Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

Zhang, Hui; Hao, Ying; Manor, Bradley; Novák, Péter; Milberg, William; Zhang, Jue; Fang, Jing; Novak, Vera

doi:10.2337/db14-1000

Cited by 135 publications

(117 citation statements)

References 50 publications

(58 reference statements)

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“…These studies have revealed associations among impaired cognition, altered activation, and decreased functional connectivity (8)(9)(10)(11)(12)(13)(14). Although functional connectivity was measured by correlating signal time series of various and a priori-selected cerebral regions, aberrant connections outside these predefined regions remain undiscovered.…”

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confidence: 99%

Functional Brain Networks Are Altered in Type 2 Diabetes and Prediabetes: Signs for Compensation of Cognitive Decrements? The Maastricht Study

et al. 2016

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Type 2 diabetes is associated with cognitive decrements, accelerated cognitive decline, and increased risk for dementia. Patients with the metabolic syndrome, a major risk factor for diabetes, may display comparable cognitive decrements as seen in type 2 diabetes. Currently, the impact of diabetes and prediabetes on cognition and the underlying organization of functional brain networks still remain to be elucidated. This study investigated whether functional brain networks are affected in type 2 diabetes and prediabetes. Forty-seven participants with diabetes, 47 participants with prediabetes, and 45 control participants underwent detailed cognitive testing and 3-Tesla resting state functional MRI. Graph theoretical network analysis was performed to investigate alterations in functional cerebral networks. Participants with diabetes displayed altered network measures, characterized by a higher normalized cluster coefficient and higher local efficiency, compared with control participants. The network measures of the participants with prediabetes fell between those with diabetes and control participants. Lower processing speed was associated with shorter path length and higher global efficiency. Participants with type 2 diabetes have altered functional brain networks. This alteration is already apparent in the prediabetic stage to a somewhat lower level, hinting at functional reorganization of the cerebral networks as a compensatory mechanism for cognitive decrements.The worldwide prevalence of diabetes is increasing rapidly, with the majority of patients having type 2 diabetes (1). Along with cardiovascular risk factors, type 2 diabetes is associated with cognitive decrements, accelerated cognitive decline, and an increased risk for dementia and Alzheimer disease (2,3). A broad range of cognitive domains are affected in type 2 diabetes, and one of the most commonly affected is processing speed (4,5). However, the underlying pathological mechanism is not yet clear.The progression of normal glucose metabolism to type 2 diabetes is a gradual process in which insulin resistance plays a crucial role. Before the clinical presentation of type 2 diabetes, insulin resistance often is accompanied by other metabolic and vascular abnormalities. The cluster of these cardiovascular risk factors is referred to as the metabolic syndrome and is considered a major risk factor for diabetes (6). Patients with the metabolic syndrome have a high likelihood for diabetes and may display comparable cognitive decrements as seen in patients with type 2 diabetes (5). Furthermore, the cardiovascular risk factors are associated with an increased risk of late-life dementia (7).

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Functional Brain Networks Are Altered in Type 2 Diabetes and Prediabetes: Signs for Compensation of Cognitive Decrements? The Maastricht Study

et al. 2016

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“…Two recent proof-of-concept studies evaluated the acute effects on cerebral vasoreactivity and cognition of a single 40 IU dose of intranasal insulin (Novolin®) via a ViaNase™ device compared with placebo in type 2 Diabetes (T2DM; [64,65]). Across all subjects, intranasal insulin administered improved visuospatial memory and increased resting-state functional connectivity in older adults with T2DM.…”

Section: Is N2b Insulin Appropriate As Therapy For Neurodegenerative mentioning

confidence: 99%

Nose-to-Brain delivery of insulin for Alzheimer’s disease

Stützle¹,

Flamm²,

Carle

et al. 2015

ADMET DMPK

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The transport of small molecules, peptides and proteins via the olfactory epithelium and along olfactory and trigeminal nerve pathways from the nasal cavity to the brain is very well known and clinically established for central nervous system (CNS) active drugs like oxytocin, sumatriptan or insulin. Insulin is a clinically well-established biopharmaceutical with a validated function in cognition. Central supply with insulin via intranasal administration improves cognition in animal models CNS delivery -an unmet medical needThe World Health Organization (WHO) estimates that more than a billion people worldwide are suffering from diseases of the central nervous system (CNS; [1,2]). Alzheimer's disease (AD) is the most common neurodegenerative dementia in the industrialized world, with prevalence rates well over 30 % in the over 80-years-old population [1,2]. AD causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. Like most neurodegenerative diseases, AD has a poor prognosis and only symptomatic therapy is currently available. Efficient treatment strategies are still limited and an aging society in demographic change presents an enormous challenge to the health systems of industrialized nations. Despite the extensive research and effort to uncover the mechanism of AD pathogenesis, more or less all drug candidates failed to demonstrate significant effects on cognition in clinical trials [3,4].A highly critical point in that context is the low central availability of drugs. The passage of most CNSactive drugs and in particular of biopharmaceuticals is massively hampered by the blood-brain barrier

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“…In this issue of Diabetes, Zhang et al (8) present their work on unraveling the underlying mechanisms behind intranasal insulin and neurocognitive function. In their cohort of patients with diabetes, they showed that a single dose of 40 IU of intranasal insulin not only improved neurocognitive performance in test batteries but also restored the connectivity of hippocampal regions and the mediofrontal cortex back to a level comparable to healthy subjects.…”

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confidence: 99%

“…The proof-of-concept study of Zhang et al (8) might open new perspectives for patients with an impairment of the neurocognitive function but is far from forcing us to treat every patient with intranasal insulin. It calls for prospective trials in larger populations to evaluate the effect on daily life and investigations to broaden the indication and to further unravel the underlying mechanisms.…”

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confidence: 99%