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Insulin Null β-cells Have a Prohormone Processing Defect That Is Not Reversed by AAV Rescue of Proinsulin Expression

Adam Ramzy1, Nazde Edeer1, Robert K Baker1

  • 1Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.

Endocrinology
|April 18, 2022
PubMed

Insights

Gene therapy using adeno-associated virus (AAV) showed promise for monogenic diabetes. However, insulin gene delivery to beta cells revealed prohormone processing defects, highlighting the need for endogenous proinsulin production for proper function.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Gene Therapy

Background:

  • Monogenic diabetes, caused by insulin gene mutations, affects up to 6% of diabetes cases.
  • Gene therapy presents a potential treatment for these patients.
  • Adeno-associated virus (AAV)-mediated gene therapy is being explored for diabetes treatment.

Purpose of the Study:

  • To assess the efficacy of AAV-mediated gene therapy delivering human or mouse insulin genes to beta cells.
  • To investigate prohormone processing defects in insulin-deficient mouse models.
  • To explore the role of endogenous proinsulin production in beta cell function.

Main Methods:

  • Utilized mouse models of permanent neonatal and adult inducible diabetes.
  • Employed AAV vectors with rat insulin 1 promoter (Ins1) to deliver human insulin (INS) or mouse insulin 1 (Ins1) genes.
  • Assessed beta cell infection, insulin expression, prohormone processing, secretion, and subcellular localization of prohormone convertase 1/3 (PC1/3).

Main Results:

  • AAV delivery successfully conferred insulin expression but revealed prohormone processing defects in insulin-null beta cells.
  • Secretion of proinsulin transiently reversed diabetes, but processing defects persisted.
  • Impaired pro-islet amyloid polypeptide (proIAPP) processing and elevated circulating proIAPP were observed in inducible models.
  • Defective sorting of PC1/3 to glycogen-containing vacuoles and ER retention were identified as potential mechanisms.
  • Persistent endogenous proinsulin production was found necessary for proper beta cell storage and processing.

Conclusions:

  • AAV-mediated insulin gene therapy faces challenges due to beta cell prohormone processing defects.
  • Endogenous proinsulin production is crucial for maintaining normal beta cell function, including proinsulin storage and processing.
  • Further research is needed to overcome processing defects for effective gene therapy in monogenic diabetes.
Keywords:
AAVMODYdiabetesgene therapymonogenicproinsulin

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