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Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring.

ABSTRACT: Adverse effects in diabetic mothers offspring (DMO) are a major concern of increasing incidence. Among these, chronic central complications in DMO remain poorly understood, and in extreme cases, diabetes can essentially function as a gestational brain insult. Nevertheless, therapeutic alternatives for DMO are limited.Therefore, we have analyzed the central long-term complications in the offspring from CD1 diabetic mothers treated with streptozotozin, as well as the possible reversion of these alterations by insulin administration to neonates. Brain atrophy, neuronal morphology, tau phosphorylation, proliferation and neurogenesis were assessed in the short term (P7) and in the early adulthood (10 weeks) and cognitive function was also analyzed in the long-term.Central complications in DMO were still detected in the adulthood, including cortical and hippocampal thinning due to synaptic loss and neuronal simplification, increased tau hyperphosphorylation, and diminished cell proliferation and neurogenesis. Additionally, maternal diabetes increased the long-term susceptibility to spontaneous central bleeding, inflammation and cognition impairment in the offspring. On the other hand, intracerebroventricular insulin administration to neonates significantly reduced observed alterations. Moreover, non-invasive intranasal insulin reversed central atrophy and tau hyperphosphorylation, and rescued central proliferation and neurogenesis. Vascular damage, inflammation and cognitive alterations were also comparable to their counterparts born to nondiabetic mice, supporting the utility of this pathway to access the central nervous system.Our data underlie the long-term effects of central complications in DMO. Moreover, observed improvement after insulin treatment opens the door to therapeutic alternatives for children who are exposed to poorly controlled gestational diabetes, and who may benefit from more individualized treatments.

SUBMITTER: Ramos-Rodriguez JJ

PROVIDER: S-EPMC5541692 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:ObjectiveTo examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).DesignRandomized, double-blind, placebo-controlled trial.SettingClinical research unit of a Veterans Affairs medical center.ParticipantsThe intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).Main outcome measuresPrimary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.ResultsOutcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.ConclusionsThese results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568.

Project description:Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer's disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

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Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring.

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