Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans.

Abstract

The aim of this study was to determine whether the duration of antecedent hypoglycemia regulates the magnitude of subsequent counterregulatory failure. A total of 31 lean healthy overnight-fasted individuals (16 men/15 women) were studied. There were 15 subjects (8 men/7 women) who underwent two separate 2-day randomized experiments separated by at least 2 months. On day 1, 2-h hyperinsulinemic (9 pmol · kg -1 · min -1 ) euglycemic (5.2 ± 0.1 mmol/l) or hypoglycemic (2.9 ± 0.1 mmol/l) glucose clamps (prolonged hypoglycemia) were carried out in the morning and afternoon. Of the other subjects, 16 participated in a 2-day study in which day 1 consisted of morning and afternoon short-duration hypoglycemia experiments (hypoglycemic nadir of 2.9 ± 0.1 mmol for 5 min), and 10 of these individuals underwent an additional 2-day study in which day 1 consisted of morning and afternoon intermediate-duration hypoglycemia (hypoglycemic nadir of 2.9 ± 0.1 mmol for 30 min). The next morning (day 2) all subjects underwent an additional 2-h hyperinsulinemic-hypoglycemic clamp (2.9 ± 0.1 mmol/l). The rate of fall of glucose (0.07 mmol/min) was carefully controlled during all hypoglycemic studies so that the glucose nadir was reached at 30 min. Despite equivalent day 2 plasma glucose and insulin levels, there were significant differences in counterregulatory physiological responses. Steady-state epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels were similarly significantly blunted (P < 0.01) by the differing duration day 1 hypoglycemia compared with day 1 euglycemia. Muscle sympathetic nerve activity and endogenous glucose production were also similarly blunted (P < 0.01) by day 1 hypoglycemia (relative to day 1 euglycemia). Day 2 hypoglycemic symptoms were significantly reduced (P < 0.01) after day 1 prolonged intermediate-but not short-duration hypoglycemia. In summary, two episodes of short-duration moderate hypoglycemia can produce significant blunting of key neuroendocrine and metabolic counterregulatory responses. Hypoglycemic symptom scores are reduced by prolonged but not short-duration prior hypoglycemia. We conclude that in healthy overnight fasted humans, 1) neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses are sensitive to the blunting effects of even short-duration prior hypoglycemia, and 2) the duration of antecedent hypoglycemia results in a hierarchy of blunted physiological responses with hypoglycemic symptom awareness less vulnerable than neuroendocrine responses. Diabetes 49: [1897][1898][1899][1900][1901][1902][1903] 2000 N umerous studies have demonstrated that antecedent hypoglycemia can blunt subsequent counterregulatory responses to hypoglycemia (1-7). Recent work has focused on determining the in vivo factors and mechanisms responsible for this finding. Depth of antecedent hypoglycemia (8), number of prior episodes of hypoglycemia (2,4,8), and sex (9) can all independently regulate the magnitude of subsequent counterregulatory failure.To ...

Effects of a Selective Serotonin Reuptake Inhibitor, Fluoxetine, on Counterregulatory Responses to Hypoglycemia in Healthy Individuals

“…The origin of hypoglycemic symptoms during hypoglycemia is complex. Previous studies demonstrated scenarios whereby discordant responses between autonomic symptoms and catecholamine responses can exist during hypoglycemia (17,(31)(32)(33). Generally, studies have determined that autonomic symptoms can be preserved despite reduced activity in other branches of the sympathetic nervous system.…”

“…Direct measurement of muscle sympathetic nerve activity. Muscle sympathetic nerve activity (MSNA) was recorded from the peroneal nerve at the level of the fibular head and popliteal fossa (16,17). The approximate location of this nerve was determined by transdermal electrical stimulation to produce painless muscle contraction of the foot.…”

From Bedside to Bench and Back Again: Research Issues in Animal Models of Human Disease

“…This reduction in counterregulatory responses occurs after as little as one episode of hypoglycemia (Heller & Cryer, 1991;Robinson, Parkin, MacDonald, & Tattersall, 1995). Other investigators demonstrated this phenomenon after repeated episodes of hypoglycemia delivered on consecutive days (2 days, blood glucose averaging 45 mg/dl for 60 min each day) (Widom & Simonson, 1992) or two episodes in a single day involving morning and afternoon sessions (hypoglycemia ranging from 52 to 70 mg/dl maintained for up to 2 hr in each session) (Davis et al, 2000;Davis, Shavers, Mosqueda-Garcia, & Costa, 1997). These studies support the concept that recent hypoglycemia acutely induces HAAF in humans (Cryer, 2001).…”

“…All of these studies report suppression of hypoglycemia-induced epinephrine secretion after prior hypoglycemia, and most report similar declines in hypoglycemia-induced norepinephrine, glucagon, growth hormone, and cortisol secretion. When hypoglycemic symptoms were assessed, these responses were also reduced after prior hypoglycemia (Davis et al, 2000;Heller & Cryer, 1991;Widom & Simonson, 1992).…”

Antecedent hypoglycaemia does not diminish the glycaemia-increasing effect and glucoregulatory responses of a 10 s sprint in people with type 1 diabetes

“…Following this, euglycaemia was restored once more by decreasing the insulin infusion rate and gradually reducing the glucose infusion rate. The depth and duration of this hypoglycaemic episode were chosen on the basis that they were expected to attenuate glucoregulatory hormone responses to a subsequent stimulus such as moderate-intensity exercise or hypoglycaemia [22,25,26]. At time intervals before and during euglycaemia and hypoglycaemia, blood samples were collected for the assessment of glucoregulatory hormone levels.…”