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      A Comprehensive Review of Intranasal Insulin and Its Effect on the Cognitive Function of Diabetics

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          Abstract

          Diabetes mellitus continues to be a disease that affects a good percentage of our population. The majority affected need insulin on a day-to-day basis. Before the invention of the first manufactured insulin in 1978, dealing with diabetes took a significant toll on patient's lives. As technology and human innovation prevail, significant advancements have taken place in managing this chronic disease. Patients have an option to decide their mode of insulin delivery. Intranasal insulin, one such form, has a rapid mode of action while effectively controlling postprandial hyperglycemia. It has also been proven to reduce hypoglycemia and insulin resistance problems, which seem to be the main adverse effects of using conventional insulin regularly. However, due to the large dosages needed and high incurring costs, Intranasal Insulin is currently being used as adjunctive therapy along with conventional insulin. 

          We conducted a literature search in PubMed indexed journals using the medical terms "Intranasal insulin," "diabetes," and "cognitive impairment" to provide an overview of the mechanism of action of Intranasal Insulin, its distinctive cognitive benefits, and how it can be compared to the standard parenteral insulin therapy. One unique feature of intranasal insulin is its ability to directly affect the central nervous system, bypassing the blood-brain barrier. Not only does this help in reducing the peripheral side effects of insulin, but it has also proven to play a role in improving the cognitive function of diabetics, especially those who have Alzheimer's or mild cognitive impairment, as decreased levels of insulin in the brain has been shown to impact cognitive function negatively. However, it does come with its limitations of poor absorption through the nasal mucosa due to mucociliary clearance and proteolytic enzymes, our body's natural defence mechanisms. This review focuses on the efficacy of intranasal insulin, its potential benefits, limitations, and role in cognitive improvement in people with diabetes with pre-existing cognitive impairment. 

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          Insulin and insulin resistance.

          As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalization, urbanisation and industrialization have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits.
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            Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

            Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer's disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.
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              Diabetes and Cognitive Impairment.

              Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structural and functional brain magnetic resonance imaging (MRI). Cognitive deficits may occur at the very earliest stages of diabetes and are further exacerbated by the metabolic syndrome. The duration of diabetes and glycemic control may have an impact on the type and severity of cognitive impairment, but as yet we cannot predict who is at greatest risk of developing cognitive impairment. The pathophysiology of cognitive impairment is multifactorial, although dysfunction in each interconnecting pathway ultimately leads to discordance in metabolic signaling. The pathophysiology includes defects in insulin signaling, autonomic function, neuroinflammatory pathways, mitochondrial (Mt) metabolism, the sirtuin-peroxisome proliferator-activated receptor-gamma co-activator 1α (SIRT-PGC-1α) axis, and Tau signaling. Several promising therapies have been identified in pre-clinical studies, but remain to be validated in clinical trials.
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                Author and article information

                Journal
                Cureus
                Cureus
                2168-8184
                Cureus
                Cureus (Palo Alto (CA) )
                2168-8184
                16 August 2021
                August 2021
                : 13
                : 8
                : e17219
                Affiliations
                [1 ] Internal Medicine, Andhra Medical College, Visakhapatnam, IND
                [2 ] Internal Medicine, Himalayan Hospital, Dehradun, IND
                [3 ] Internal Medicine, Sir Ganga Ram Hospital, New Delhi, IND
                [4 ] Pediatrics, Karnataka Institute of Medical Sciences, Hubli, IND
                [5 ] Internal Medicine, Smt. Nathiba Hargovandas Lakhmichand Municipal Medical College, Ahmedabad, IND
                [6 ] Internal Medicine, Universidad del Zulia, Maracaibo, VEN
                [7 ] Internal Medicine, JC Medical Center, Orlando, USA
                [8 ] Internal Medicine, Shri Sathya Sai Medical College and Research Institute, Chennai, IND
                Author notes
                Article
                10.7759/cureus.17219
                8442633
                34540446
                7926dea0-314c-45a1-bff1-2d97e976101d
                Copyright © 2021, Gaddam et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 August 2021
                Categories
                Endocrinology/Diabetes/Metabolism
                Neurology
                Therapeutics

                intranasal insulin,alzheimer’s disease,diabetes mellitus,cognitive functions,type 2 diabetes mellitus,type 1 diabetes mellitus,mild cognitive impairment,intranasal administration,hyperglycemia,mitochondrial biogenesis

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