Hypothalamic arousal, insulin resistance and Type 2 diabetes mellitus

Type 2 diabetes mellitus (DM) develops when insulin resistance overcomes the capacity of compensatory insulin secretion. Insulin resistance may be induced via psychoneuroendocrine pathways, a possibility which has received little previous attention.

We have used salivary cortisol measurements to monitor the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the major controller of hormones involved in the regulation of peripheral insulin sensitivity under everyday conditions. The influence of external challenges, as well as the sensitivity of feedback regulation, were followed in randomly selected middle-aged population samples.

In health there is a rhythmicity of cortisol secretion, with a high plasticity and efficient feedback control. In contrast, a group of subjects were identified with a flat, rigid day curve and poor feedback control, who showed consistent abnormalities in stress-related cortisol secretion, including inhibited secretions of sex steroids and growth hormone; insulin resistance; abdominal obesity; elevated leptin levels; hyperglycaemia; dyslipidaemia and hypertension with elevated heart rate. The endocrine abnormalities are probably responsible for the anthropometric and metabolic abnormalities. The circulatory perturbations seem to be induced by a parallel activation of the central sympathetic nervous system suggesting an 'hypothalamic arousal syndrome', gradually developing into an independent risk for disease. An associated cluster of environmental factors, including psychosocial and socio-economic stress, traits of depression and anxiety, alcohol consumption and smoking, all factors known to activate hypothalamic centres, has been identified. A polymorphism of the glucocorticoid receptor gene, with 13.7% homozygotes in the male Swedish population, parallels receptor dysfunction, and may be responsible for the associated insulin resistance, central obesity and hypertension.

This is the first detailed examination of psychoneuroendocrinological processes in the natural environment on a population basis in relation to somatic health. The results suggest that an hypothalamic arousal syndrome, with parallel activation of the HPA axis and the central sympathetic nervous system, is responsible for development of endocrine abnormalities, insulin resistance, central obesity, dyslipidaemia and hypertension, leading to frank disease, including Type 2 DM. We suggest that this syndrome is probably based on environmental pressures in genetically susceptible individuals.