Heat shock proteins contribute to diabetes-induced complications and are affected by
glycemic control. Our hypothesis was that
hypoglycemia-induced heat shock and related
protein changes would be amplified in
type 2 diabetes (T2D). This prospective, case-control study enrolled 23 T2D patients and 23 control subjects who underwent hyperinsulinemic-induced
hypoglycemia (≤ 2.0 mmol/L (36 mg/dl)) with blood sampling at baseline, at
hypoglycemia and after a 24-h post-
hypoglycemia follow-up period. Proteomic analysis of heat shock-related and pro-inflammatory
proteins was performed. At baseline,
MAPKAPK5 (p = 0.02) and UBE2G2 (p = 0.003) were elevated and STUB1 decreased (p = 0.007) in T2D. At
hypoglycemia: PPP3CA (p < 0.03) was increased and EPHA2 (p = 0.01) reduced in T2D; by contrast, three
proteins were reduced in controls [HSPA1A (p = 0.007), HSPB1 (p < 0.02), SMAD3 (p = 0.005)] while only
MAPKAPK5 was elevated (p = 0.02). In the post-
hypoglycemia follow-up period, most
proteins normalized to baseline by 24-h; however, STIP1 (p = 0.003), UBE2N (p = 0.004) and UBE2L3 (p < 0.04) were decreased in controls at 24-h. No
protein differed from baseline at 24-h in T2D. Pro-inflammatory
interleukin-6 increased at 4-h post-
hypoglycemia in controls and T2D (p < 0.05 and p < 0.003, respectively) and correlated with HSPA1A; anti-inflammatory
IL-10 decreased 2-h post-
hypoglycemia in T2D only. Other pro-inflammatory
proteins, IL-1α, IFN-γ and TNF-α, were unchanged. Heat shock and related
proteins differed at baseline between T2D and controls, with an exaggerated response of heat shock and related
proteins to
hypoglycemia that returned to baseline, though with changes at 24-h in controls alone. An increase in pro-inflammatory
IL-6, with a decrease in anti-inflammatory
IL-10, suggests that the HSP system is overactivated due to underlying
inflammation in T2D.Trial registration: ClinicalTrials.gov NCT03102801.