There is substantial evidence to suggest that even
at these blood glucose levels, significant risk exists for both micro- and macrovascular com-
plications. This paper introduces a conceptual framework of care for prediabetes that includes
both screening and the provision of up-to-date clinical therapies in conjunction with an evi-
dence-based health coaching intervention. In combination, these modalities represent the
most effective means for delaying or even preventing the onset of diabetes in a prediabetes
population. This paper concludes with a brief example in which these principles are applied
to a hypothetical patient. (Disease Management 2007;10:6–15)

blown and/or irreversible disease states, stillresult in their own cluster of abnormalities and DISEASE MANAGEMENT (DM) is principally a impaired health. These conditions do not fall
secondary prevention model. Individuals squarely into the primary or secondary pre- are usually identified as having a chronic con- vention domain, and therefore tend to be in- dition via hospital claims and the intent is to adequately addressed by interventions in ei- prevent further costly acute exacerbations. In ther health promotion or disease management.
contrast, health promotion efforts generally op- Prediabetes is defined as having an impaired erate within the primary prevention domain fasting glucose (IFG; fasting glucose of 100–125 and mainly target populations with preventive mg/dL), impaired glucose tolerance (IGT; two- health messages with the intent of averting the hour postprandial glucose of 140–199 mg/dL), onset of disease altogether. That said, there are or both. There is substantial evidence to sug- conditions that, while being precursors to full- gest that even at these blood glucose levels, 1 Regional Hospitalist Program Director, Apogee Medical, Tucson, Arizona.
2Oregon Health & Science University, School of Nursing, Portland, Oregon.
3Linden Consulting Group, Portland, Oregon.
4Oregon Health & Science University, School of Medicine and School of Nursing, Portland, Oregon.
significant risk exists for both micro- and factors are present in insulin resistant, non-di- abetic individuals. Patients with prediabetes Fortunately, multiple studies have indicated may have a dyslipidemia characterized by high that the onset of diabetes can be delayed or triglycerides and low high-density lipoprotein even prevented in prediabetes patients by fol- (HDL) levels.
lowing the appropriate therapeutic regimens Insulin resistance and hyperinsulinemia and adopting healthy lifestyle behaviors.6–17 also are associated with polycystic ovarian Given that there are approximately 41 million syndrome, nonalcoholic fatty liver disease, people in the United States aged 40–74 who prostate and pancreatic cancer, congestive have prediabetes,18 implementing clinical and heart failure, HIV lipodystrophy, antipsychotic behavioral change interventions in this popu- medications, and sleep disordered breathing.
lation makes sense from a societal and payer Insulin resistance is also common in systemic perspective. However, this may be easier said inflammatory diseases such as rheumatoid than done. Individuals with prediabetes are arthritis. Aging is frequently associated with highly likely to have entrenched habits such as insulin resistance and glucose intolerance.
sedentary lifestyles, poor eating patterns, and Smoking, gestational diabetes, and a diet high overall poor weight management practices.19 in sweet soft drinks, refined grains, and This paper introduces a conceptual frame- processed meats are associated with increased work of care for prediabetes that includes risk of diabetes.
screening and the provision of up-to-date clin- Prediabetes begins with an excessive intake ical therapies in conjunction with an evidence- of fatty acids in the diet. This excessive intake based health coaching intervention. We believe of fatty acids leads to an accumulation of that, in combination, these modalities represent triglycerides in adipose tissue. A net spillover the most effective means for delaying or even of fatty acids from adipose tissue to non-adi- preventing the onset of diabetes in a predia- pose tissues such as muscle, liver, and the pan- betes population. This paper concludes with a creas occurs. There is a reciprocal relationship brief example in which these principles are ap- between intramyocellular lipid accumulation plied to a hypothetical patient.
