Effects of Differing Antecedent Hypoglycemia on Subsequent Counterregulation in Normal Humans

Abstract

The aim of the study was to determine the effects of specific levels of antecedent hypoglycemia on subsequent autonomic, neuroendocrine, and metabolic counterregulatory responses. Eight healthy, overnight-fasted male subjects were studied during 2-day protocols on four separate randomized occasions separated by at least 2 months. On day 1, insulin was infused at a rate of 9 pmol x kg(-1) x min(-1) and 2-h clamped euglycemia (plasma glucose 5.2 +/- 0.2 mmol/l) or differing hypoglycemia (plasma glucose 3.9 +/- 0.1, 3.3 +/- 0.1, or 2.9 +/- 0.1 mmol/l) was obtained during morning and afternoon. The next morning after an evening meal and 10-h overnight fast, each subject underwent a 2-h hyperinsulinemic (9 pmol x kg(-1) x min[-1]) hypoglycemic (2.9 +/- 0.1 mmol/l) clamp study. Despite equivalent day 2 plasma glucose and insulin levels, differing levels of antecedent hypoglycemia produced specific blunting of subsequent counterregulatory responses. Day 1 hypoglycemia of 3.9 mmol/l resulted in significantly (P < 0.01) blunted epinephrine, muscle sympathetic nerve activity, and glucagon responses. Day 1 hypoglycemia of 3.3 mmol/l resulted in additional significant blunting (P < 0.01) of pancreatic polypeptide, norepinephrine, growth hormone, endogenous glucose production, and lipolytic responses. Deeper day 1 hypoglycemia of 2.9 mmol/l produced similar day 2 counterregulatory failure as day 1 hypoglycemia of 3.3 mmol/l. In summary, in healthy overnight-fasted men, mild antecedent hypoglycemia of 3.9 mmol/l significantly blunts sympathoadrenal and glucagon, but not other forms of neuroendocrine counterregulatory responses, to subsequent hypoglycemia. Antecedent hypoglycemia of 3.3 mmol/l resulted in additional significant blunting of all major neuroendocrine and metabolic responses to subsequent hypoglycemia. We conclude that in normal humans, there is a hierarchy of blunted counterregulatory responses that are determined by the depth of antecedent hypoglycemia.

Improving management of type 1 diabetes in the UK: the Dose Adjustment For Normal Eating (DAFNE) programme as a research test-bed. A mixed-method analysis of the barriers to and facilitators of successful diabetes self-management, a health economic analysis, a cluster randomised controlled trial of different models of delivery of an educational intervention and the potential of insulin pumps and additional educator input to improve outcomes

“…The literature was searched for evidence of existing programmes and three were found: Blood Glucose Awareness Training (BGAT), 123,124 Hypoglycaemia Anticipation, Awareness and Treatment Training (HAATT) 125 and HyPOS. 126 All aimed to foster improved symptom recognition and self-treatment practices and all were predicated on data showing that impaired hypoglycaemia awareness could be induced/reversed by hypoglycaemia exposure/avoidance [127][128][129][130][131][132] and increased the risk of severe hypoglycaemia sixfold. 133 Although all had led to some improvements, none had resulted in full restoration of awareness or obliteration of severe hypoglycaemia.…”

Effects of equivalent sympathetic activation during hypoglycemia on endothelial function and pro-atherothrombotic balance in healthy individuals and obese standard treated type 2 diabetes

“…In order to ensure comparable SNS responses in the two groups, type 2 diabetes individuals with intact and robust counterregulatory responses (shorter duration of disease, rarely experienced hypoglycemic episodes, moderate glycemic control) were studied. In non-diabetic individuals the hypoglycemic threshold for counterregulatory hormone release occurs around ~70 mg/dL and hormone levels double for each subsequent 10 mg/dL decrements of plasma glucose [49]. As counterregulatory hormone responses occur at higher glucose levels in standard treated type 2 diabetes, a hypoglycemic difference of 6 mg/dL between the two study groups was needed to create equivalent SNS activation in type 2 diabetes and healthy individuals.…”

Management of diabetes mellitus. The new period of self-control: detection of glucose trends and patterns

“…Однако многие иссле-дователи признают биохимически значимую гипогли-кемию при уровне глюкозы плазмы 3,5-3,9 ммоль/л, а симптоматическую гипогликемию с включением контринсулярной регуляции -при значениях ниже 3,2 ммоль/л [13][14][15]. В то же время нижний целевой ди-апазон обсуждается в отношении категорий пациентов с острой коронарной патологией, в периоперационном периоде, с тяжелой хирургической патологией, для па-циентов, находящихся на лечении в реанимационном от-делении.…”