Spontaneous Obesity-Linked Type 2 Diabetes in the Absence of Islet Amyloid in a Cynomolgus Monkey Infected With Bovine Spongiform Encephalopathy

A9-year-oldcynomolgusmonkey(Macacafascicularis)infectedorallywithbovinespongiformencephalopathy(BSE)waspresentedfor necropsyfollowingeuthanasia4yearspostinfection(p.i.).ThismacaqueR984wasexposedtoaBSEdosethatcausesasimianformof variantCreutzfeldt-Jakobdisease(vCJD)within5yearsp.i.inothermacaques.AllorallyBSE-infectedmacaquesdevelopedasignificant weightgainwithinthefirst2yearsp.i.comparedwithnon-BSE-infectedage-andsex-matchedcontrolanimals,suggestingincreasedrisk of type2 diabetes (T2D).In contrast, macaque R984developed rapidweight loss, hyperglycemia, and glucosuria and had to beeuthanatized4 yearsp.i.beforeclinical signsof vCJD. Pancreashistopathological evaluationrevealedsevereislet degenerationbut,remarkably, no islet amyloid deposits were present. Immunostaining of pancreas sections for insulin and glucagon confirmed the loss of endocrinecells.Inaddition,prionswerepresentintheadenohypophysisbutnotinotherareasofthebrain,indicatingcentripetalprion spread from the gutduringthepreclinical phase ofBSE infection. Plasma glucoseandinsulin concentrationsof macaque R984became abnormalwithageandresembledT2D.ThisunusualcaseofspontaneousT2Dintheabsenceofisletamyloiddepositscouldhavebeen due to early prion spread from the periphery to the endocrine system or could have occurred spontaneously.