|Ahead of print publication
2020 Sidney licht lecture: Metabolic syndrome and obesity negatively impact function
Lynn H Gerber
Inova Health System, Medicine Service Line, George Mason University, Fairfax, Virginia, United States
|Date of Submission||09-Oct-2020|
|Date of Decision||09-Oct-2020|
|Date of Acceptance||09-Oct-2020|
|Date of Web Publication||04-Mar-2021|
Lynn H Gerber,
George Mason University, Fairfax, Virginia
Source of Support: None, Conflict of Interest: None
There are important connections between metabolic abnormalities and poor function. This is relevant because the World Health Organization and the Centers for Disease Control and Prevention indicate that we are facing an epidemic of obesity and pre-diabetes/diabetes, which present substantial and challenging health-care concerns. Most of these people have metabolic syndrome (MS), including hypertension, hyperglycemia, obesity, hyperlipidemia, and hypertriglyceridemia. The relationships among function and MS seem intuitive and reasonable. One link could include abnormal energy production and mitochondrial efficiency in the generation of adenosine triphosphate(ATP). Another link might result from insulin resistance and its impact on interfering with glucose uptake. Sedentary behavior with increased waist circumference is associated with obesity and fatigue. In addition, there has been a reported association between sarcopenia and obesity, both associated with reduced function. The health implications include increased all-cause mortality and is thought to be mediated through processes that include inflammation of muscle and MS. Human function is likely to be influenced by physiological and anatomical as well as environmental and personal factors. These factors will be discussed in an effort to integrate them and explain why people with MS have significant functional problems. The premise is that fatigue is frequently reported, negatively impacts activity and exercise tolerance, and may explain why this group of people is so sedentary. We have effective treatments for fatigue that is associated with MS and obesity. Unfortunately, at this time in the history of medicine, the best treatments are behavioral and require patience and commitment. Risks are very low, rewards are high but not instantaneous.
Keywords: Fatigue, function, metabolic syndrome
This paper is a summary of the Sidney Licht Lecture presented at the ISPRM meeting March 8, 2020.
I wish to thank the executive committee of the ISPRM for inviting me to present the Sidney Licht Lectureship here in Orlando. It is indeed an honor to be selected for this award, carry on the great traditions of Dr. Licht who was a respected and gifted educator and advocate for people with disability. Thank you to the Awards Committee for selecting me.
When I was informed of this honor and had to select a topic for a presentation, I debated whether the talk should focus on cancer rehabilitation or the impact of the metabolic syndrome (MS) on function. Cancer rehabilitation is a new and growing area of interest in our field and has attracted a significant number of people who are participating in the special interest group and working on projects to develop teaching materials. The impact of obesity and MS, a global epidemic, on function, is relatively unknown. I selected the latter topic for presentation: “The MS and Obesity Negatively Impact Function.” I hope this will generate interest on the part of our members to help tackle this daunting worldwide problem.
| Background/Introduction|| |
This paper aims to defend the position that there are important connections between metabolic abnormalities and poor function. This is a particularly relevant issue because, according to the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), we are facing an international epidemic of obesity and prediabetes/diabetes, which presents substantial and challenging health-care concerns (https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf).
Most of these people have the MS, a condition which is often silent and undiagnosed. Investigators are assessing possible relationships among these phenotypes and function.,,
For the purposes of this discussion, the definition of the word “function” is taken from the International Classification of Functioning, Disability, and Health (ICF) construct. Functioning, as used in the ICF model, is “a dynamic interaction between her or his health conditions, environmental factors, and personal factors.” In addition, I have selected the MS as the condition to address because it includes a variety of measures, all of which are thought to contribute to metabolic imbalance and possible consequence thereto. The term MS adheres to the National Cholesterol Education Program definition: hyperglycemia: >100 mg/dL; high-density lipoprotein cholesterol <40 mg/dL for males and <50 mg/dL for females; (2) triglycerides: >150 mg/dL mmol/L (150 mg/dL); (3) obesity: waist >40 in men or >35 in women; and (4) blood pressure >130/85 mmHg. Often, the body mass index (BMI) is used to establish the diagnosis of obesity, but the score differs among countries, with Asian countries having different cut points. The presence of MS is often detected at the time of diagnosing hypertension, prediabetes, or diabetes, but its prevalence is estimated at about 30' in the US population. CDC has identified the prevalence of the MS/obesity burden in the USA as 39'. The WHO has identified the same prevalence worldwide. The prevalence is rising. An interesting observation was published about what the prevalence trends are for the individual components of the MS between 1999 and 2010 [Figure 1]. All have improved with the exception of waist circumference (obesity). In my opinion, this is evidence of improved pharmacological management of MS without measurable changes in weight-loss, hence no evidence of behavioral change. We are all well aware that one of the most difficult things to change is behavior, despite knowing that behavioral changes in this condition are likely to be the most effective and have the fewest adverse effects.