and insulin sensitivity in healthy subjects. Thedeposition manifests as the visceral accumula-tion of fat and can be measured by computed ETIOLOGY AND SCREENING
tomography (CT) scan. This visceral accumu- lation of fat also explains insulin resistance inthe lean individual because it is the fat sur- Prediabetes and insulin-resistant states rounding such organs as the liver that leads to insulin resistance, not necessarily subcuta- Currently, most experts agree that type 2 di- abetes mellitus (T2DM) is a multiorgan diseaseinvolving defects of glucose and fat metabo- Prediabetes as a vascular disease lism in several organs, including not only thepancreatic beta cell, liver, and skeletal muscle, The pathophysiology of atherosclerosis and but also other organs such as the gut, kidney, insulin resistance is similar in that both condi- brain, and nervous system. Diabetes begins as tions are characterized by a proinflammatory a prediabetic state characterized by insulin re- state. There is convincing evidence that low- sistance. Resistance to the actions of insulin in grade inflammation is a strong independent many tissues, including the liver, adipose tis- risk factor for the development of cardiovas- sue, and muscle, is a central metabolic abnor- cular disease. It has become increasingly clear mality in patients who have prediabetes. Con- that inflammation correlates with endothelial siderable information is available to suggest dysfunction and insulin resistance, with the that a cluster of metabolic abnormalities related best evidence coming from patients with the to insulin resistance and hyperinsulinemia in- metabolic syndrome.20 creases cardiovascular risk and that these risk Although there are many abnormal bio- BIUSO ET AL.
chemical and transcriptional changes in the in- glucose but an abnormal two-hour postpran- sulin resistant cell, researchers still do not agree dial glucose level. The overlap between sub- on the initial triggering events. That said, in- jects with IFG and IGT is incomplete and teractions between a sensitive genotype and di- suggests that they describe different patho- etary factors such as a high-energy fatty diet physiologic aspects of dysregulated glucose interfere with normal cellular biochemical and fat metabolism. Multivariate analyses functions and insulin sensitivity. Scientists are show that two-hour plasma glucose is closely studying nutrient-gene interactions, particu- associated with risk factors for diabetes and larly with fatty acids as initial events in patho- with cardiovascular variables, including genesis. These triggering events cause a cas- triglycerides and apolipoprotein B. Individuals cade of biochemical and pathophysiologic with high normal two-hour plasma glucose are reactions characterized by the activation of more insulin resistant than normal individuals, proinflammatory genes and the release of have reduced insulin secretion, and higher adipocytokines such as tumor necrosis factor, plasma triglycerides and cholesterol/HDL ra- IL-6, leptin and macrophage migration inhibi- tion factor. Their release contributes to insulin There are three subsets of patients that must resistance in the liver, fat cell, pancreas, and be identified in order to personalize treatment.
skeletal muscle. In many cases, prediabetes pa- They may be described in the following way: tients already have vascular disease before de- obese insulin resistant, metabolically healthy veloping diabetes. Vascular disease may man- but obese (MHO), and metabolically obese nor- ifest as retinal vasculopathy, carotid artery mal weight (MONW) individuals. Obese indi- atherosclerosis, coronary artery disease, or pe- viduals who are metabolically normal have ripheral artery disease. It is interesting that lower levels of visceral fat, fasting insulin,the SHAPE Task Force strongly recommends plasma triglycerides, highly sensitive CRP (hs- screening at-risk asymptomatic men 45–75 CRP), and higher levels of HDL.25 They are not years of age and women 55–75 years of age for insulin resistant. MONW patients have higher coronary artery disease.21 Many of these levels of visceral fat and are insulin resistant as asymptomatic individuals have subclinical measured by fasting insulin, intact proinsulin, atherosclerosis and prediabetes.
and fasting glucose. These categorical subsetsapply to younger age groups as well. Obesechildren and adolescents may be metabolically Screening for prediabetes normal or abnormal. Young, obese patients Unfortunately, we still define a large portion may have elevated hs-CRP, abnormal triglyc- of the population as "normal" based upon di- erides, and early carotid atherosclerosis as chotomous values for blood pressure, urinary manifestations of insulin resistance.
