Still Excited, but Less Aroused—The Effects of Nutritional Ketosis on Epinephrine Response and Hypothalamic Orexin Neuron Activation Following Recurrent Hypoglycemia in Diabetic Rats

Abstract

Hypoglycemia-associated autonomic failure (HAAF) is a serious, life-threatening complication of intensive insulin therapy, particularly in people with type 1 diabetes. The ketogenic diet is reported to beneficially affect glycemic control in people with type 1 diabetes, however its effects on the neurohormonal counterregulatory response to recurrent hypoglycemia and HAAF development are understudied. In this study we used Sprague Dawley rats to establish a HAAF model under non-diabetic and streptozotocin (STZ)-induced diabetic conditions and determined how nutritional ketosis affected the neurohormonal counterregulation and the activity of energy-sensing orexin (OX) neurons. We found that antecedent hypoglycemia diminished the sympathoexcitatory epinephrine response to subsequent hypoglycemia in chow-fed non-diabetic rats, but this did not occur in STZ-diabetic animals. In all cases a ketogenic diet preserved the epinephrine response. Contrary to expectations, STZ-diabetic keto-fed rats showed reduced OX activity in the recurrent hypoglycemia group, which did not occur in any other group. It is possible that the reduced activation of OX neurons is an adaptation aimed at energy conservation accompanied by diminished arousal and exploratory behaviour. Our data suggests that while a ketogenic diet has beneficial effects on glycemia, and epinephrine response, the reduced activation of OX neurons could be detrimental and warrants further investigation.

Role of the Adrenal Medulla in Hypoglycaemia-Associated Autonomic Failure—A Diabetic Perspective

“…Nedoboy and Farnham [88] showed in their study that rats, injected with a single dose of streptozotocin to induce diabetes, did not show a reduction in the adrenaline counter regulatory response following recurrent (3 consecutive days) insulin injections in contrast to their non-diabetic counterparts. This result could potentially be explained by the fact that diabetic rats may have undergone some episodes of antecedent hypoglycaemia prior to the initiation of the HAAF protocol.…”

“…The authors used insulin implants in diabetic rats that could potentially lead to undocumented antecedent hypoglycaemia. Interestingly, a counterregulatory glucagon response was not induced by single nor recurrent insulin injections in both diabetic rats and non-diabetic rats [88]. Thus, the HAAF model in diabetic rats requires further development and refinement to better reproduce the human condition.…”

“…[37] Twice a day for 3 days [37] ↓ expression of genes of proteins associated with exocytosis [37] 60 min from the last injection [37] Did not measure [37] Insulin, 5 U/kg; i.p. [88] Once a day for 3 days [88] ↓ adrenaline response [88] 2 h from the last injection [88] 1317/170.7 pg/mL [88] Diabetic rats Insulin, 30-40 IU/kg; i.p. [87] Once a day for 3 days [87] ↓ adrenaline response [87] 90 min from the last injection [87] 5000/2500 pg/mL [87] Insulin, 5 U/kg; i.p.…”

“…[87] Once a day for 3 days [87] ↓ adrenaline response [87] 90 min from the last injection [87] 5000/2500 pg/mL [87] Insulin, 5 U/kg; i.p. [88] Once a day for 3 days [88] ↔ adrenaline response [88] 2 h from the last injection [88] 2958/3804 pg/mL [88] Adrenal sympathetic nerve activity/ stimulation Non-diabetic rats Insulin, 1.5 U/kg; s.c. [36] Once a day for 2 days [36] ↔ASNA [36] During the subsequent hypoglycaemic episode [36] ~2800/1200 pg/mL [36] Insulin, 2 U/kg; s.c. [31] Once a day for 2 days [31] ↔ASNA [31] During the subsequent hypotensive episode [31] ~1100/700 pg/mL [31] Insulin, 1 U/kg; s.c. [35] Once a day for 3 days [35] a. ↓ Ad and NAd release in response to nerve stimulation; b.…”