IRS-2 Deficiency impairs NMDA receptor-dependent long-term potentiation.

The beneficial effects of insulin and insulin-like growth factor I on cognition have been documented in humans and animal models. Conversely, obesity, hyperinsulinemia, and diabetes increase the risk for neurodegenerative disorders including Alzheimer's disease (AD). However, the mechanisms by which insulin regulates synaptic plasticity are not well understood. Here, we report that complete disruption of insulin receptor substrate 2 (Irs2) in mice impairs long-term potentiation (LTP) of synaptic transmission in the hippocampus. Basal synaptic transmission and paired-pulse facilitation were similar between the 2 groups of mice. Induction of LTP by high-frequency conditioning tetanus did not activate postsynaptic N-methyl-D-aspartate (NMDA) receptors in hippocampus slices from Irs2(-/-) mice, although the expression of NR2A, NR2B, and PSD95 was equivalent to wild-type controls. Activation of Fyn, AKT, and MAPK in response to tetanus stimulation was defective in Irs2(-/-) mice. Interestingly, IRS2 was phosphorylated during induction of LTP in control mice, revealing a potential new component of the signaling machinery which modulates synaptic plasticity. Given that IRS2 expression is diminished in Type 2 diabetics as well as in AD patients, these data may reveal an explanation for the prevalence of cognitive decline in humans with metabolic disorders by providing a mechanistic link between insulin resistance and impaired synaptic transmission.

Loss of protein tyrosine phosphatase 1B increases IGF-I receptor tyrosine phosphorylation but does not rescue retinal defects in IRS2-deficient mice.

PURPOSE: Mice with deletion of insulin receptor substrate (IRS) 2 develop type 2 diabetes and photoreceptor degeneration. Loss of protein tyrosine phosphatase 1B (PTP1B) in diabetic IRS2(-/-) mice restores insulin sensitivity and normalizes glucose homeostasis. Since insulin-like growth factor (IGF)-IR promotes survival of photoreceptors and is a substrate of PTP1B, we investigated IGF-IR-mediated survival signaling and visual function in PTP1B(-/-) and double mutant IRS2(-/-)/PTP1B(-/-) mice. METHODS: IGF-IR-mediated Akt signaling was evaluated in IGF-I-stimulated retinal explants. Histologic and electroretinogram analysis was performed in wild-type (WT), IRS2(-/-), PTP1B(-/-), and the double mutant IRS2(-/-)/PTP1B(-/-) mice. RESULTS: IGF-I stimulated the tyrosine phosphorylation of its receptor and Akt activation in retinal explants of WT mice. In PTP1B(-/-) retinal explants, these responses were enhanced. Conversely, in retinas from IRS2(-/-) mice, expression of PTP1B was increased, coincident with decreased IGF-I-mediated Akt serine 473 phosphorylation. PTP1B deletion in IRS2(-/-) mice also enhanced IGF-IR tyrosine phosphorylation but, unexpectedly, did not rescue Akt activation in response to IGF-I. One potential explanation is that PTEN was increased in retinas of IRS2(-/-) and IRS2(-/-)/PTP1B(-/-) mice. Histologic evaluation revealed alterations in various structures of the retina in IRS2(-/-) and IRS2(-/-)/PTP1B(-/-) mice, specifically in the outer nuclear layer (ONL) and retinal outer segments (ROS). Electroretinogram (ERG) analysis confirmed that PTP1B deficiency did not restore visual function in IRS2(-/-) mice. CONCLUSIONS: Although loss of PTP1B enhances tyrosine phosphorylation of the IGF-IR in retinal explants of IRS2(-/-) mice, Akt activation remains defective owing to elevated PTEN levels and, thus, structural and functional visual defects persist in this model.

Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring.

BACKGROUND: Bisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the base compound in the manufacture of polycarbonate plastics. In humans, epidemiological evidence has associated BPA exposure in adults with higher risk of type 2 diabetes and heart disease. OBJECTIVE: We examined the action of environmentally relevant doses of BPA on glucose metabolism in mice during pregnancy and the impact of BPA exposure on these females later in life. We also investigated the consequences of in utero exposure to BPA on metabolic parameters and pancreatic function in offspring. METHODS: Pregnant mice were treated with either vehicle or BPA (10 or 100 microg/kg/day) during days 9-16 of gestation. Glucose metabolism experiments were performed on pregnant mice and their offspring. RESULTS: BPA exposure aggravated the insulin resistance produced during pregnancy and was associated with decreased glucose tolerance and increased plasma insulin, triglyceride, and leptin concentrations relative to controls. Insulin-stimulated Akt phosphorylation was reduced in skeletal muscle and liver of BPA-treated pregnant mice relative to controls. BPA exposure during gestation had long-term consequences for mothers: 4 months post-partum, treated females weighed more than untreated females and had higher plasma insulin, leptin, triglyceride, and glycerol levels and greater insulin resistance. At 6 months of age, male offspring exposed in utero had reduced glucose tolerance, increased insulin resistance, and altered blood parameters compared with offspring of untreated mothers. The islets of Langerhans from male offspring presented altered Ca2+ signaling and insulin secretion. BrdU (bromodeoxyuridine) incorporation into insulin-producing cells was reduced in the male progeny, yet beta-cell mass was unchanged. CONCLUSIONS: Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and that BPA may be a risk factor for diabetes.