albumin, lipids, and glucose levels. There isreason to believe that our current definition of"normal" values with respect to these parame-ters is really abnormal. Randomized trials il- lustrate the benefit of treating high-risk indi- viduals with "normal" blood pressure.22 Thesame applies to glucose levels. Two recent Although current treatment for prediabetes studies of non-diabetic individuals demon- includes a pharmacological and lifestyle mod- strated that higher fasting plasma glucose lev- ification approach, lifestyle interventions are els within the normoglycemic range constitute the cornerstone of treatment for this condi- an independent risk factor for type 2 diabetes tion.26 Insulin resistance is part of the underly- and that coronary disease is more severe in ing pathology associated with the metabolic those patients with higher postload glycemia syndrome, and patients identified with insulin and hemoglobin A1c (HbA1c) levels.23,24 resistance may have hypertension, dyslipi- The best ways to screen for prediabetes are demia, visceral obesity, and vascular disease.
with an oral glucose tolerance test and/or a Obesity, sedentary lifestyle, and high calorie, fasting glucose. One can have a normal fasting high-fat diets correlate with the development TARGETING PREDIABETES WITH LIFESTYLE MANAGEMENT INTERVENTIONS
of insulin resistance. Lifestyle changes and as diet and exercise in delaying the onset of di- therapeutic dietary intervention have been abetes and was nearly ineffective in older peo- demonstrated to prevent or delay the develop- ple (age  60 years) or in those with a BMI  30 ment of diabetes. In the Diabetes Prevention kg/m2. Metformin was as effective as lifestyle Program (DPP), a 58% relative reduction in the modification in those subjects aged 24–44 years progression to diabetes was observed in the or in those with a BMI of 35 kg/m2.
lifestyle group versus a 31% relative reduction The thiazolidinediones are oral antidiabetic in progression for the metformin group after agents that improve insulin resistance and de- crease plasma glucose and insulin concentra- Current recommended lifestyle changes in- tions in patients with T2DM. They are selective clude a reduction in energy intake and an in- PPAR- receptor agonists that have antiather- crease in physical activity. Both are inversely osclerotic properties. These receptors are found associated with the degree of insulin resistance.
in target organs that are integral for insulin Lifestyle changes can prevent the development action including the liver, adipose tissue, and of diabetes. A moderate decrease in caloric bal- skeletal muscle. Thiazolidinediones improve ance (500–1000 kcal/day) results in slow, pro- the dyslipidemia of T2DM and the metabolic gressive weight loss when coupled with regu- syndrome. Studies are currently under way to lar moderate-intensity physical activity (150 investigate the impact of using these agents to min/week of aerobic activity).27 Reduction in treat prediabetes.31 saturated and trans fatty acids and cholesterol The Xenodos Trial32 followed subjects intake improves lipid status and insulin sensi- (BMI  30 kg/m2) treated with Xenical over 4 tivity. The most recent National Cholesterol years. Orlistat normalized blood glucose in Education Program guidelines recommend to- 72% of individuals in this group versus 49% in tal fat intake between 25% and 35% of total placebo. Three percent of patients treated with calories and saturated fat of 7%.28 orlistat versus 7.6% in the placebo group pro- In the Da Qing trial, 577 subjects with IGT gressed to diabetes, a greater than 50% reduc- were randomized into diet only, exercise only, tion in incident diabetes. Sibutramine is a diet plus exercise groups, and control groups weight reducing medication that suppresses and followed over six years. There was a 31% appetite by preventing the reuptake of sero- (p  0.03), 46% (p  0.0005), and 42% (p  tonin, norepinephrine, and, to a lesser extent, 0.005) reduction in the risk of developing dia- dopamine. In a double-blind randomized con- betes in these groups, respectively. This bene- trolled trial,33 359 obese subjects without hy- fit applied to both lean and obese individuals pertension or diabetes at baseline were ran- even after controlling for insulin resistance, domized to the drug or placebo. Sibutramine body mass index (BMI), and two-hour post- was associated with significant weight loss and glucose level.11,29 improvement in insulin sensitivity.
