Effects of insulin per se on neuroendocrine and metabolic counter-regulatory responses to hypoglycaemia

Abstract

We examined and compared findings from studies aimed at detecting and quantifying an effect of insulin per se on counter-regulatory responses to hypoglycaemia. The experimental protocols used in many of these studies were very different with regard to study design and patient population, resulting at times in inconsistencies and discrepancies. Taken together, the results from this extensive body of work clearly indicate that, at similar levels of hypoglycaemia, greater hyperinsulinaemia results in enhanced counter-regulatory responses. This enhancement includes higher circulating levels of counter-regulatory hormones (adrenaline, noradrenaline, cortisol and growth hormone, but not glucagon), more intense activation of hypoglycaemic symptoms (both neural-sympathetic and adrenal-sympathetic), and greater deterioration of neuropsychological skills. The insulin-induced enhancement of counter-regulatory responses is not influenced by gender, is present in several animal species, and applies to healthy subjects as well as to patients with Type I diabetes. The underlying mechanisms remain speculative, and possibly include a direct neuromodulatory effect and/or suppression of glucose utilization in various areas of the brain, which either independently or in a hierarchical fashion trigger the sequence of downstream counter-regulatory events.

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

“…Once within the brain, insulin, alone or in interaction with other peptides, regulates processes such as energy homeostasis, satiety, counterregulation to hypoglycemia, cognitive function, and neuronal survival, among others (43). With regard to responses to hypoglycemia, the evidence, although not uniformly in agreement, indicates that higher plasma insulin concentrations, which imply higher cerebral insulin concentrations, may elicit greater counterregulatory responses, increased symptoms, and deterioration of cognitive function to insulin-induced hypoglycemia (20). The best evidence for such conclusions is provided by Lingenfelser et al (19), who performed hyperinsulinemic stepped hypoglycemic clamps in subjects with type 1 diabetes.…”

“…In addition, plasma concentrations of insulin detemir are greater than those of human insulin because of its binding to albumin (15) and because of its higher (four time) molar concentration than human insulin (16). This might directly influence counterregulatory responses because high plasma concentrations of insulin might modulate per se counterregulation to hypoglycemia (17)(18)(19)(20)(21)(22).…”

Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia

“…Similar phenomena have been observed in people with type 1 diabetes, whereby epinephrine responses can only be fully elicited at lower glucose concentrations (26). The depth of hypoglycemia has also been suggested to be an important factor in determining insulin's ability to amplify the sympathoadrenal response (27).…”

Metabolic, endocrine and mood responses to nocturnal eating in men are affected by sources of dietary energy

“…Cortisol affects energy expenditure [19], and protein [19], CHO [30] and fat metabolism [94], Cortisol displays a clear and steady circadian rhythm [6] but is not substantially affected by macronutrient composition [119].…”

“…Their (n=7) mean (range) age was 32 (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43) years; weight 84.3 (69-95) kg; body mass index 23.8 (19.9-26.6) kg/m2; body fat 20.0 (11.4-31.2) %; and estimated maximal oxygen uptake 47 (36-60) mL/min/ kg. All were in good health as determined by medical history and physical examination; none of the subjects were smokers or had excessive alcohol consumption.…”