Diabetes Mellitus Type 2 in Aviators:
A Preventable Disease

Lawrence W. Steinkraus, Walter Cayce, andAllan Golding STEINKRAUS LW, CAYCE W, GOLDING A. Diabetes mellitus type 2 in
of DMT2 include aging of the population and, more aviators: a preventable disease. Aviat Space Environ Med 2003; 74:
importantly, the increasing prevalence of obesity in developed and developing countries. This impending Introduction: The current epidemic of obesity and resultant diabetes
mellitus type 2 (DMT2) is a tsunami that will impact healthcare world- metabolic disaster mandates that the aeromedical com- wide and lap over into aerospace medicine. Metabolic syndrome (MBS) munity understand current approaches to the preven- is the major link between obesity and DMT2. Methods: A review of U.S.
tion and recognition of this disease.
Air Force Aeromedical Consult Service (ACS) records was accomplished Metabolic syndrome (also insulin resistance syn- looking at aviators with a diagnosis of DMT2. Case reports of three flyers drome, dysmetabolic syndrome, syndrome X, Reaven with DMT2 are presented and discussed. Other aeromedical agencieswere contacted regarding their experiences and this information was syndrome, pluri-metabolic syndrome, Chaos syn- summarized. A literature review on DMT2, obesity, and metabolic drome, diabesity) is the current term for a constellation syndrome was accomplished. Results: Of 70 charts for flyers identified
of metabolic and physiologic abnormalities defined var- with diabetes mellitus at the ACS between 1975 and 2000, over 95% iously by the National Cholesterol Education Program were for DMT2. The mean body mass index for these aviators was 26.2.
Currently, all services grant restricted waivers for (from the National Heart, Lung, and Blood Institute), Delivered by Ingenta to : some aviators with DMT2, none in high performance, single-seat aircraft. The FAA is cur- the WHO, and the ICD-9-CM.* The three authorities rently allowing most flyers with stable DMT2 to operate aircraft unknown agree that metabolic syndrome (MBS) includes excess categories with specific restrictions. Discussion: Obesity
IP : abdominal adipose tissue, hypertension, hypertriglyc- syndrome are becoming increasingly prevalent in the aviation commu- eridemia, low HDL-cholesterol, and elevated fasting nity. Aggressive actions to limit weight gain and Thu, 17 Nov 2005 20:15:02 identify those at risk for developing DMT2 must be considered for all populations.
glucose. Insulin resistance, hyperuricemia, and hyper- Keywords: diabetes mellitus type 2, obesity, metabolic syndrome, insu-
coagulability are also included by the WHO and ICD- lin resistance.
9-CM. MBS is part of a spectrum of metabolic abnor-malities that, if not interrupted, can lead to thedevelopment of DMT2 and its complications. Visceral THE CURRENT EPIDEMIC of obesity and resultant abdominal fat (VAT) appears to be key to this process.
diabetes mellitus type 2 (DMT2) is a tsunami that Supporting this connection are numerous studies dem- will impact all healthcare worldwide and lap over into onstrating direct biochemical and pathophysiologic aerospace medicine (Fig. 1) (54). It is estimated that
links between excess VAT, abnormalities in insulin reg- presently, in the U.S., there are over 16 million people ulation, and disordered glucose metabolism (50).
with DMT2, of which only about one-half to two-thirds The aeromedical community is and will be increas- have been diagnosed (33). The 2001 Behavioral Risk ingly faced with the problem of how to deal with over- Factor Surveillance System, developed by the Centers weight flyers. Being overweight [defined as a body for Disease Control and Prevention, found the preva- mass index (BMI⫽ kilograms of body weight per meter lence of diabetes had increased from 7.3% in 2000 to squared body height) of 25–29.9] or obese (BMI ⱖ 30) is 7.9% in 2001 (34). In 2000, it was estimated that over 151 rapidly becoming one of the most common medical million people worldwide had been diagnosed withdiabetes mellitus (DM). These numbers will continue togrow, with over 221 million having been diagnosed From the USAF School of Aerospace Medicine, Brooks AFB, TX (L. W. Steinkraus, W. Cayce), and the Wilford Hall Medical Center, with DM by 2010. These numbers do not account for Lackland AFB, TX (A. Golding).
those who have not been diagnosed (estimated at 30 – This manuscript was received for review in August 2002. It was 50% of actual DM cases) and those with impaired glu- revised in March and May 2003. It was accepted for publication in cose tolerance syndromes. DM is presently the sixth Address reprint requests to: Lawrence W. Steinkraus, Lt. Col., leading cause of death in the U.S., with about 50% of USAF, MC, FS USAFSAM/GERAM, Bldg 775, Brooks City-Base, TX those with DM dying from coronary heart disease (9).
By 2050, the World Health Organization (WHO) esti- * Supplemental data are available on-line at www.ingentaselect.
mates that cardiovascular disease, of which DMT2 is a major contributor, will be the number one cause of Reprint & Copyright by Aerospace Medical Association, Alexan- death worldwide. Reasons for the increasing prevalence Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
drome, obesity, overweight, adipose, body fat, bodycomposition, central obesity, visceral adipose tissue,visceral fat, aviation, flyers, aviators, aerospace, aero-medical, pilots, and weight gain. The information onother aeromedical agency experiences was obtained us-ing published documents from those agencies, as wellas communication with each agency via telephone, e-mail, and written communication.