Rimonabant is another drug associated with weight loss and improvement in insulin sensitivity. Rimonabant is the first selective Pharmacologic intervention also may pre- blocker of the cannabinoid receptor type 1 vent the development of diabetes. The DPP (CB1). These receptors are present in all tis- concluded that metformin may prevent pro- sues that play an important role in the regu- gression to diabetes in insulin-resistant indi- lation of food intake. Rimonabant increases viduals. Participants in the STOP-NIDDM adiponectin levels, leads to significant weight trial30 with impaired glucose tolerance ran- loss, and has glucose lowering properties. The domized to acarbose had a 25% relative risk re- drug also reduces the expression of multiple duction in progression to diabetes after 3.3 proinflammatory cytokines that are upregu- years. Interestingly, 72% of cardiovascular lated in obesity.34 events occurred prior to the subjects develop- Finally, blockade of the renin angiotensin ing diabetes. This fact emphasizes the impor- system (RAS) by angiotensin-converting en- tance of identifying prediabetes.
zyme inhibitors or angiotensin receptor block- In the DPP,7 metformin was half as effective ers have antidiabetic effects. Several insulin sig- BIUSO ET AL.
naling systems are influenced by RAS, and sev- trials on diabetes prevention have confirmed eral studies show that blockade of this system that lifestyle changes targeting diet, weight ameliorates insulin resistance. Long-term clin- loss, and exercise can substantially delay or ical trials will clarify their role in the treatment prevent the progression from impaired metab- of prediabetes.35 olism to type 2 diabetes.6–8,11 However, while The role of pharmacologic intervention in there are numerous examples of successful in- prediabetics needs further definition and on- terventions to improve diet, activity patterns, going studies will answer those questions. Cer- and weight regulation, there is still no consen- tainly, anti-obesity drugs are appropriate for sus on a standard or systematic approach that some obese patients. Surgery also has a place supports sustained behavior change in any of in the treatment of these patients. Over the last these areas.39,40 A significant mediating factor several years, bariatric surgical intervention determining successful behavior change is self- has played an increasingly important role in efficacy (SE), or one's belief about his or her the care of morbidly obese patients. This sur- ability to accomplish something.41 It has been gical technique has rapidly diffused among cited as a correlate with clinical outcomes, and surgeons in the United States, and appropriate influences whether an individual will even at- selection criteria exist in order to minimize tempt to make behavioral changes.42 Other morbidity and mortality in the perioperative mediating factors that have been cited in the period. Numerous studies have shown that in literature include readiness to change43; am- carefully selected patients there is significant bivalence and motivation44; beliefs, values, and weight loss (over 30% in some studies), de- expectations35; and implementation inten- crease in BMI, reduction in blood pressure, and amelioration of insulin resistance.36 In addition to the challenges of changing en- In summary, there is convincing evidence to trenched lifestyle habits, comorbid conditions suggest that prediabetes can be managed suc- such as depression can be a complicating fac- cessfully with lifestyle and clinical interventions.
tor when addressing any chronic medical con- However, getting patients to make and maintain dition.46 In the case of prediabetes, the presence behavior changes and adhere to treatment of depression or chronic stress has been shown regimes requires a compelling approach. In ad- to exacerbate the diabetes disease process, and dition, one must consider the costs. Private pay- has been correlated with poor participation in ers often are reluctant to cover preventive inter- education programs and poor adherence to ventions that have substantial initial costs and self-care behaviors such as medication and diet delayed benefits.37 Coverage decisions are often regimens.47,48 Moreover, a meta-analysis con- based on a strong business case that is defined firmed that depressed patients were three times as a positive return on investment (ROI). In a re- more likely than non-depressed patients to be cent paper, Ackerman and colleagues addressed non-compliant with physician recommenda- the costs for a payer to treat members with pre- diabetes aged 50–64.38 Compared with placebo, Traditionally, diabetes education (which is the DPP intervention could prevent 37% of new similar to prediabetes education) has empha- cases of diabetes before age 65 at a cost of $1288 sized increasing knowledge about diabetes, per QALY. A private payer could contribute risk factors, and diabetes self-care; however, 24% of total discounted intervention costs and multiple studies have demonstrated that this achieve positive ROI after 3 years. Each year pedagogical approach does not result in opti- thereafter (years 4–15) results in cost savings for mal clinical or behavioral outcomes.50–52 the health plan. In this scenario, the residual Rather, efforts should focus on improving cop- payment by the employer or member amounts ing, communication, and control by enhancing to $44 per month.