The relationships among function and MS, diabetes, and obesity seem intuitive and reasonable. One link would include energy production and mitochondrial efficiency in the generation of ATP. Associations between sedentary behavior and increased waist circumference have been reported and are often associated with obesity, which may offer another relationship. In addition, there has been a reported association between sarcopenia and obesity recently. The health implications for this include increased all-cause mortality and are thought to be mediated through processes that include inflammation of muscle and MS. The phenotype is typically over 65, with elevated BMI, increased ' body fat, and decreased lean mass and decreased strength. Other distinguishing features include the presence of the MS, hypertension, hyperlipidemia, and hyperglycemia. This combination of metabolic abnormalities and aging negatively impact function and, most importantly, activity level, which is significantly reduced in people with sarcopenia and nonalcoholic fatty liver disease (NAFLD), the liver manifestation of MS [[Figure 2], unpublished results].
|Figure 2: Comparison of physical activity level in people with nonalcoholic fatty liver disease with/without sarcopenia. Inact = Inactive/sedentary; Intermediate level of activity; Ideal = CDC recommendations for amount of time spent in daily activity|
Click here to view
| Understanding Metabolic Syndrome in the Context of Function|| |
Within the context of the ICF, human function and activity or participation are likely to be influenced by physiological and anatomical as well as environmental and personal factors. These factors will be discussed in this section in an attempt to integrate them into a cohesive point of view to explain why people with MS have significant functional problems. The premise is that fatigue is a frequently reported symptom, negatively impacts activity and exercise tolerance, and may explain why this group of people is so sedentary.
| Fatigue|| |
Fatigue is a chronic, complex, and commonly reported difficulty for this population that costs the US >$2 billion in direct medical expenses. It is often overlooked by clinicians, despite the fact that it is a distressing symptom and may be the reason people are seeking medical attention. Explanations for this are protean. People may use the word fatigue to represent an inability to do physical activities or think clearly. They may characterize fatigue as lacking energy, motivation, or stamina, (Fritschi, Spatero). Sometimes, it is used in the place of feelings of depression or hopelessness. This poses a challenge for the specificity of measurement and for the most frequently used measures of fatigue, which are self-reports (fatigue severity scale, FACIT-F, and vitality subscale of the SF-36).
Many clinicians wish to use objective measures along with patient self-reports. This provides reliable, quantitative measures that are associated with performance measures. These include physical performance measures (treadmill testing and strength testing) and cognitive testing. Cognitive testing is objective, but it is not a measure of central fatigue. Given that it is difficult to objectively measure fatigue, all fatigue studies must include some patient-reported measures.
Recently, researchers and clinicians have been discussing the value of separating fatigue into physical or peripheral fatigue and central or mental fatigue. The former is thought to be neuromuscular in origin and is associated with the inability to sustain or complete physical activity. It is a deficiency of energy production or inefficient energy utilization. Central fatigue, by contrast, originates in the central nervous system (CNS) and is exercise independent. Patients experience these two types of fatigue very differently. Peripheral fatigue may be experienced as weakness, but it is not true muscle weakness, that is, a deficit in the maximum voluntary-force generation. Peripheral fatigue is a decrement in endurance (endurance is resistance to fatigue).
