New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome

Abstract

Recent data suggests that (pre)diabetes onset is preceded by a period of hyperinsulinemia. Consumption of the “modern” Western diet, over-nutrition, genetic background, decreased hepatic insulin clearance, and fetal/metabolic programming may increase insulin secretion, thereby causing chronic hyperinsulinemia. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, polycystic ovarian syndrome, and Alzheimer’s disease. Recent data suggests that the onset of prediabetes and diabetes are preceded by a variable period of hyperinsulinemia. Emerging data suggest that chromic hyperinsulinemia is also a driving force for increased activation of the hypothalamic-adrenal-pituitary (HPA) axis in subjects with the metabolic syndrome, leading to a state of “functional hypercortisolism”. This “functional hypercortisolism” by antagonizing insulin actions may prevent hypoglycemia. It also disturbs energy balance by shifting energy fluxes away from muscles toward abdominal fat stores. Synergistic effects of hyperinsulinemia and “functional hypercortisolism” promote abdominal visceral obesity and insulin resistance which are core pathophysiological components of the metabolic syndrome. It is hypothesized that hyperinsulinemia-induced increased activation of the HPA axis plays an important etiological role in the development of the metabolic syndrome and its consequences. Numerous studies have demonstrated reversibility of hyperinsulinemia with lifestyle, surgical, and pharmaceutical-based therapies. Longitudinal studies should be performed to investigate whether strategies that reduce hyperinsulinemia at an early stage are successfully in preventing increased activation of the HPA axis and the metabolic syndrome.

Obesity in pregnancy—Long‐term effects on offspring hypothalamic‐pituitary‐adrenal axis and associations with placental cortisol metabolism: A systematic review

“…Correspondingly the study by Elhassan et al found cortisol levels in young children to be affected by earlier exposure to maternal pregnancy weight gain but not maternal pre‐pregnancy BMI (Elhassan et al, 2015). It could be speculated that the reason behind this could be that excessive weight gain in pregnancy causes hyperinsulinemia and in this way introduces an increased activation of the HPA axis (Anagnostis et al, 2009; Janssen, 2022; Miranda et al, 2016) in contrast to a potential flatting of the cortisol curve in pregnancies with a continues exposure to obesity before and during pregnancy. It should also be noted that to get at an overall understanding of the cortisol transport and metabolism several other types of transport and extrusion proteins involved in cortisol transport should also be taken into account, especially the glucocorticosteroid eliminating enzyme cytochrome P450 CYP3A4 (van Keulen et al, 2020) and placental p‐glycoprotein (Ge et al, 2021; Lye et al, 2018).…”

Sensitivity of the Neuroendocrine Stress Axis in Metabolic Diseases

“…The hypothalamus, a crucial regulator of appetite, energy expenditure, and glucose homeostasis, has been implicated in the pathogenesis of metabolic diseases, such as obesity and type 2 diabetes mellitus [26]. As mentioned above, hormones like leptin, as well as other adipokines, play a critical role in regulating the functions of the hypothalamus.…”

“…As mentioned above, hormones like leptin, as well as other adipokines, play a critical role in regulating the functions of the hypothalamus. In addition to altered hormone levels, chronic inflammation, gliosis, and endoplasmic reticulum stress can affect the hypothalamic function in metabolic diseases, leading to insulin resistance and metabolism dysfunction [26]. The alterations of cortisol and insulin concentrations can impact the progression of metabolic diseases through their effects on hypothalamic neuropeptide Y (NPY) [26].…”

“…In addition to altered hormone levels, chronic inflammation, gliosis, and endoplasmic reticulum stress can affect the hypothalamic function in metabolic diseases, leading to insulin resistance and metabolism dysfunction [26]. The alterations of cortisol and insulin concentrations can impact the progression of metabolic diseases through their effects on hypothalamic neuropeptide Y (NPY) [26]. In particular, GCs can inhibit insulin transport to the blood-brain barrier, leading to the increased expression of NPY in the hypothalamus, which is associated with enhanced appetite and obesity.…”

The impact of diabetes and obesity on fertility and the potential role of gut hormones as treatment

“…Insulin has direct stimulatory effects on the hypothalamussecreting GnRH while promoting oogenesis and ovulation in the 67,68 In the adrenals, insulin stimulates steroidogenesis steroidogenesis factor 1 establishing its direct involvement in regulating adrenal gland hormones. 69 Further, it is postulated that hyperinsulinaemia during PCOS can release free IGF-1 into circulation by inhibiting IGFBP-1 production in the ovaries thereby encouraging LH-stimulated androgen production. 70 Hence, in vitro and in vivo studies suggest stimulatory roles for insulin on reproduction that have been illustrated in Figure 3.…”