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According to the current paradigm, the development of type 2 diabetes is driven by insulin resistance and the gradual failure of beta cells to compensate for this by secreting adequate amounts of insulin. Obesity is an important risk factor for type 2 diabetes and is considered to influence disease development primarily by induction of insulin resistance, via mechanisms that have not been fully elucidated. Insulin-antagonistic, counter-regulatory neurohormonal pathways, including glucagon, cortisol (stimulated by the pituitary hormone ACTH), growth hormone and the autonomic nervous system have glucose-raising properties and constitute a physiological defense to hypoglycemia that is coordinated from the brain and brainstem. Glucose variations also trigger responses of several inflammatory mediators, that may also oppose the actions of insulin. The overarching aim of this thesis was to explore the importance of glucose-dependent dysregulation of these counter-regulatory pathways – hormonal, neural and inflammatory – in the development of type 2 diabetes. 

All selected papers in this thesis are based on data obtained during stepwise hyperinsulinemic-euglycemic-hypoglycemic clamps and hyperglycemic clamps, in which glucose levels are lowered or raised to prespecified target levels. 

In papers I and II, we found that overweight and insulin resistance was associated with cortisol/ACTH hyperreactivity to hypoglycemia and general hyperglucagonemia, insensitive to glucose-dependent suppression. Furthermore, in paper I, the autonomic nervous system was more rigid to glucose variations in overweight and insulin resistant individuals, with a failure to inhibit parasympathetic activity during hypoglycemia and an attenuated activity of sympathetic relative to parasympathetic activity during hyperglycemia. In paper III, cortisol/ACTH hyperreactivity was present already in individuals with prediabetes, with no further exacerbation in individuals with type 2 diabetes. By contrast, hyperglycemia-insensitive hyperglucagonemia and, in addition, general growth hormone downregulation was found to be more pronounced in individuals with type 2 diabetes. In paper IV, no unfavorably altered reactivity of inflammatory markers was found in obese compared to lean individuals. 

In conclusion, glucose-dependent dysregulation of several insulin-antagonistic neurohormonal pathways appears to be present at different stages of type 2 diabetes development and may drive disease development via aggravation of insulin resistance.