Central Proliferation and Neurogenesis Is Impaired in Type 2 Diabetes and Prediabetes Animal Models

Abstract

Type 2 diabetes (T2D) is an important risk factor to suffer dementia, including Alzheimer’s disease (AD), and some neuropathological features observed in dementia could be mediated by T2D metabolic alterations. Since brain atrophy and impaired neurogenesis have been observed both T2D and AD we analyzed central nervous system (CNS) morphological alterations in the db/db mice (leptin receptor KO mice), as a model of long-term insulin resistance and T2D, and in C57Bl6 mice fed with high fat diet (HFD), as a model of diet induced insulin resistance and prediabetes. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. We also detected increased neurogenesis and cell proliferation rates in young db/db mice when compared with control littermates. Our study shows that metabolic parameters serve as predictors of both atrophy and altered proliferation and neurogenesis in the CNS. Moreover in the cortex, atrophy, cell proliferation and neurogenesis were significantly correlated. Our data suggest that T2D may underline some of the pathological features observed in the dementia process. They also support that blood glucose control in elderly patients could help to slow down dementia evolution and maybe, improve its prognosis.

Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia

“…As for the role of hyperglycemia in neurogenesis, some studies indicate that long-term hyperglycemia suppresses proliferation of hippocampus NSPCs using streptozotocin-(STZ) induced type 1 diabetes model (Jackson-Guilford et al, 2000;Saravia et al, 2004;Beauquis et al, 2006;Zhang et al, 2008;Guo et al, 2010) or spontaneous type 1 diabetes model (Beauquis et al, 2008;Guo et al, 2010), while other researches find an enhanced proliferation of NSPCs employing type 2 diabetes model (Lang et al, 2009;Ramos-Rodriguez et al, 2014). The discrepancy among studies may be attributed to different hyperglycemic models and target blood glucose levels.…”

“…Neuroscience 303 (2015) 138-148 reduced in type 1 and type 2 diabetic models (JacksonGuilford et al, 2000;Beauquis et al, 2006Beauquis et al, , 2008Zhang et al, 2008;Lang et al, 2009;Ramos-Rodriguez et al, 2014), which suggested a potential role of blood glucose in self-renewal and proliferation of NSPCs.…”

Insulin Resistance as Common Molecular Denominator Linking Obesity to Alzheimer’s Disease

“…HFD was previously shown to induce a remarkable brain insulin resistance as well as spatial memory impairment in a normal mouse or a transgenic model of AD [25]. However, whether the state of hyperinsulinemia in rodents can induce alterations in the central nervous system (CNS) remains controversial and observations seem to depend on the experimental approach to induce hyperinsulinemia and the specific tests performed [26][27][28][29]. Therefore this study was undertaken in an attempt to understand the underlying mechanisms by which adipose tissue might influence cerebral structures related to learning and memory.…”

Brain Signaling Systems in the Type 2 Diabetes and Metabolic Syndrome: Promising Target to Treat and Prevent These Diseases

“…Such weakening can be provoked by the central leptin deficiency, the altered activity of leptin receptor and IRS-proteins, and the decreased response of hypothalamic neurons to insulin [175,176]. It was shown that the leptin deficiency and the leptin resistance in the CNS were involved in the impairment of cognitive functions in T2DM, MS and also in experimental type 1 DM [171,174,177,178]. Since leptin stimulates the transcription of genes encoding IR and IRS-proteins, a decrease of its regulatory effects at the early stages of insulin resistance leads to weakening of function of the brain insulin system and exacerbates insulin resistance.…”

“…This is due to the development of leptin resistance, a decrease of the level of endogenous leptin, and inefficiency of leptin therapy in the case of the central leptin signaling being impaired [171,179]. In some cases the replacement therapy with leptin is effective.…”