TY - JOUR
T1 - The impact of prior exposure to hypoglycaemia on the inflammatory response to a subsequent hypoglycaemic episode
AU - Verhulst, Clementine E M
AU - van Heck, Julia I P
AU - Fabricius, Therese W
AU - Stienstra, Rinke
AU - Teerenstra, Steven
AU - McCrimmon, Rory J
AU - Tack, Cees J
AU - Pedersen-Bjergaard, Ulrik
AU - de Galan, Bastiaan E
AU - Hypo-RESOLVE Consortium
PY - 2024/2/8
Y1 - 2024/2/8
N2 - BACKGROUND: Hypoglycaemia has been shown to induce a systemic pro-inflammatory response, which may be driven, in part, by the adrenaline response. Prior exposure to hypoglycaemia attenuates counterregulatory hormone responses to subsequent hypoglycaemia, but whether this effect can be extrapolated to the pro-inflammatory response is unclear. Therefore, we investigated the effect of antecedent hypoglycaemia on inflammatory responses to subsequent hypoglycaemia in humans. METHODS: Healthy participants (n?=?32) were recruited and randomised to two 2-h episodes of either hypoglycaemia or normoglycaemia on day 1, followed by a hyperinsulinaemic hypoglycaemic (2.8?±?0.1 mmol/L) glucose clamp on day 2. During normoglycaemia and hypoglycaemia, and after 24 h, 72 h and 1 week, blood was drawn to determine circulating immune cell composition, phenotype and function, and 93 circulating inflammatory proteins including hs-CRP. RESULTS: In the group undergoing antecedent hypoglycaemia, the adrenaline response to next-day hypoglycaemia was lower compared to the control group (1.45?±?1.24 vs 2.68?±?1.41 nmol/l). In both groups, day 2 hypoglycaemia increased absolute numbers of circulating immune cells, of which lymphocytes and monocytes remained elevated for the whole week. Also, the proportion of pro-inflammatory CD16 -monocytes increased during hypoglycaemia. After ex vivo stimulation, monocytes released more TNF-a and IL-1ß, and less IL-10 in response to hypoglycaemia, whereas levels of 19 circulating inflammatory proteins, including hs-CRP, increased for up to 1 week after the hypoglycaemic event. Most of the inflammatory responses were similar in the two groups, except the persistent pro-inflammatory protein changes were partly blunted in the group exposed to antecedent hypoglycaemia. We did not find a correlation between the adrenaline response and the inflammatory responses during hypoglycaemia. CONCLUSION: Hypoglycaemia induces an acute and persistent pro-inflammatory response at multiple levels that occurs largely, but not completely, independent of prior exposure to hypoglycaemia. Clinical Trial information Clinicaltrials.gov no. NCT03976271 (registered 5 June 2019).
AB - BACKGROUND: Hypoglycaemia has been shown to induce a systemic pro-inflammatory response, which may be driven, in part, by the adrenaline response. Prior exposure to hypoglycaemia attenuates counterregulatory hormone responses to subsequent hypoglycaemia, but whether this effect can be extrapolated to the pro-inflammatory response is unclear. Therefore, we investigated the effect of antecedent hypoglycaemia on inflammatory responses to subsequent hypoglycaemia in humans. METHODS: Healthy participants (n?=?32) were recruited and randomised to two 2-h episodes of either hypoglycaemia or normoglycaemia on day 1, followed by a hyperinsulinaemic hypoglycaemic (2.8?±?0.1 mmol/L) glucose clamp on day 2. During normoglycaemia and hypoglycaemia, and after 24 h, 72 h and 1 week, blood was drawn to determine circulating immune cell composition, phenotype and function, and 93 circulating inflammatory proteins including hs-CRP. RESULTS: In the group undergoing antecedent hypoglycaemia, the adrenaline response to next-day hypoglycaemia was lower compared to the control group (1.45?±?1.24 vs 2.68?±?1.41 nmol/l). In both groups, day 2 hypoglycaemia increased absolute numbers of circulating immune cells, of which lymphocytes and monocytes remained elevated for the whole week. Also, the proportion of pro-inflammatory CD16 -monocytes increased during hypoglycaemia. After ex vivo stimulation, monocytes released more TNF-a and IL-1ß, and less IL-10 in response to hypoglycaemia, whereas levels of 19 circulating inflammatory proteins, including hs-CRP, increased for up to 1 week after the hypoglycaemic event. Most of the inflammatory responses were similar in the two groups, except the persistent pro-inflammatory protein changes were partly blunted in the group exposed to antecedent hypoglycaemia. We did not find a correlation between the adrenaline response and the inflammatory responses during hypoglycaemia. CONCLUSION: Hypoglycaemia induces an acute and persistent pro-inflammatory response at multiple levels that occurs largely, but not completely, independent of prior exposure to hypoglycaemia. Clinical Trial information Clinicaltrials.gov no. NCT03976271 (registered 5 June 2019).
KW - Antecedent hypoglycaemia
KW - Clamp
KW - Diabetes
KW - Humans
KW - Inflammatory responses
KW - Blood Glucose/metabolism
KW - C-Reactive Protein
KW - Hypoglycemia/chemically induced diagnosis
KW - Epinephrine
KW - Insulin
KW - Hypoglycemic Agents/adverse effects
KW - Diabetes Mellitus, Type 1
U2 - 10.1186/s12933-023-02095-w
DO - 10.1186/s12933-023-02095-w
M3 - Article
SN - 1475-2840
VL - 23
JO - Cardiovascular Diabetology
JF - Cardiovascular Diabetology
IS - 1
M1 - 55
ER -