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Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes.

ABSTRACT: The aim of this study was to identify factors that regulate the bulk of adult brain mass, and test the hypothesis that concomitantly reduced insulin and insulin-like growth factor (IGF) levels are pathogenic for brain atrophy associated with impaired learning and memory in diabetes. Doses of insulin, or insulin plus IGF-I that were too small to prevent hyperglycemia were infused for 12 weeks into the brain lateral ventricles of streptozotocin-diabetic adult rats. Brain wet, water and dry weights were significantly decreased in diabetic rats; insulin prevented these decreases. The decrease in brain DNA and protein contents in diabetic rats was prevented by the combination treatment, but not by insulin alone. Levels of several glia- and neuron-associated proteins were reduced in diabetes; these reductions were also prevented by the combination treatment. Although hyperglycemia was not prevented in plasma or cerebrospinal fluid, insulin prevented brain atrophy but not bulk DNA loss in diabetes, whereas the combination prevented both. Insulin actively prevented the loss of brain water content as well. Brain atrophy is associated with concomitantly reduced levels of insulin and IGF in other disorders such as Alzheimer's disease.

SUBMITTER: Serbedzija P

PROVIDER: S-EPMC2828498 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Insulin aspart (IAsp) and its biphasic preparations BIAsp50 and BIAsp70 (containing 50% and 70% IAsp, respectively) have distinct glucose-lowering properties as compared to human insulin (HI). We investigated whether this affected the circulating IGF-system which depends on the hepatic insulin exposure.In a randomized, four-period crossover study, 19 patients with type 1 diabetes received identical doses (0.2 U/kg sc) of IAsp, BIAsp70, BIAsp50 and HI together with a standardized meal. Serum total IGF-I and IGFBP-1 to -3 were measured by immunoassays for nine hours post-prandially. Bioactive IGF was determined by an in-house, cell-based IGF-I receptor kinase activation (KIRA) assay.Despite marked differences in peripheral insulin concentrations and plasma glucose, the four insulin preparations resulted in parallel decreases in IGFBP-1 levels during the first 3 hours, and parallel increases during the last part of the study (3-9 hours). Thus, only minor significances were seen. Insulin aspart and human insulin resulted in a lower area under the curve (AUC) during the first 3 hours as compared to BIAsp70 (p?=?0.009), and overall, human insulin resulted in a lower IGFBP-1 AUC than BIAsp70 (p?=?0.025). Nevertheless, responses and AUCs of bioactive IGF were similar for all four insulin preparations. Changes in levels of bioactive IGF were inversely correlated to those of IGFBP-1, increasing during the first 3 hours, whereafter levels declined (-0.83???r???-0.30; all p-values <0.05).Total IGF-I and IGFBP-3 remained stable during the 9 hours, whereas IGFBP-2 changed opposite of IGFBP-1, increasing after 3-4 hours whereafter levels gradually declined. The four insulin preparations resulted in similar profiles and AUCs of total IGF-I, IGFBP-2 and IGFBP-3.Despite distinct glucose-lowering properties, the tested insulin preparations had similar effects on IGF-I concentration and IGF bioactivity, IGFBP-2 and IGFBP-3 as compared to HI; only small differences in IGFBP-1 were seen and they did not affect bioactive IGF. Thus, insulin aspart containing preparation behaves as HI in regards to the circulating IGF-system. However, bioactive IGF appeared to be more sensitive to insulin exposure than total IGF-I. The physiological significance of this finding remains to be determined.NCT00888732.

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Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes.

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