Three Typical Case Reports from the ACS Files Case reports were generated using records from the files of the U.S. Air Force Aeromedical Consult Service Fig. 1. Trend line for number of people (in millions) diagnosed with
(ACS) at Brooks AFB, TX. An exemption was applied diabetes mellitus worldwide (WHO/NCD).
for and granted from the USAFSAM Institutional Re-view Board for use of the data from these files. Identi- problems among Americans. Per the 1999 National fying information was removed from the cases de- Health and Nutrition Examination Survey (NHANES) and NHANES II data, 61% of American adults were Case 1: Senior Officer A, a 35-yr-old active duty U.S.
either overweight or obese. The number of obese adults Air Force male pilot, was seen at the ACS in 1967. He has nearly doubled since 1980 to an estimated 27% of presented for evaluation of incomplete right bundle the U.S. population (10). The 2001 Behavioral Risk Fac- branch block (RBBB), diagnosed on a routine flight tor Surveillance System found the prevalence of obesity physical exam. This eventually progressed to a com- had increased from 19.8% in 2000 to 20.9% (34). It is plete RBBB. On his first evaluation, Senior Officer A estimated that deaths due to causes related to obesity was without cardiac or diabetic symptoms. His cardiac account for approximately 300,000 deaths per year and and metabolic evaluation was unremarkable and he for direct healthcare costs of nearly 4.3–10% of the was granted an unrestricted waiver for return to flying.
healthcare budget (1,35,46,52). The ill effects of excess Over the next 24 yr, he underwent nine follow-up ex- VAT are a continuum beginning with MBS, leading to ams at the ACS. There was no family history of diabetes impaired glucose tolerance (IGT), Delivered by Ingenta to : impaired fasting glu- mellitus. Physical exams were noted as being normal cose (IFG), and finally, DMT2. The concept of " unknown except for "labile hypertension" in 1977 and, in 1991, a sity" has been created to emphasize this 5-d BP check showed an average reading of 142/92. His IP : (54). A recent study by Robbins et al. documented the BMI increased from 25.4 to 30.3 from 1967 to 1991.
Thu, 17 Nov 2005 20:15:02 cost of excess weight gain among active duty U.S. Air Measured body fat percentages (using neck, waist, and Force personnel. They found that for 1997, approxi- upper arm circumference calculations (11,25) showed a mately 20% of the U.S. Air Force population exceeded steady rise from 14% to 25%. Laboratory results showed maximum allowable weight for height standards. Total no glucosuria, proteinuria, or ketonuria. Over the years, excess body-weight attributable costs (direct and indi- his fasting blood glucose (FBG) went from 98 to 143 mg rect) were estimated at $22.8 million/yr. They also cal-  dl⫺1. In 1991, his glucose tolerance test (GTT) 2-h level culated that attributable lost workdays were approxi- was 185 mg  dl⫺1. Lipid measurements also demon- mately 28,351/yr (39).
strated gradual increases in total cholesterol from 215 to In this paper, we will present three cases of flyers 260 mg  dl⫺1; HDLs were low, usually in the low 30s or modeling various levels of progression from MBS to high 20s. Triglycerides were usually above 250 mg  IGT and then DMT2. We will present U.S. and Cana- dl⫺1. His complete blood count, thyroid tests, liver pan- dian aeromedical agencies' current experiences with els, and electrolytes were normal. Diagnoses included DMT2 in flyers. We will then discuss some current the RBBB, labile hypertension, and excess body fat. At ideas about the pathophysiology of DMT2, MBS, and his last evaluation in 1991, he was diagnosed with obesity. Additionally, we will review the waiver impli- diet-controlled diabetes mellitus. By this time, he had cations of MBS and DMT2 in aviators and present some been retired for almost 4 yr. Except for his first evalu- ation, he was recommended for waiver for unrestrictedpilot duties at all ACS visits. Treatment recommenda-tions typically consisted of diet, exercise, and avoidance of tobacco products.
The reference list for the review was compiled after a Case 2: Senior Officer B was a 50-yr-old active duty Medline search, review of U.S. Air Force School of U.S. Air Force single-seat jet pilot initially evaluated in Aerospace Medicine (USAFSAM) library resources, re- 1982 at the ACS for a history of elevated cardiac risk view of primary source documents, and use of Internet index identified under the Tactical Air Command Risk resources such as the Google search engine. Key words Factor Identification Program. He had no cardiac or for searches included, but were not limited to: diabetes diabetic symptoms. There was a history of several ab- mellitus, diabetes mellitus type 2, adult onset diabetes, normal fasting blood glucose levels in the past with non-insulin dependent diabetes, metabolic syndrome, normal 2-h GTTs. Family history was positive for both Reaven's syndrome, pluri-metabolic syndrome, insulin parents and one of four sisters being diabetic. His father resistance, insulin resistance syndrome, Chaos syn- had died of a myocardial infarction in his 60s and his Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
mother had died of a stroke at age 59. Initial ACS progression of disease. Diagnoses included coronary evaluation included full cardiac work-up (with angiog- atherosclerosis, diabetes mellitus, and obesity. Recom- raphy), and complete metabolic evaluations. His phys- mendations included weight loss, diet, exercise, and ical was remarkable for overweight with a BMI of 27.4.
follow-up with his personal physician for the diabetes.
Angiography showed left anterior descending coronary On his last visit to the ACS in 1995, Senior Officer C was intimal roughening and right coronary artery ectasia. A reporting a stable anginal symptom pattern, nocturia FBG was 153 mg  dl⫺1. Fasting lipids revealed a total four to six times per night, occasional paroxysmal noc- cholesterol of 172 mg  dl⫺1 with an HDL of 33 mg  dl⫺1 turnal dyspnea, and two-pillow orthopnea. He was tak- and triglyceride of 294 mg  dl⫺1. No GTT was per- ing Hytrin, allopurinol, Glucotrol, and aspirin. In the formed. His diagnoses included coronary artery intimal interim, he had been diagnosed with gouty arthritis and roughening on cardiac catheterization, fasting hyper- renal lithiasis. Physical showed his BMI at 31.6 and a glycemia, and mild hypertriglyceridemia. Waiver was III/VI systolic murmur. Labs showed a FBG of 151 mg recommended for continuation of unrestricted pilot du-  dl⫺1, normal chemistries, a total cholesterol of 224 mg ties, and this was granted. Treatment recommendations  dl⫺1, HDL at 37 mg  dl⫺1, triglyceride of 97 mg  dl⫺1, included weight loss, diet, exercise, daily aspirin, avoid- and calculated LDL of 171 mg  dl⫺1. Thyroid functions ance of tobacco, and follow-up in 1 yr. He returned for were normal. Urinalysis was normal. Coronary cathe- re-evaluation 2 yr later after an abnormal thallium terization demonstrated severe three-vessel coronary stress test. There were no cardiac or diabetic symptoms artery disease (CAD). Diagnoses included severe CAD noted. FBG levels in the intervening period were con- requiring surgical intervention, atrial fibrillation with sistently elevated with values ranging from 130 to 204 slow ventricular response, angina, DMT2, gouty arthri- mg  dl⫺1. ACS evaluation included repeat thallium and tis, dyslipoproteinemia, and obesity. Recommendations exercise testing, as well as metabolic screening. Physical included surgical intervention for his severe CAD, ap- exam continued to show an elevated BMI of 27. Thal- propriate cardiac risk factor interventions per his car- lium and exercise testing were interpreted as borderline diologist, weight loss, diet, and reduction of LDL to ⬍ and normal, respectively. A FBG was 133 mg  dl⫺1 and 100 mg  dl⫺1.
