Lifelong Enhanced Diabetes Susceptibility and Obesity after Temporary Intrahypothalamic Hyperinsulinism during Brain Organization

Abstract

Newborn male Wistar-rats received bilateral intrahypothalamic insulin-agar-implants on the 2nd or 8th day of life. In male control animals only the insulin-free indifferent agar-vehicle was implanted at the same age. In both experimental groups with temporary intrahypothalamic hyperinsulinism during brain organization the following results were obtained: 1) Higher body weight gain starting at the end of the hypothalamic differentiation period and continuing during juvenile life until adulthood, resulting in increased relative body weight as a sign of obesity; 2) A tendency to basal hyperinsulinaemia in juvenile and adult age; 3) Impaired glucose tolerance in adulthood; 4) Increased diabetes susceptibility to a single "subdiabetogenic" dose of streptozotocin in adult age. In view of these and previous observations a teratogenetic role of high insulin concentrations during the organization of glucoregulatory hypothalamic structures is hypothesized and the possible relevance of such hyperinsulinism as a predisposing factor for a lifelong enhanced diabetes and/or obesity risk is suggested.

Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

“…Consistent with a trophic role of insulin in the developing hypothalamus, offspring of insulin-deficient mothers display a reduced number of ARC neurons, and this reduction of neuronal cell number is preventable by the normalization of glycemia using pancreatic islet transplantation (156). Moreover, hypoinsulinemic pups born to protein-restricted dams display a reduction in the number of astrocytes (411), while the offspring of gestationally diabetic mothers, which have increased insulin levels, have increased numbers of astrocytes (409,412). In addition to influencing hypothalamic cell numbers, insulin can also influence hypothalamic neuronal connectivity.…”

“…Pups born to insulin-deficient dams display abnormally organized POMC and NPY/AgRP neural projections that could result from the attenuated responsiveness of hypothalamic neurons to the neurotrophic actions of leptin during neonatal development (491). Notably, intrahypothalamic insulin injections during early postnatal life cause life-long metabolic dysregulation, raising the importance of neonatal insulin in the developing brain on life-long metabolic regulation (410,412).…”

Increased Adiposity Programmed by Catch-Up Growth: Requirement for Leptin Signals?

“…For example, hyperinsulinemia has also been associated with catch-up growth and has been implicated in mediating persistent effects on metabolic outcomes (9,11,12). Going forward, we also need to define the relationship between the timing of processes mediating metabolic programming in rodents and corresponding stages of human development.…”

“…Studies to identify molecular mechanisms underlying metabolic programming due to catch-up growth initially focused on the potential role of hyperinsulinemia (11,12); however, two seminal discoveries shifted the focus to leptin. First, Ahima et al (13) characterized a surge in plasma leptin levels in the first 2 wk of life, a period when leptin does not influence food intake or body weight (13)(14)(15)(16).…”

Hormonal and nutritional regulation of postnatal hypothalamic development

“…Insulin is a third hormone important in 155 the development of this circuitry. Although insulin remains relatively constant in early 156 postnatal life, with a gradual increase to adult levels just prior to puberty (Ahima et al,157 1998), perturbations in insulin signalling can also influence the development of hypothalamic 158 metabolic circuitry (Plagemann et al, 1992;Plagemann et al, 1999;Vogt et al, 2014). 159 160…”