Fly model of type 2 diabetes: processing of proIAPP makes a difference

• Patients  with type 2 diabetes  have a marked  reducedbeta cell mass and fail to produce  sufficient amounts of insulin required  for regulation  of glucose home- ostasis. Recent research supports that intracellular aggregation of islet amyloid polypeptide  (IAPP) leads to cell death and therefore makes IAPP aggregation a plausible cause for the beta cell reduction. Little is known about the mechanisms that precede amyloid formation  or which cellular pathways are involved in this process.  To  gain better  understanding we haveestablished  a Drosophila melanogaster model,  where GAL4 drives expression  of UAS-targeted transgenes in a cell or tissue specific pattern. The  fruit fly offers a unique  option  to manipulate any cellular  pathway with  different   genetic   tools.   The   knowledge   that*70%  of all Drosophila  melanogaster genes  have anorthologue in humans  stress  the  potential  for path- ways found in D. melanogaster to be of importance in humans  as well. Transgenic flies expressing  human proIAPP  (the precursor of IAPP)  and IAPP and the non-amyloidogenic mouse IAPP (mIAPP) have been generated.  Expression    of  proIAPP    in   the   brain reduced the lifespan of the fly whereas neither  IAPP nor mIAPP expression influenced survival. Immu- nolabelling  with  an  antibody  raised  against  human IAPP   and   that   cross-reacts    with   murine    IAPP labelled neurons  in all three strains, whereas a concomitant loss of cell nuclei only appeared  during proIAPP and IAPP expression. Furthermore, we detected  an early potentiated activation of the autophagy  pathway  in  proIAPP   flies. Interestingly, even  though  IAPP  expression  was not  related  to  a shorter  lifespan, both IAPP and proIAPP  expression in the  central  nervous  system  led  to  amyloid deposition  in the fat body of the head as shown with Congo  red  and  pFTAA,   a  newly  synthesised luminescent conjugated polymer. Our results de- monstrate that  D. melanogaster has a great  potential as a model  for studies  of proIAPP  and  IAPP expression with subsequent amyloid formation  and connected cellular  response  mechanisms. The  find- ing that proIAPP  aggregation  seems to exert a more toxic  impact  at  a  cellular  level is in  line  with  ourresults from mammalian cell lines.

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