repeat was 109 mg  dl⫺1. Diagnoses were essentially In the first case (Senior Officer A), we see a demon- unchanged and an unrestricted pilot waiver was again stration of the relationship between obesity and DMT2.
recommended and granted. Treatment recommenda- The elevation of the BMI followed by the appearance of tions were unchanged. At his last ACS evaluation in frank DM is classic. In the case of Senior Officer B, there Delivered by Ingenta to : 1991, Senior Officer B was retired and without symp- was a delay in diagnosing diabetes or further address- toms of heart disease or diabetes. Physical ing the elevated FBGs during his active duty evalua- showed a BMI of 29. Repeat cardiac IP : tions. No GTTs were performed during any of his eval- show progression of disease. His Thu, 17 Nov 2005 20:15:02 showed FBG levels above 160 mg  dl⫺1. Lipids re- phenomenon and the elevated body fat had been mained abnormal with low HDLs. He was diagnosed present for years. In the last case (Senior Officer C), with adult-onset diabetes mellitus and referred to an there is a clear pattern of increased weight and progres- sion to diabetes along with acceleration of coronary Case 3: Senior Officer C was evaluated three times disease. These cases show several themes. All met cur-rent National Cholesterol Education Program criteria over a period of 19 yr beginning when he was 44 yr old for MBS at some point. There was a clear progression of and a rotary wing senior pilot with the U.S. Army. He weight gain and glucose levels. In the last two cases, was initially referred in 1976 for the USAFSAM Cardio- coronary disease was diagnosed in the fifth and sixth vascular Disease Follow-up Study. He had a history of decades. Finally, the recommended therapies were un- elevated cholesterol. He had no history of cardiac or successful in preventing the appearance of diabetes diabetic symptoms or diagnoses. Family history was mellitus in all cases. Table I lists some biometric and lab
positive for his father having had his first heart attack at values for each case chronologically.
age 60 and dying of one at age 69. Physical examshowed a BMI of 24. Body composition studies usingthe 40K technique (15,17) revealed a body fat percent of 24. Laboratory testing was normal. Cardiac catheteriza- Summary of Aeromedical Experience from the ACS and tion showed a 20% occlusion of the left main artery.
Other Agencies Diagnoses included coronary atherosclerosis and obe-sity. Waiver was not recommended. Close follow-up of A 1994 U.S. Army report estimated that the U.S.
cardiac risk factors was recommended, along with Army aviation community could expect about 21 new weight loss, diet, and abstention from tobacco. Senior cases of DM and impaired glucose tolerance (IGT) each Officer C subsequently retired and was followed up in year. They expected that 78.4% and 10.9%, respectively, 1988 at the ACS. At that point, he was 56 yr old and had would not be granted waivers based on inability to no symptoms of heart disease or diabetes. He was on no achieve control with diet and exercise, or existence of medications. Physical showed a substantial weight gain concurrent disease. They noted that most cases were with BMI of 32.4. Labs showed FBGs of 236 and 244 mg being seen in aviators over age 35 and recommended  dl⫺1. Lipid testing showed a total cholesterol of 242 mg appropriate screening measures (30). Others have noted  dl⫺1, HDL of 25 mg  dl⫺1, and triglycerides of 171 mg a similar increase in incidence and prevalence of DMT2  dl⫺1. Non-invasive cardiac testing did not indicate with age in aviators (26). Table II summarizes current
Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
aeromedical agency information on flyers with DM.
ians and others working as contractors. Over the last 10 The following paragraphs outline some specific find- yr there has been a distinct increase in average weight ings from each aeromedical agency.
for aviators in the Army (average 10 lb). Interestingly, A record review of all patients diagnosed with dia- there has also been an increase in average height for the betes mellitus (ICD9: 250.0) seen at the ACS at Brooks same aviator group. A number of flyers have been AFB since 1975 was accomplished. Of 70 records re- returned to duty with a diagnosis of IGT (diet con- viewed, 68 were patients with DMT2 (including adult trolled). A number of Air Traffic Control members have onset, diet controlled, and non-insulin dependent dia- been returned to duty with DMT2 on oral hypoglyce- betes). U.S. Air Force flyers were patients in 39 of the 70 mics. Two aviators have been followed with DMT2 on cases. Of those, 62% had BMIs over 26 and the mean Metformin. These were described as special cases with BMI was 26.5. All were male and 90% were over age 35.
the individuals in critical specialties who were close to There were three cases with flyers who were not over- retiring. No individuals with type 1 DM have been weight (or were losing weight) and who had rapid resolution of their diabetes with diet and exercise. This For the FAA, the most common reason for denial of raises the question of whether these Delivered by Ingenta to : cases were in the waivers for aviators with DM is inadequate control. The early stages of DM type I (DMT1). Lower weight unknown second most common reason is secondary complica- weight loss are more commonly seen in either DMT1 or tions. Of those with DMT2, approximately 1500 or 30% atypical cases (such as chemically induced IP : were not on medication (diet-controlled). There has honeymoon period for insulin Thu, 17 Nov 2005 20:15:02 dependent DM may take been at least one case where abnormal glucose levels months to resolve with patients being initially misdiag-nosed as "chemical" or non-insulin dependent diabetes may have played a role in pilot error leading to an (8). Without these atypical cases in the case series, the aircraft mishap (7). However, no reliable estimates can average BMI would increase to over 27. Waivers have be made regarding near-misses, poor landings, or loss not been granted for flyers on insulin, and limited waiv- of situational awareness related to abnormal plasma ers (non-single seat) have been granted for a few flyers glucose levels in flight. Specifically, there is no good on oral hypoglycemics. The majority of waivers re- information on the frequency of hypoglycemia or re- viewed were for diet-controlled DMT2. Per the U.S. Air lated aircraft mishaps in aviators with DMT2 or glucose Force Safety Center, there have been no mishaps iden- tified where DM was found to be a causal factor.
The Canadian Forces do not grant waivers but may In the Navy, flyers with DMT2 are not allowed to fly return diabetic aircrew to flying duties on a case-by- single-seat aircraft. There is no record of DM related case basis with an operational flying restriction if ap- mishaps. Metformin is an insulin-sensitizing biguanide propriate. The CF aircrew database indicates 15 pilots that does not stimulate insulin production, and thus and navigators with DMT2 (personal communication).
does not cause hypoglycemia. It has been waived for Pilots diagnosed with DMT2 are generally restricted to use in the Navy for Class 2 and 3 aviators.
flying "with or as copilot" unless fully controlled by The Army tends to have the oldest military aviators, diet and exercise alone. Metformin is typically used as with many working for the Department of Army Civil- a first-line medication to which rosiglitazone and acar- TABLE II. SUMMARY OF EXPERIENCE WITH DM IN AEROMEDICAL AGENCIES.
Aeromedical Agency decision pending) Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
abose may be added. The addition of a sulfonylurea im- kine tumor necrosis factor ␣ is possibly one such factor poses a requirement for an operational flying restriction.
(14). Plasma free fatty acids (FFAs) released from adi- Administrative program actions for overweight mil- pocytes after lipolysis of triglycerides are another. Ele- itary members are problematic, as they are for many vations in FFAs have been associated with obesity and medical prevention programs (27). Potential adverse contribute to the development of insulin resistance.
administrative outcomes may stimulate members to try FFAs may be responsible for up to 50% of the insulin to maintain appropriate fitness standards. Some mem- resistance seen in DMT2 (4). FFAs are essential for ␤ cell bers may follow unhealthy programs to maintain pre- function in the normal state, but chronically elevated scribed weights. Higher rates of eating disorders and levels are toxic (36). Once ␤ cell dysfunction develops, use of non-prescribed diet supplements may result.
hyperglycemia appears. Hyperglycemia desensitizes ␤ There may be a reluctance to follow through on iden- cells and impairs insulin secretion in response to insulin tifying overweight individuals due to perceived ad- secretogogues, including glucose itself. This is referred verse administrative outcomes for members or the to as glucotoxicity, which contributes to further ␤ cell member's unit. Evidence points to significant variabil- decline. ␤ cell dysfunction is also accompanied by the ity in how flyers are measured (e.g., U.S. Army experi- development of amyloid fibrils containing islet amyloid ence), with the benefit of the doubt often stretched polypeptide. Amyloid deposition is associated with de- considerably. Unfortunately, as outlined in this paper, clining ␤ cell mass and further impairment of ␤ cell the longer individuals take to identify and address their function, thus worsening hyperglycemia (20).
overweight status, the higher the likelihood of develop- Adipose tissue, traditionally considered a simple de- ing problems such as MBS and DM.
pot for fat energy, has become a major focus of research.
It is becoming apparent that this tissue is quite active metabolically. Evidence that adipose cells, specifically Understanding the pathophysiology and course of visceral adipose cells, are intimately involved in various DMT2 requires an understanding of the role of insulin energy management feedback loops, has stimulated a resistance (IR) and VAT. A cluster of metabolic disor- search for modifiable factors in the development and ders was described by Reaven in 1988 and has been pathophysiology of obesity (53). The "adipostat" con- expanded on since (38). MBS classically consists of hy- cept suggests a feedback mechanism between brain, fat, pertension, central (visceral) obesity, hyperinsulinemia, and other tissues. Adipokines such as leptin, resistin, dyslipidemia (low HDL, small LDL Delivered by Ingenta to : particles, and high adiponectin, and anti-tumor necrosis factor ␣ are being triglycerides), hyperuricemia, and a studied as potential adipose-derived messengers that state (elevated levels of plasminogen activator-1). MBS may play parts in pathogenic processes identified in has been associated with endocrine IP : diagnoses such as MBS. Adipose tissue appears to be a critical component polycystic ovary syndrome and Thu, 17 Nov 2005 20:15:02 acromegaly. Impor- of a toxic regulatory cascade leading to hypertension, tantly, MBS has been closely correlated with a high risk atherosclerosis, and other endothelial disease processes.
for cardiovascular disease.
There is a clear relationship between increasing BMI or Most experts feel that DMT2 is a multi-factorial dis- waist circumference (and thus VAT) and levels of IR.
ease. Genetics play a major role in the susceptibility to Present evidence points to a gradual progression of developing DMT2. This is seen especially with the ten- higher levels of visceral fat leading to IR (especially in dency for some racial groups to develop DMT2, includ- those more genetically susceptible), initial increased ing Native Americans, African-Americans, Pacific Is- pancreatic ␤ cell hypertrophy, and insulin production landers, Hispanic groups, and Asian groups. Lifestyle with maintenance of normoglycemia, followed by waning influences are also directly linked as risk factors for the ␤ cell function, the appearance of hyperglycemia, and development of DMT2 and include high-fat, high-calo- clinical DMT2 (Fig. 2). An important concept is that IGT is
rie diets, sedentary lifestyle, and the development of a precursor to DMT2 and may exist for years before DMT2 obesity. DMT2 involves three metabolic abnormalities: becomes established. Impaired fasting glucose (IFG) oc- peripheral insulin resistance (mostly skeletal muscle curs later in the progression toward DMT2 than IGT.
and adipose tissue), insulin secretory dysfunction (pan- Intensive research is ongoing utilizing innovative ge- creatic ␤ cell), and increased hepatic glucose produc- netic techniques (transgenic mice, knockout mice, gene tion. Insulin resistance develops as the result of genetic mapping) to identify the specific substances involved in and acquired factors. Supporting a genetic risk compo- the various metabolic processes within adipocytes. Lep- nent is strong evidence that in non-diabetic relatives of tin, and more recently ghrelin, have been under intense those with Type II DM, there is a higher prevalence of study as potential agents to assist with weight loss.
IR (18,48). Support for acquired risk factors for IR comes Other agents are being investigated for their ability to from numerous studies linking obesity and sedentary ameliorate complications related to MBS and DMT2 lifestyle with higher IR rates (24).
(6,12,13,40,42,43). The list of mediators and substances Insulin resistance, almost universal in the obese and involved in what is a complex set of feedback loops has the elderly, does not necessarily lead to hyperglycemia.
also continued to grow.** ␤ cell functional decline is a prerequisite. By the timefasting hyperglycemia is evident, ␤ cell function hasdeclined by approximately 50% (4,20). The proposed ** Supplemental data are available on-line at www.ingentaselect.
mechanism for ␤ cell decline is a ␤ cell gene defect, probably in combination with other factors. The cyto- 1.htm (Table B).
Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003

drome with more intra-abdominal fat as a percent oftotal body fat, higher insulin, and elevated serum trig-lycerides in rodents (49). The cases described did nothave any waiverable or available options for weightloss other than diet and exercise. Presently, liposuction,after recovery, is waiverable or a non-factor for returnto flying in all aeromedical agencies.
All evidence points to the critical need to recognize and treat IGT, IFG, and MBS to prevent or delay theonset of DMT2 and its complications. There is often atemptation to avoid diagnosing flyers with DMT2 be-cause of career implications. This is a disservice to theindividual as delayed aggressive therapy clearly speedsthe onset of micro- and macrovascular complications Fig. 2. Progression of disease: normal to diabetes mellitus type 2.
with increased morbidity and mortality. In the military,programs designed to identify overweight membersprovide a ready means to motivate those who are over- Patient Issues weight to lose that weight. Physicians must get over- The cases presented here demonstrated a progression weight individuals to begin reduction efforts before of disease from MBS to IGT or IFG to DMT2 followed they become obese. There is evidence that the body's by the appearance of secondary complications in two of homeostasis system may be programmed for weight three. Physicians or patients do not always appreciate gain, implying a need for more aggressive and specific this progression. In the aeromedical world, IGT or IFG therapies (41). If we are serious about obesity, we may is often viewed as a relatively benign state addressable have to consider more radical approaches such as strin- with diet and exercise advice. It is clear, however, that gent behavioral therapies, medication, and surgery. It patients with MBS are at higher risk for macrovascular may be time to loosen obesity treatment waiver restric- complications (threefold increase in Delivered by Ingenta to : risk for coronary tions. Medical and surgical approaches together may be disease and stroke) (19). Those with frank diabetes required to reduce obesity in some individuals. This microvascular risk (renal, retinal, and autonomic dis- means taking a hard look at current and future obesity ease). MBS is not uncommon. Recent IP : evidence points to therapies and their aeromedical implications.
an age-adjusted prevalence of MBS of Thu, 17 Nov 2005 20:15:02 23.7% in the U.S.
population (16). At any point until the appearance of frank DM, there is the potential to stop the progression.
Primary prevention efforts including exercise, low-fat The results from the Diabetes Prevention Program con- diets, and avoidance of obesity should be the core of firm that progression to diabetes can be slowed with any aeromedical program in addressing these issues.
appropriate diet and exercise therapies. Reduction of These approaches have been suggested previously for the VAT mass is the key. The higher the VAT mass, the MBS in the flying population, specifically in Germany.
higher the risk and the harder it is to return the indi- There, researchers noted that it was possible to identify vidual to a normal state. Unfortunately, non-medical flyers with higher potential for developing full-blown and non-surgical approaches to weight loss, while ef- MBS using standard flight physical techniques (21).
fective, are problematic (28). Behavioral therapy alone Obesity, especially excess VAT, is a disease. Weight often fails to halt the progressive accumulation of VAT.
gain is a surrogate marker for MBS and increased risk The worldwide epidemic of "diabesity" points to a for development of DMT2. We must address those with need for more aggressive approaches to reduce body fat BMIs above 25 and elevated VAT (central obesity) as we (54). Medical therapies, such as diets, medications, and address flyers with elevated BPs. If these individuals psychotherapy, have all had varying levels of success.
cannot reduce their increased VAT levels given close Surgical therapy, including gastroplasty and liposuc- monitoring, diet, and exercise, then they may need tion, may or may not be valid approaches. Effects of grounding while therapies that are more aggressive are gastroplasty may go beyond simple reduction in meal implemented pending waiver.
size, with possible hormonal changes also being in-volved (12). Some evidence does point to potential pos- itive effects of liposuction on lipids and insulin resis-tance, but there have been no long-term controlled Secondary prevention, specifically, the identification studies to document their effects on the incidence of of those with IR, MBS, IGT, and IFG is important.
DMT2 or MBS (3). Caution is in order, however, against Numerous studies indicate that all elevations of blood this seemingly direct approach to reducing BMI. One glucose and insulin levels increase the risk for develop- study that looked at effects of large volume liposuction ment of macrovascular and microvascular disease. IGT found a disproportionate increase in visceral fat vs.
and IFG, being pre-diabetic states, are especially impor- subcutaneous fat post-surgery (31). Subcutaneous lipec- tant to detect. This is because there is still a chance to tomy has also been found to cause a metabolic syn- salvage ␤ cell function, or at least significantly prolong Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
␤ cell function and, thus, prevent or delay diabetic duce triglycerides and increase high-density lipopro- related complications. It may be true that ␤ cell function tein levels (5,22). Other pharmacological approaches declines progressively, leading to worsening of the dis- include reducing fat absorption (orlistat), and use of ease and increased medication requirements. However, weight-loss drugs (sibutramine).
with intensive glycemic control, the rate of macro- and Aeromedically, medications carry potential side ef- microvascular complications can be reduced to nearly fects with negative impacts for aviators. Sulfonylureas that of nondiabetics.
carry the potential for hypoglycemia, and stability of In the Finnish Diabetes Prevention Study, patients glucose levels on these medications is required by the with impaired glucose tolerance were randomly as- FAA before approval for use. Metformin may rarely signed to either control or intervention (increased di- induce lactic acidosis in susceptible individuals. Addi- etary fiber, increased physical activity) groups and tionally, Metformin is associated with gastrointestinal were followed for 3.2 yr. The risk of diabetes was re- side effects including diarrhea and nausea. B12 defi- duced by 58% in the intervention group (47). In a re- ciency and minor decreases in hemoglobin and hemat- cently published study, The Diabetes Prevention Pro- ocrit have been reported with Metformin as well. Orl- gram Research Group enrolled 3,234 nondiabetic istat and acarbose are associated with gastrointestinal middle-aged, overweight patients with elevated fasting side effects such as diarrhea and bloating, each poten- and post-load glucose. They were randomized to one of tial distracters. Thiazolidinediones such as rosiglitazone three groups: placebo, metformin, or lifestyle interven- (Avandia®) and pioglitizone (Actos®) are associated tion with a goal of 7% weight loss and 150 min/wk of with small decreases in hemoglobin and hematocrit (1 physical activity. The incidence of diabetes was reduced g/3.3% and 2– 4% respectively). Adverse reactions for by 31% and 58% in the metformin and lifestyle groups both drugs include a slight increase in incidence of as compared with placebo (23). These results demon- anemia in treated patients. Increases in median plasma strate that early, aggressive lifestyle intervention in pa- volume with edema have been noted in patients taking tients with glucose intolerance can prevent or at least either drug. Finally, combination therapy with other delay the development of overt diabetes and its associ- diabetic drugs may increase the risk for hypoglycemia.
ated complications.
Sibutramine, used in weight reduction, is a centrallyacting neurotransmitter re-uptake inhibitor, with atten- dant potential for central nervous system side effects.
Insulin is associated with significant potential for hypo- Once DMT2 is diagnosed, tertiary Delivered by Ingenta to : prevention of po- tential complications becomes important.
complications accompany DMT2. Micro- and macro- IP : Implications of Waiver vascular complications are of special concern. Thepathophysiology of these vascular Thu, 17 Nov 2005 20:15:02 complications is en- Because of the potential for sudden incapacitation dothelial dysfunction mediated by a blunted vasodila- related to hypoglycemia, most aeromedical authorities tion response to endothelial-derived nitric oxide and are not allowing flyers with DMT1 to continue flying.
excess production of vasoconstrictors (45). Treatment of Evidence for a direct relationship between hypoglyce- DMT2 has changed based on our knowledge of the mia and aircraft mishaps is scanty. Part of the problem underlying pathophysiology. Diet and exercise remain is the post-mortem change in glucose levels, allowing the bedrock on which anyone with DMT2 should start hyperglycemia but not hypoglycemia, to be diagnosed (2). Reduction of VAT decreases IR, improves lipid (7). The potential for using glycosylated hemoglobin to status, reduces BP, and delays onset of DMT2. Exercise monitor control, and to assess control post-accident, is and increased muscle mass positively influence glucose of interest (51). One 20-yr study of Air France pilots uptake, IR, and BP. It has been shown that calorie looked at 10 cases of sudden incapacitation. Only one restriction and lowered fat intake, along with increases case was diagnosed as hypoglycemia, with most related in complex carbohydrates, all improve metabolic status to cardiovascular events (29). In a review of 216 fatal U.S. general aviation accidents from 1990 –1998, wherepossible physical impairment or incapacitation was mentioned by the FAA, only one identified a pilot withprobable Type 1 diabetes (insulin bottles present). Hy- The sulfonylureas are glucose-independent insulin poglycemia was not mentioned as being causal per the secretogogues and increase ␤ cell insulin production for report (44). The issue of whether subtle degradation of any level of blood glucose. They are probably most sensory, motor, and information processing function effective in leaner patients with relative insulin defi- may have contributed to mishaps is still pending, but ciency. Metformin reduces hepatic glucose production the potential certainly has to be considered in aviators and has some effect in decreasing peripheral insulin taking medications with the potential to produce hypo- resistance by enhancing skeletal muscle glucose uptake.
glycemia, but not complete incapacitation.
Metformin may be an appropriate first choice in more The Canadian Forces have one pilot with DMT1 fly- obese patients with higher levels of insulin resistance.
ing with an operational flying restriction to fly with or The thiazolidinediones reduce peripheral insulin resis- as copilot, and a geographic restriction that prohibits tance in skeletal muscle and adipose tissue (2). These deployments. The FAA is the only agency in the U.S.
agents may also positively influence lipid status, for that has allowed type 1 diabetics to continue flying in example: pioglitizone (Actos®) has been shown to re- non-commercial settings, and there are strict guidelines Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
Aeromedical Agency ⬍126 mg  dl⫺1 ⬍126 mg  dl⫺1 ⬍126 mg  dl⫺1 ⬍7.0 mmol  l⫺1 (126 mg  dl⫺1) Postprandial Glucose ⬍11.0 mmol  l⫺1 (198 mg  dl⫺1) ⬍7% every 3–6 upper limitof normal Treatments (flyers) Medications Allowed Annual ophthalmology, exercise test Q 2–3 and restrictions in place. Of note, most investigators feel follow-up to ensure compliance and look for incipient that the risk for hypoglycemia increases with the dura- complications is mandatory.
tion of the disease, the intensity of Delivered by Ingenta to : therapy, and a his- tory of previous hypoglycemia (32,44). Concerns hypoglycemia and the potential for sudden IP : tion (especially in those with hypoglycemia unaware- DMT2, MBS, and obesity are rapidly increasing in Thu, 17 Nov 2005 20:15:02 ness) has led the FAA to advocate less strenuous control prevalence. Complications and costs associated with of blood sugars for pilots on insulin. This raises the these diseases are enormous. MBS appears to be a crit- concern for potential long-term complications associ- ical link between excess VAT and the development of ated with looser glucose control. Potential DM compli- DMT2, CAD, and other complications. More flyers will cations that could effect crewmembers include third be presenting with these diseases and associated meta-bolic precursors (IR, MBS, IGT, and IFG) within the cranial nerve palsies, acute cardiac events related to aeromedical community. The case reports described il- higher risks for atherosclerosis, visual problems related lustrate a classic progression of overweight, high-risk to retinopathy, or changes in the lens due to hypergly- individuals from IGT to DMT2. The appearance of cemia. Gastroparesis and other enteropathies related to macro- and microvascular disease in these high-risk diabetic autonomic neuropathy problems could de- settings validates the need to address metabolic abnor- grade mission performance. Various sensory and auto- malities as early as possible. Waiver experience among nomic neuropathies may certainly affect performance the various aeromedical agencies varies from least re- capabilities, and, in deployed military settings, could strictive (FAA) to most restrictive (U.S. Air Force and result in such problems as foot ulcers and intolerance of U.S. Army). There are no military agencies allowing environmental extremes. MBS-related conditions, espe- pilots with DM to fly single-seat aircraft at this point.
cially hypertension and dyslipidemia, increase the risk Aeromedical specialists must focus on the identification for cardiovascular and cerebrovascular events. Medica- of, and prevention of, obesity and MBS, even if this tions for DMT2 could be a problem, whether it would means grounding flyers to provide aggressive VAT- be hypoglycemia with long-duration sulfonylureas, or lowering therapy. Additionally, the identification of the need for monitoring of liver enzymes with the thia- those with obesity, MBS, IGT, and IFG should be zolidinediones. Drug interactions with medications viewed as a secondary prevention approach, with the such as the anti-malarials have not been entirely aim of preventing the appearance of DMT2. Obesity, specifically excess VAT, is a disease. In view of the Table III lists waiver considerations for some aero-
critical role VAT has in this progression of disease, it is medical agencies. Generally, flyers should have high time to re-assess our approach to treating obesity.
motivation, stable glucose levels, no medication side Whether the choice is medical or surgical, it may be effects (if on medication), and no evidence of end-organ time to aggressively approach any flyer with obesity vs.
complications (CAD, renal disease, peripheral vascular taking what has been historically a more passive ap- disease, retinopathy, neuropathy). Regular and close Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
21. Kalff KG, Maya-Pelzer P, Andexer A, Deuber HJ. Prevalence of The authors would like to acknowledge the generous assistance of the the metabolic syndrome in military and civilian flying person- following agencies and individuals in the preparation of this manuscript: nel. Aviat Space Environ Med 1999; 70:1223– 6.
the U.S. Air Force School of Aerospace Medicine, the U.S. Air Force 22. Khan MA, St. Pete JV, Xue JL. A prospective, randomized com- Residency in Aerospace Medicine, the U.S. Air Force Aeromedical Con- parison of the metabolic effects of pioglitazone or rosiglitazone sult Service, the U.S. Air Force Wilford Hall Medical Center (Endocri- in patients with type 2 diabetes who were previously treated nology), the Naval Operational Medicine Institute (Internal Medicine), with troglitazone. Diabetes Care 2002; 25:708 –11.
the U.S. Army Aeromedical Center, the Civil Aerospace Medical Insti- 23. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the tute, and G.W. Gray, M.D., Ph.D., FRCPC Consultant in Medicine, Med- incidence of type 2 diabetes with lifestyle intervention or met- ical Assessment Section, Defense R&D, Canada.
formin. N Engl J Med 2002; 346:393– 403.
24. Krentz AJ. Insulin resistance. Br J Med 1996; 313(7069):1385–9.
25. Krzywicki HJ, Ward GM, Rahman DP, et al. A comparison of methods for estimating human body composition. Am J Clin 1. Allison DB, Zannolli R, Narayan KM. The direct health care costs Nutr 1974; 27:1380 –5.
of obesity in the United States. Am J Public Health 1999; 26. Lancaster M. Aeromedical consult service experience in causes of 89:1194 –9.
grounding over the past fifteen years. Brooks AFB, TX: USAF 2. American Association of Clinical Endocrinologists Diabetes Med- School of Aerospace Medicine, 1972; 72A28316 (Open Litera- ical Guidelines Taskforce. The American association of clinical ture; vol 19720044650 A).
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3. Berntorp E, Berntorp K, Brorson H, Frick K. Liposuction in Der- Aviat Space Environ Med 1999; 70:1029 –37.
cum's disease: impact on haemostatic factors associated with 28. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expendi- cardiovascular disease and insulin sensitivity. J Intern Med ture resulting from altered body weight. N Engl J Med 1995; 332:621– 8.
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29. Martin-Saint-Laurent A, Lavernhe J, Casano G, Simkoff A. Clin- Endocrinol Metab Clin North Am 2001; 30:801–15.
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5. Boyle PJ, King AB, Olansky L, et al. Effects of pioglitazone and Aviat Space Environ Med 1990; 61:256 – 60.
rosiglitazone on blood lipid levels and glycemic control in 30. Mason KT, Shannon SG. Army aviators with diabetes mellitus patients with type 2 diabetes mellitus: a retrospective review of and imparied glucose tolerance. Fort Rucker, AL: U.S. Army randomly selected medical records. Clin Ther 2002; 24:378 –96.
Aeromedical Res Laboratory 1994; USAARL Report No: 6. Bray GA. Physiology, and consequences of obesity [diabetes, and endocrinology management modules]. Golden, CO: Medical 31. Matarasso A, Kim RW, Kral JG. The impact of liposuction on Education Collaborative; 2000.
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7. Canfield DV, Chaturvedi AK, Boren HK, et al. Abnormal glucose 32. Mokan M, Mitrakou A, Veneman T, et al. Hypoglycemia un- levels found in transportation accidents. Aviat Space Environ awareness in IDDM. Diabetes Care 1994; 17:1397– 403.
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Delivered by Ingenta to : 33. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epi- 8. Cayce WR, Osswald SS, Thomas RA, et al. Diabetes demics of obesity and diabetes in the United States. JAMA advances and their implications for aerospace medicine. Aviat Space Environ Med 1994; 65:1140 – 4.
IP : 34. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, 9. Centers for Disease Control and Prevention diabetes, and obesity-related health risk factors, 2001. JAMA Thu, 17 Nov 2005 20:15:02 Statistics. Diabetes surveillance, 1999. Chapter 1: The public 2003; 289:76 –9.
health burden of diabetes mellitus in the United States: mor- 35. Must A, Spadano J, Coakley EH, et al. The disease burden asso- tality. CDC, 2000.
ciated with overweight and obesity. JAMA 1999; 282:1523–9.
10. Centers for Disease Control and Prevention NCfCDPaHP- 36. Poitout V, Robertson RP. Minireview: secondary beta-cell failure DoNaPA. Basics about overweight and obesity. CDC, 2001.
in type 2 diabetes—a convergence of glucotoxicity and lipo- 11. Clark DA. A model for estimating body fat. Brooks AFB, TX: toxicity. Endocrinology 2002; 143:339 – 42.
