Examination of the Role of the Pituitary-Adrenocortical Axis, Counterregulatory Hormones, and Insulin Clearance in Variable Nocturnal Insulin Requirements in Insulin-dependent Diabetes

Abstract

In insulin-dependent diabetics, insulin requirements increase significantly after 0600 h, resulting in prebreakfast hyperglycemia with either conventional insulin therapy or constant insulin infusions with insulin infusion devices. In order to clarify the role of the pituitary-adrenocortical axis and further examine the mechanisms of the phenomenon of nocturnal variability in insulin requirements, we studied five IDDs using a closed-loop insulin infusion device (Biostator, GCIIS). The subjects were given saline (SAL) or dexamethasone (DEX) i.v. from 1800 to 0900 h on successive nights. From 2400-0300 to 0600-0900 h, mean insulin infusion rates required to maintain blood glucose values between 109 and 120 mg/dl increased by 0.21 +/- 0.05 mU/kg/min during the SAL infusion, and 0.16 +/- 0.04 mU/kg/min during the DEX infusion, when plasma cortisols were suppressed to less than or equal to 2 micrograms/dl. Mean free insulin concentrations did not increase and remained constant throughout both study nights in spite of the significantly higher 0600-0900-h insulin infusion rates. Growth hormone, glucagon, epinephrine, and norepinephrine concentrations showed normal nocturnal and early morning patterns during both study nights. We conclude that the nocturnal variability in insulin requirements persists despite suppression of the pituitary-adrenocortical axis, and that increased free insulin clearance or degradation may contribute to the "dawn phenomenon" of rising prebreakfast glucose despite constant insulin infusion.

Demonstration of a Dawn Phenomenon in Normal Human Volunteers

“…An early morning increase in insulin clearance 7 also seems an unlikely mechanism in view of the increases in plasma insulin found by Schmidt et al 17 and ourselves along with the increases in plasma C-peptide demonstrated in the present studies. Our observations, as well as those of Skor et al 7 and Stene et al, 9 of increases in plasma catecholamines (mainly norepinephrine) at a time anticipated to precede or coincide with initiation of the dawn phenomenon raise the possibility that adrenergic mechanisms may have been involved. Finally, it is also possible that surges in growth hormone secretion that occurred earlier in the evening may have subsequently decreased the sensitivity of the liver to insulin.…”

Influence of glucocorticoids and growth hormone on insulin sensitivity in humans

“…B). In spite of this, early morning rises in cortisol levels have limited contribution to the dawn phenomenon as studies have shown that the hyperglycaemic actions of cortisol are delayed and that the dawn phenomenon persists despite pharmacological suppression of cortisol secretion ; however, the exact mechanism through which GH mediates the dawn phenomenon remains speculative. In this regard, Type 1 diabetes is a useful model to understand the effects of GH on insulin sensitivity, as GH excess and insulin‐like growth factor‐I deficiency are characteristic of this condition during periods of poor glycaemic control owing to portal insulinopenia (Fig.…”

Dawn phenomenon in Type 1 (insulin-dependent) diabetic adolescents: influence of nocturnal growth hormone secretion

“…The term "dawn phenomenon" indicates a condition in which insulin requirements increase between 04.00 hours and 08.00 hours (or hyperglycaemia develops if the increased insulin requirements are not met) in the absence of declining insulin delivery or preceding hypoglycaemia [1]. The dawn phenomenon has been extensively studied in adults with Type 1 (insulindependent) [2][3][4][5][6][7][8][9][10][11][12] or Type 2 (non-insulin-dependent) diabetes [11] and in normal subjects [13]. However, there are no data available on its possible occurrence in Type I diabetic children and adolescents, in whom elevated pre-breakfast blood glucose (BG) are a common clinical observation.…”