SE, increasing motivation to initiate and/orchange behaviors, and facilitating an individu-alized plan of action that takes into account personal needs, barriers, and preferences.44,53,54 As mentioned above, along with pharmaco- Therefore, considerable care must be taken to logical interventions, several recent controlled implement a behavioral change program that TARGETING PREDIABETES WITH LIFESTYLE MANAGEMENT INTERVENTIONS
includes these components. Likewise, recent though more well-controlled research was rec- literature supports interventions for pa- tients/members with chronic conditions that MI has also been used successfully to pro- also screen for and address depression and mote self-care for both adolescents and adults chronic stress.55 with diabetes.73–76 All studies demonstrated A novel intervention modality recently in- significant improvement in diabetes self man- troduced in DM that includes these criteria is agement and/or clinical outcomes such as a health coaching approach that utilizes the HbA1c scores, and in one study,73 the adoles- Motivational Interviewing (MI) technique to cents reported less anxiety about their condi- address lifestyle-related issues known to im- tion and more confidence that they could con- pede the member/patient's self-management of chronic illness. Health coaching is an emerg- Promising results have also been shown in ing field in which health professionals (eg, di- the application of MI to mental health issues etitians, nurses, counselors) facilitate behavior (in addition to substance abuse) such as anx- modification in clients to improve their health.
iety and depression.77–79 In one study, MI- MI-based health coaching embraces a set of based health coaching significantly improved techniques that is evidence based and involves mental as well as physical health status scores, a discrete skill set of the coach/provider that although the health coaches were not coun- can be objectively coded and measured.56 selors and the presenting health concerns were MI was originally developed for addictions typical lifestyle-related ones such as weight counseling in the 1980s and is described as a management, exercise, stress management, and "directive, client-centered counseling style for eliciting behavior change by helping clients to Supporting SE is one of the four principle ob- explore and resolve ambivalence.44 It has been jectives of MI.44 As mentioned previously, the well researched in randomized controlled tri- client's belief that change is possible is an im- als for use in treating addictions such as illegal portant motivator to succeeding in making a drugs, smoking, and alcoholism.57–59 As the value of lifestyle management has becomemore fully realized, MI has expanded into The client can be helped to develop a be- health promotion and disease management set- lief that he or she can make a change. For tings and typically is employed in a health example, the clinician might inquire about coaching application in the format of several other healthy changes the client has made in their life, highlighting skills the client This method is different from traditional already has. Sharing brief clinical exam- health education approaches in that it is not ples of other, similar clients' successes at based on the information model, does not use changing the same habit or problem can scare tactics, and is not confrontational, force- sometimes be helpful. In a group setting, ful, guilt-inducing, or authoritarian44; rather it the power of having other people who is shaped by an understanding of what triggers have changed a variety of behaviors dur- change.60 A recent meta-analysis found that in ing their lifetime gives the clinician enor- a scientific setting MI outperforms traditional mous assistance in showing that people advice-giving in the treatment of a broad range of behavioral problems and diseases.53 Studies in this area have utilized the MI ap- In supporting and increasing SE, the health proach in the intervention for increasing fruit coach or provider can increase motivation for and vegetable intake,61,62 promoting physical change and increase the likelihood of a suc- activity,63–66 medication adherence,67,68 manag- cessful behavior change effort, which will re- ing hypertension and hypercholesterolemia,69,70 sult in a better clinical outcome.
and behavioral obesity treatment.71,72 A recent In a successful session using MI-based health meta-analysis by Knight of MI in the physical coaching, the coach emphasizes the three un- healthcare setting indicated that MI had high derlying assumptions of MI—collaboration, the face validity across a number of domains, al- evocative element, and autonomy—in order to BIUSO ET AL.
establish rapport, reduce resistance, improve SE, bivalence; assessment of importance/confi- and elicit "change talk" (one's own reasons and dence/readiness; development of discrepancy arguments for change).44,82 The intended out- (acknowledging the gap between current and come of these MI sessions is for clients to resolve ideal behaviors); support of SE; identification ambivalence (a central goal), move through the of action plan; appropriate referrals, resources, stages of change,43,83 and follow through on de- or information; and a follow-up plan.
