Visual Abstract

Introduction: Heat shock proteins (HSPs) protect against protein misfolding, contribute to diabetes-induced complications and are affected by hypoglycemia. Misfolded proteins are degraded by ubiquination through UBE2L3/UBE2N proteins.

Methods: Two prospective case-control induced hypoglycemia studies were compared: Study1, hypoglycemic clamp to 2.8mmol/l(50mg/dl) for 1-hour, 17 subjects (T2D(n=10); controls(n=7));Study2, hypoglycemic clamp to 2.0mmol/l(36mg/dl) transiently, 46 subjects (T2D(n=23); controls(n=23)).Blood sampling: baseline, hypoglycemia and 24-hours; Somalogic proteomic analysis of HSPs was undertaken.

Results: HSP changes were seen in both studies separately; however, percentage-change baseline to hypoglycemia differed between studies for seven of 19 HSP panel proteins, with notable changes in Study 1: elevated levels in controls at hypoglycemia for TLR4:MD-2(p=0.01) and CD274(p=0.04), and at 24-hours for MAPKAPK5(p=0.047); elevated levels in T2D at hypoglycemia for DNAJB1(p=0.01), STIP1(p=0.01), UBE2L3(p=0.01) and UBE2N(p=0.001) (Figure1).

Conclusion: Milder-prolonged hypoglycaemia caused greater HSP changes than severe-acute hypoglycaemia for HSPs protective against protein misfolding and for increasing UBE2L3/UBE2N degradation proteins in T2D, suggesting hypoglycemic duration may cause greater cell damage than severity.


A. Moin: None. A. S. Atkin: None. H. Kahal: None. A. Al-qaissi: None. T. Sathyapalan: Research Support; Self; Abbott, Eli Lilly and Company, Novo Nordisk. S. Atkin: None. A. E. Butler: None.

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