Central fatigue has a strong affective component and is often associated with a lack of motivation and/or lassitude. The signal for fatigue is thought to originate proximal to the neuromuscular junction, not at the neuromuscular junction, as is the case with peripheral fatigue. Clinically, it is sometimes difficult to distinguish fatigue from depression. A fundamental difference is that depression is always associated with sadness and anhedonia and, not infrequently, hopelessness. This is not true of fatigue. Other symptoms are common to both, such as lack of energy, change in sleep patterns, and memory and concentration difficulties.
To complicate the classification of fatigue further, fatigability is a term that is used to describe clinical fatigue in the context of the relationship between an individual's perceived fatigue and the activity level with which the fatigue is associated. It tends to be used in the older population.,
Fatigue is also classified as normal and pathological. The distinction is an empirical one and centers on the following differences: pathological fatigue is usually of long-standing, unassociated with an identifiable cause, not relieved by rest, difficult to treat, and over time, it usually affects mood and sleep causing distress and disruption of daily routines. In the latter context, it has a significant functional impact. In fact, fatigue (exhaustion) is a major component of frailty indices, is a substantial component of diagnosing and measuring sarcopenia, and is a significant contributor to functional “disease activity” measures for autoimmune diseases, diabetes, cancer, and multiple sclerosis. Fatigue is a central contributor to function and activity and secondarily influences mood and behavior.
| Obesity|| |
Obesity is often a component of MS. Even as a single contributor, it has an impact on function. People who are obese have a higher incidence of falls, which is associated with increased percent body fat and sarcopenia (sarcopenic obesity). Reasons for this association include inactivity and muscle weakness. A pathway model connecting physical activities, including ADLs, demonstrate that there is a significant connection between obesity and executive function, implying that multi-tasking and the need for a coordinated activity requiring CNS and peripheral nervous system activities is impaired in obese people.
| Biosignature|| |
In addition to assessing patient symptoms and activities, elucidating the physiology and/or the biochemistry of function presents opportunities for identifying treatment targets, appropriate outcomes for assessing effectiveness. Human function, or functionality, is often a desired goal of medical care. It is certainly an outcome sought by patients and professional health-care providers. Research has shown that there are many contributors to peripheral fatigue, including SaO2, arterial hemoglobin oxygen saturation; Q, cardiac output; [H+], hydrogen ion concentration; [NH4+], ammonium ion concentration; [Pi], inorganic phosphate concentration; PCr, phosphocreatine; and Ca2+, calcium ion. One's cardiorespiratory function is critical to meeting the oxygen needs of exercise muscle. In addition, good mitochondrial function is required to generate ATP and can easily be compromised by a fatty or an inflamed liver, in which gluconeogenesis is impaired. The muscle itself is subject to physiological challenges in people with the MS. In this condition, one sees insulin resistance, overproduction of myostatin, increased fat in muscle, decreased capillary blood flow, and a high level of inflammatory cytokines. The impact of diabetes and hyperlipidemia is often sarcopenia, with or without obesity.
Our research team has been studying the impact of liver disease on fatigue and function and has identified key biological markers that associate with poor function. We evaluated a convenience sample of people referred to our liver disease clinic. All had NAFLD as determined by abdominal ultrasonography and elastography. Sixty-two participants (62.9' NAFLD, 45.2' male, 61.3' White, 46.8 ± 13.7 years) involved in nonpharmacological, clinical research studies within an outpatient setting, 6.4' T2DM, 25.8' dyslipidemia, and 33.9' hypertension. NAFLD was determined through abdominal ultrasonography and transient elastography performed at the Inova Center for Liver Diseases. Participants underwent cardiopulmonary exercise testing to volitional exhaustion using a Modified Bruce treadmill protocol of 3-min stages, with progressive levels of work. Perceived exertion (Borg) was collected at each stage through self-report. People with NAFLD showed significant differences in select performance variables (peak VO2 and peak heart rate [HR]). They reported increased levels of exertion at Stages 1 and 2 (9.04 vs. 8.02 and 10.86 vs. 9.65). At each stage of testing, HR/RPE ratio was elevated in participants with NAFLD compared to controls (P < 0.0001), which remained significant after adjusting for age, gender, White race, and BMI (P < 0.0068). Individuals with NAFLD demonstrate an altered perceived exertion relative to their HR compared to those without NAFLD. After controlling for confounders, they reported the same exertion level with a ± 20 bpm difference in their exercising heart rate. In other words, for any level of work (Bruce stage), participants with NAFLD experience a greater perceived exertion not necessarily related to their HR. According to the studies done in establishing the BORG, perceived exertion rises concomitantly with HR increase. This was not found in the group with NAFLD. There is some literature assessing possible biosignatures of central fatigue. These include 5-HT, concentration of the neurotransmitter serotonin, and concentration of dopamine.