sirable lifestyle change, which would ideally re- In this example, Ruth, a 52-year-old woman sult in improved health outcomes.
with a family history of diabetes has an IFG of Other characteristics of this technique that 119 and an IGT of 165. She has high cholesterol make it particularly suitable for use in disease (257) and mild hypertension (142/92), and is management to address prediabetes are as fol- obese (BMI  35). Her provider has prescribed lows: (1) it is most effective when implemented enalapril and lovastatin, and recommended with clients who are considered difficult (ie, re- lifestyle change.
luctant to change, stuck, or ambivalent about During the initial rapport-building segment changing their behavior); (2) it has been found of health coaching, the health coach (Maria) ex- to be efficacious in small doses (2–3 sessions); plores Ruth's current health habits, and over- (3) it has been found to work across gender, all knowledge of and attitude about her condi- age, cultural, and socioeconomic boundaries; tion. Maria establishes that Ruth is sedentary, and (4) it has been found to be an effective pre- lives alone, does not like to cook, and is taking treatment adjunct to traditional disease man- her medication on a regular basis. Ruth is fairly agement programs.84,85 well informed about prediabetes and is very It is becoming more widely acknowledged concerned about it developing into diabetes.
that most lifestyle changes are infused with Maria ascertains that Ruth has low SE about psychosocial dynamics such as ambivalence, her ability to lose weight because she has failed SE, self-image, motivation, self-doubt, and core at several previous attempts.
identity.43,44,86–88 As described by Prescott: During the agenda-setting portion of health coaching, Maria validates Ruth's medication MI views people as complex, driven by adherence and directs her toward exercise and competing motives and in conflict with appropriate dietary choices as her primary themselves. This complexity is noticeable goals. Over the course of the first three sessions, in motivational conflict (ambivalence) and Maria has explored Ruth's ambivalence, barri- fluctuating levels of self efficacy (both op- ers, and available resources. They jointly de- timism and doubts about being able to velop a feasible and detailed plan of action that change grow and fade).89 includes walking five days a week, cutting backon fast food, including more fruits and vege- Thus it appears that MI is also particularly well tables in her food preparations, and eating suited for impacting the psychosocial aspects smaller portion sizes. Maria continues to work of desired behavior change in prediabetes.
with Ruth on improving her confidence levels.
By the fourth coaching session, success indica-tors include increased SE for weight manage- AN EXAMPLE OF MOTIVATIONAL
ment, healthier lifestyle habits, and, most im- portantly, improved blood glucose values.
Once an individual is identified as having pre- diabetes via laboratory values, a health coach isassigned to the case. Over several telephone Although there are currently no consensus sessions, the health coach uses the following guidelines on the screening and treatment ofMI-based coaching techniques: rapport-set- prediabetes, the recent literature underscores ting/building; agenda-setting (identification of the importance of screening, introducing the critical health behavior); exploration of am- appropriate therapeutic regimens, and adopt- TARGETING PREDIABETES WITH LIFESTYLE MANAGEMENT INTERVENTIONS
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Kujawa-roeleveld_2011_removal of pharmaceuticals compounds from concentrated wastewater

018530 - SWITCH Sustainable Water Management in the City of the Future Integrated Project Global Change and Ecosystems Training material Pharmaceutical compounds in environment Removal of pharmaceuticals from concentrated wastewater streams in source oriented sanitation Prepared by: dr. ir. Katarzyna Kujawa-Roeleveld Wageningen University, Wageningen, The Netherlands LeAF (Lettinga Associates Foundation) Based on deliverables of SWITCH project, other overlapping projects and literature Material to be used with PowerPoint presentations I-VIII


CASE REPORT HUGE NODULAR GOITRE WITH RETROSTERNAL EXTENSION- A rare case report Raj Nagarkar1, Shirsendu Roy1, Mohammad Akheel2, Nayana Kulkarni3 1-Surgical oncologists 2-Senior Registrar, 3-Anesthetist, Dept of head & neck oncology services, HCG Curie Manavata cancer centre, Nashik, India. ABSTRACT: