June 14, 2015
|Abstract: Diabetes prevalence continues to climb at an alarming pace across the world. Although HIV populations are no exception to this trend, diabetes prevalence varies 10-fold across studies of HIV cohorts because of differences in their composition and in diabetes definitions applied. Two of three studies that compared diabetes prevalence in people with and without HIV found higher rates in the HIV group. Among people with HIV infection, diabetes incidence is higher in U.S. cohorts than in other groups, probably because of higher risk factor rates in the U.S. groups. Though diabetes incidence was higher with than without HIV in earlier studies -- when people were taking more toxic antiretroviral regimens -- the largest and latest comparisons found lower diabetes incidence with HIV than without HIV.|
Diabetes history reads like a roster of euphoniously named heroes. Everyone knows Banting and Best, who found that insulin regulates blood sugar. But who remembers Mering and Minkowski, or Sharpey-Schafer, or Aretaeus of Cappodocia? Not to mention the team of Langerhans and Languesse. Many an endocrinologist can tell you about Paul Langerhans, father of the eponymous pancreatic islets. But how many know G.E. Languesse named those islets (Figure 1)? And we can thank Sharpey-Schafer (Sir Edward Albert) for proposing the term insulin (after the Latin for island)1 rather than Langerhansin (and the consequent Langerhansinemia). If quizzed on who first described diabetes -- or nearly any classical disease -- you're safe to credit the ancient Egyptians. That's probably not because primeval Nile valley denizens had such an acute appreciation of diverse debilities, but because they kept heaps of hieroglyphic charts. Pritzker School of Medicine dean Kenneth Polonsky notes that disease-conscious Egyptians first recorded diabetes around 1500 BCE, pinpointing two key traits -- prodigious urination and weight loss.1 In the second century CE Greek healer Aretaeus minted the term diabetes mellitus,* acknowledging the sweet taste of a diabetic's urine. Mellitus means "honey sweet," but we do not know if Aretaeus personally gathered evidence of this saccharine signal. Diabetes comes from the Greek word for siphon, a possible nod to the diabetic's unquenchable thirst.3
Islets of Langerhans
Figure 1. French histologist G.E. Languesse named islets of Langerhans, which secrete insulin, for German pathologist Paul Langerhans, who discovered them but modestly dubbed them Zellhaufen, or "cell heaps."2 (Pancreas and islets of Langerhans from Servier PowerPoint image bank. Paul Langerhans from Wikipedia Commons.)
More than 1600 years elapsed after these Aretaean observations before someone -- an English physician called Matthew Dobson -- got the idea to measure glucose in urine of diabetics and confirmed lofty values.1 In 1889 Mering and Minkowski (Austrians Joseph von and Oskar) ablated the pancreas from dogs, who promptly died of diabetes, and thereby showed that the organ plays a critical role in ruling glucose.1
But how? Sharpey-Schafer, an English physiologist, hypothesized (and named) the pancreatic chemical insulin in 1910.1 Only 11 years later Frederick Banting and Charles Best reversed diabetes induced in dogs by infusing pancreatic islet cells from healthy dogs, and their colleague James Collip purified the hormone insulin. The Nobel committee bestowed its esteemed prize on Banting and his boss John Macleod but passed up Collip and Best.4 Insulin became the first hormone ever cloned then massively produced for treatment via recombinant DNA technology,1 the first chapter in a biotech revolution that has saved countless lives.
Diabetes mellitus shares three features with HIV infection. (1) Before research identified effective therapies, both diseases remained almost universally -- and painfully -- fatal. (2) Once solid benchwork nailed down the pathogenic basics of each disease, brisk development of practical treatment turned both into manageable chronic diseases. (3) Neither can be cured. Despite diverse effective remedies for diabetes, Kenneth Polonsky argues that, "if one views diabetes from a public health and overall societal standpoint, little progress has been made toward conquering the disease during the past 200 years," largely because about 90% of cases today result from a global obesity epidemic.1
Polonsky concludes that diabetes has become "one of the most common and most serious medical conditions humankind has had to face."1 To be sure, the global burden of 35 million cases of HIV infection pales beside the 387 million with diabetes.5 The International Diabetes Federation projects that diabetes prevalence will climb to 592 million by 2035 and notes that every country in the world records a rising tally of residents with type 2 diabetes.5
The American Diabetes Association figures that 29.1 million people in the United States had diabetes in 2012, or 9.3% of the population.6 Those numbers rose from 25.8 million and 8.3% in 2010. Centers for Disease Control and Prevention (CDC) number crunchers reckon that diabetes prevalence in the country will double from 2005 to 2050.7 Parsing recent trends, Polonsky figures that 1 in 3 U.S. adults could have diabetes by 2050.1 The ADA estimates that 86 million U.S. residents 20 or older had prediabetes (blood glucose 100 to 125 mg/dL) in 2012, up from 79 million 2 years earlier.6
Research pegs diabetes prevalence in Western HIV populations at anywhere from an elfin 2.6% to a flush 14%,8-15 compared with the U.S. general population estimate of 9%.6 This wide range should spark no surprise since the HIV studies varied in diabetes definitions, populations assessed, their diabetes risk factors, and their antiretroviral treatment status. The U.S. estimate of 9% includes about 8 million people with undiagnosed diabetes, while the HIV calculations include only diagnosed people.
|Table 1. Diabetes or Severe Hyperglycemia Prevalence in Western HIV Populations|
|Author||Year(s)||Site(s)||n||Age*, M/F (%)||Diabetes Risks||Prevalence†|
|Kilby8||1988-1995||Birmingham, Alabama||1392||~44, 80/20||11 of 25 with high glucose black, 10 of 25 taking megestrol acetate, proportion on ART not reported||Glucose ≥ 250 mg/dL 1.8%|
|El-Sadr9||1999-2002||US||419||M 38.2, 79/21||60% black, 10% Hispanic, BMI 24.2, antiretroviral naive||2.6%|
|Brown10||1999-2003||US, MACS||568||M 46, 100/0||15% nonwhite, BMI 25, 72% on ART||14% on ART; 7% not on ART|
|Polsky11||2002-2006||Bronx, New York||222||M 50, 47/53||61% black, 27% Hispanic, 37% overweight, 24% obese, 79% on ART, 58% HCV||5.4%|
|Savès12||1999||France, APROCO||614||63% >34, 80/20||100% on PI therapy, 64% on d4T, 32% on ZVD, 29% on ddI, race not reported||5.7% (28 of 493 with glucose data)|
|De Wit13||1999-2005||Europe, U.S., Australia, Argentina, DAD Study||33,389||M 38, 74/26||13% nonwhite, BMI 23.0, 73% on ART, 58% on PI||2.85%|
|Calza14||2009||Bologna||755||37 w/o DM, 48 w DM, 66/34||3% nonwhite, BMI 23.1 w/o DM, 26.5 w DM, 87% on ART, 30% HCV||4.5%|
|Galli15||2008||Milan||4249||M 45.7, 76/24||BMI 23.2, 29.6% overweight or obese, 91.5% on ART, 33% HCV||4.1%|
* M, median; no M, mean.
† Diabetes mellitus defined (by reference number): 8, severe hyperglycemia defined as ≥ 250 mg/dL or antidiabetic medication; 9, history of diabetes mellitus; 10, fasting glucose ≥ 126 mg/dL, self-reported diabetes diagnosis, self-reported use of antidiabetic medication; 11, fasting glucose ≥ 126 mg/dL, 120-min glucose ≥ 200 mg/dL during OGTT, or antidiabetic medication; 12, fasting blood glucose ≥ 126 mg/dL, OGTT ≥ 200 mg/dL; 13, confirmed fasting blood glucose ≥ 126 mg/dL, physician report plus antidiabetic medication; 14, single fasting blood glucose ≥ 126 mg/dL, random blood glucose ≥ 200 mg/dL, antidiabetic medication; 15, fasting blood glucose ≥ 126 mg/dL, history of diabetes mellitus, antidiabetic medication.
ART, antiretroviral therapy; BMI, body mass index (kg/m2); d4T, stavudine; ddI, didanosine; DM, diabetes mellitus; MACS, Multicenter AIDS Cohort Study; M/F, proportions male/female; OGTT, oral glucose tolerance test; PI, protease inhibitor; w, with; w/o, without; ZVD, zidovudine.
The first report of high blood glucose in people with HIV charted proportions of patients with extremely high glucose -- at or above 250 mg/dL, that is, twice the diabetes diagnosis cutoff of 126 mg/dL -- in the 8 years before combination antiretroviral therapy (cART) arrived.8 This review from the University of Alabama at Birmingham does not say how many people were taking antiretrovirals, though most probably were since the study period began in 1988. But the study period ended in 1995, just before the cART era. Twenty-five people, almost 2%, had sky-high glucose (Table 1). Eleven of those 25 were black, and 10 were taking megestrol acetate (Megace), a synthetic progesterone then prescribed to stimulate appetite in people with HIV but now rarely used by HIV-positive people. The researchers did not report how many people met the 126-mg/dL cutoff.
In a 419-person antiretroviral-naive U.S. cohort studied from 1999 through 2002, diabetes prevalence measured only 2.6%,9 not much more than the ultrahigh glucose prevalence in the Alabama study.8 This 1999-2002 study group had two notable high-glucose risk factors -- 60% were black and 10% Hispanic, and average body mass index approached the overweight threshold at 24.2 kg/m2. But this study probably underestimated diabetes prevalence because it used a loose definition -- diabetes reported in patients' medical records.
Defined more rigorously (see footnote to Table 1), diabetes affected 3% to 6% of HIV cohorts in the Bronx, New York,11 in France,12 across Europe, the U.S., Australia, and Argentina,13 and in the Bologna14 and Milan15 regions of Italy. Almost all of these people were taking cART, high proportions were men, most were white, and most were not overweight or obese (Table 1). The Bronx group is an exception to these generalizations.11 More than three quarters in these people were taking cART, but 88% were black or Hispanic, 53% were women, 61% were overweight or obese, and 58% had HCV infection, an established diabetes risk factor.
Another U.S. analysis involved 568 HIV-positive men and 718 HIV-negative but at-risk men in the Multicenter AIDS Cohort Study (MACS) seen from 1999 through 2003 in four cities.10 Only 15% were nonwhite, and almost three quarters were taking cART (Table 1). Median body mass index in HIV-positive men measured 25 kg/m2 -- at the overweight threshold -- regardless of cART status. Prevalence of diabetes (defined as fasting glucose ≥126 mg/dL, self-reported diabetes diagnosis, or self-reported use of antidiabetic medication) stood at 5% in HIV-negative men, 7% in HIV-positive men not on cART, and 14% in HIV-positive men on cART.
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