USAF School of Aerospace Medicine, 1976; SAM-TR-76 – 41.
37. Ramlo-Halsted BA, Edelman SV. The natural history of type 2 12. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels diabetes: implications for clinical practice. Prim Care 1999; after diet-induced weight loss or gastric bypass surgery.
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secretion in 3T3–L1 adipocytes. Biochem Biophys Res Com- 41. Schwartz MW, Woods SC, Seeley RJ, et al. Is the energy ho- mun 2001; 288:1027–31.
meostasis system inherently biased toward weight gain? Dia- 15. Forbes GB, Hursh JB. Age, and sex trends in lean body mass calcu- betes 2003; 52:232– 8.
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body fat, abdominal subcutaneous adipose tissue compart- 16. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syn- ments, and visceral adipose tissue to the metabolic complica- drome among US adults: findings from the third National tions of obesity. Metabolism 2001; 50:425–35.
Health and Nutrition Examination Survey. JAMA 2002; 287: 43. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001; 409(6818):307–12.
17. Fuchs RJ, Theis CF, Lancaster MC. A nomogram to predict lean 44. Taneja N, Wiegmann DA. An analysis of in-flight impairment and body mass in men. Am J Clin Nutr 1978; 31:673– 8.
incapacitation in fatal general aviation accidents. Proceedings 18. Gray RS, Fabsitz RR, Cowan LD, et al. Risk factor clustering in the of the 46th Annual Meeting of the Human Factors and Ergo- insulin resistance syndrome: the strong heart study. Am J nomics Society; 2002; Santa Monica, CA. Los Gatos, CA: Beta Epidemiol 1998; 148:869 –78.
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47. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 51. White VL, Chaturvedi AK, Canfield DV, Garber M. Association of 2 diabetes mellitus by changes in lifestyle among subjects with postmortem blood hemoglobin a1c levels with diabetic condi- impaired glucose tolerance. N Engl J Med 2001; 344:1343–50.
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Delivered by Ingenta to : IP : Thu, 17 Nov 2005 20:15:02 Aviation, Space, and Environmental Medicine Vol. 74, No. 10 October 2003 DM TYPE 2 IN AVIATORS—STEINKRAUS ET AL.
TABLE A. NCEP, WHO, AND ICD-9-CM DEFINITIONS OF THE METABOLIC SYNDROME(1,2) Group Defining Syndrome Any 3 of the following IGT or DM, and/or IR plus 2 of the (Dysmetabolic Syndrome X) Abdominal Obesity* Waist circumference† Waist to hip ratio: Waist circumference Men ⬎102 cm (⬎40in) Men ⬎102 cm (⬎40in) Women ⬎88 cm (⬎35in) Women ⬎88 cm (⬎35in)‡ And/or BMI ⬎ 30 ⬎150 mg  dl⫺1 ⬎150 mg  dl⫺1 ⬎150 mg  dl⫺1‡ Men ⬍40 mg  dl⫺1 Men ⬍35 mg  dl⫺1 Men ⬍35 mg  dl⫺1 Women ⬍50 mg  dl⫺1 Women ⬍39 mg  dl⫺1 Women ⬍45 mg  dl⫺1‡ ⬎100 mg  dl⫺1 Impaired glucose regulation or diabetes Insulin Resistance Polycystic Ovary Syndrome Coronary Heart Disease Vascular Endothelial Dysfunction *Overweight and obesity are associated with insulin resistance and the metabolic syndrome. However, the presence of abdominal obesity is morehighly correlated with the metabolic risk factors than is an elevated body mass index (BMI). Therefore, the simple measure of waistcircumference is recommended to identify the body weight component of the metabolic syndrome.
†Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased, e.g., 94 –102 cm(37–39 in). Such patients may have a strong genetic contribution to insulin resistance. They should benefit from changes in life habits, similarlyto men with categorical increases in waist circumference.
‡Major criteria for diagnosis. The CDC does not require that a given number of components be present for the diagnosis.
Delivered by Ingenta to : 1. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a unknown WHO consultation. Diabet Med 1998; 15:539 –53.
2. Centers For Disease Control and Prevention.
IP : Dysmetabolic syndrome X. ICD-9-CM Coordination and Maintenance Committee meeting; Thu, 17 Nov 2005 20:15:02 TABLE B: ADIPOCYTE METABOLISM - IDENTIFIED FACTORS AND CURRENT STATUS Fat derived peptide; decreases insulin resistance, FFAs, TGs; increases energy Serine protease—same as human complement factor D, secreted by adipose cells—gene expression decreased in some forms of genetic and acquired obesity—may act asobesity regulating protein.
AMP activated kinase (AMPK) Critical part of a biochemical cascade that helps regulate the energy metabolism in cells.
Free Fatty Acids (FFAs) Increased levels implicated in insulin resistance and inflammation.
An orexigenic hormone secreted primarily in the stomach and duodenum—implicated in both mealtime hunger and long-term regulation of body weight (1).
Cytokine produced by adipose tissue; acts on CNS receptors to inhibit food intake/increase energy metabolism.
Melanocortin-4 Receptor (MCR-4) Central neuroendocrine receptor: appears to modulate features of the MBS; involved with energy metabolism.
Peroxidase Proliferator Activated Receptors Ligand activated transcription factors; act at the nuclear receptor level to modify fat cell (alpha, delta, gamma) - PPARs Resistin (FIZZ) or Adipose-Tissue Specific Fat derived cysteine rich adipose tissue-specific secretory factor that inhibits adipocyte differentiation; may be associated with increased insulin resistance (3).
Tumor Necrosis Factor alpha (TNF-a) Increased in obese subjects; negative regulator of resisting gene expression (2).
1. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2. Fasshauer M, Klein J, Neumann S, et al. Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2001; 288:1027–31.
3. Kim KH, Lee K, Moon YS, Sul HS. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem

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HIGHLIGHTS OF PRESCRIBING INFORMATION ------------------------------- WARNINGS AND PRECAUTIONS ------------------------- These highlights do not include all the information needed to use EPIDUO • Ultraviolet Light and Environmental Exposure: Avoid exposure to sunlight and FORTE gel safely and effectively. See full prescribing information for EPIDUO