Tryptophan catabolism has been studied in an effort to better understand mood, affect, and central fatigue. Tryptophan is an essential amino acid and is the substrate for kynurenine, kynurenic acid, serotonin, melatonin, quinolinic acid, various indols, and NAD+.,, Many tryptophan metabolites cross the blood–brain barrier and influence mood, cognition, and fatigue. Others influence NAFLD pathogenesis, energy homeostasis, and eating behavior. Serotonin is generated by specific gut epithelial cells and serotonergic neurons and is indirectly regulated by a number of relevant factors, such as inflammation. Kynurenine production is regulated by inflammation and dysbiosis, but its clearance is modulated by exercise [Figure 3].
Neurotransmitters play a role in influencing fatigue, mood, and cognitive performance. A decreased concentration of dopamine and the accumulation of serotonin (5HT) associate with a high level of fatigue. Low ratio of serotonin to dopamine is associated with a high level of performance and a high ratio of serotonin to dopamine is associated with a lower level of performance.,,
To a degree, peripheral fatigue, as measured by physical performance, is influenced by metabolic abnormalities and, to a lesser degree, inflammation. In our cohort of patients, significant differences were found between performance levels and they associated with increased interleukin (IL) (IL-8) (P = 0.04), IL-6 (P = 0.006), C-peptide (P = 0.04), and high HOMA scores (P = 0.03), higher BMI (P ≤ 0.05), and increased prevalence MS (P ≤ 0.05). It appears that both regulations of metabolic and inflammatory pathways are in disarray. The findings for central fatigue included association, with reports of depressive symptoms and elevated tumor necrosis factor-alpha.
Our work demonstrates that obesity and MS are associated with fatigue, functional loss, and mood changes., These are associated with abnormalities of biological homeostasis: glucose, lipid, and inflammatory cytokine regulation, changes in the trytophan pathway; physical performance: less activity than norms, low METs expenditure, and high perceived level of exertion for workload. Perceived problems associated with fatigue are the experience of low energy, moderate disability in participation in needed and desired activities, and mood changes.
As with every symptom, and certainly with fatigue, it is important to treat other symptoms which may cluster with fatigue (e.g., pain and insomnia) and rule out other medical comorbidities and treat them. Common concerns include anemia, hyperglycemia, thyroid abnormalities, and pulmonary and cardiac diseases.
| Treatments|| |
We have effective treatments for fatigue that is associated with MS and obesity. Unfortunately, at this time in the history of medicine, the best treatments are behavioral and require patience and commitment. Risks are very low, rewards are high but not instantaneous.
Prescriptions that promote aerobic fitness and muscle strengthening are effective. Leisure activity is as effective in improving mood, fatigue, and all-cause mortality, though it is less effective in improving cardiovascular fitness.
Weigh loss is effective in reducing the metabolic abnormalities and has been demonstrated to be effective in helping to control fasting blood sugar, lowering lipids, and improving blood pressure and fatigue.
Pharmacological interventions work well in controlling blood pressure, improving metabolic abnormalities (blood sugar and lipids), and modestly help to control appetite (e.g., Orlistat). However, no medication as of yet, has been shown to effectively ameliorate fatigue, including psychostimulants, antidepressants, and anxiolytics. Cognitive and behavioral therapies have shown benefit for central fatigue in cancer patients but have not yet been subject to careful clinical trials.
Finally, in planning fatigue interventions, it is critical to treat any underlying conditions and combine this with multimodal interventions aimed at treating identifiable underlying etiologies of fatigue as well as ameliorating the symptom itself. Exercise, diet, stress reduction, and sleep hygiene are likely to contribute to a reduction in both physical (peripheral) and central fatigue.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]