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      A nationwide cohort study on diabetes severity and risk of Parkinson disease

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          Abstract

          There is growing evidence that patients with type 2 diabetes mellitus (DM) have an increased risk of developing Parkinson’s disease (PD) and share similar dysregulated pathways. We aimed to determine whether the risk of PD increases as diabetes progresses among patients with type 2 DM. Using a nationally representative database from the Korean National Health Insurance System, 2,362,072 individuals (≥40 years of age) with type 2 DM who underwent regular health checkups during 2009–2012 were followed up until the end of 2018. The diabetes severity score parameters included the number of oral hypoglycemic agents, diabetes duration, insulin use, or presence of chronic kidney disease, diabetic retinopathy, or cardiovascular disease. Each of these characteristics was scored as one unit of diabetes severity and their sum was defined as a diabetes severity score from 0–6. We identified 17,046 incident PD cases during the follow-up. Each component of the diabetes severity score showed a similar intensity for the risk of PD. Compared with subjects with no parameters, HR values (95% confidence intervals) of PD were 1.09 (1.04–1.15) in subjects with one diabetes severity score parameter, 1.28 (1.22–1.35) in subjects with two parameters, 1.55 (1.46–1.65) in subjects with three parameters, 1.96 (1.82–2.11) in subjects with four parameters, 2.08 (1.83–2.36) in subjects with five parameters, and 2.78 (2.05–3.79) in subjects with six parameters. Diabetes severity was associated with an increased risk of developing PD. Severe diabetes may be a risk factor for the development of PD.

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          Intranasal insulin improves cognition and modulates beta-amyloid in early AD.

          Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes. We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta-amyloid, and cortisol. Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment. Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide (A beta 40; p = 0.0471) without affecting the longer isoform (A beta 42), resulting in an increased A beta 40/42 ratio (p = 0.0207). The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.
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            Impact of age, age at diagnosis and duration of diabetes on the risk of macrovascular and microvascular complications and death in type 2 diabetes

            Data are inconsistent regarding the associations between age, age at diagnosis of diabetes, diabetes duration and subsequent vascular complications.
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              Insulin resistance and Parkinson's disease: A new target for disease modification?

              There is growing evidence that patients with Type 2 diabetes have an increased risk of developing Parkinson's disease and share similar dysregulated pathways suggesting common underlying pathological mechanisms. Historically insulin was thought solely to be a peripherally acting hormone responsible for glucose homeostasis and energy metabolism. However accumulating evidence indicates insulin can cross the blood-brain-barrier and influence a multitude of processes in the brain including regulating neuronal survival and growth, dopaminergic transmission, maintenance of synapses and pathways involved in cognition. In conjunction, there is growing evidence that a process analogous to peripheral insulin resistance occurs in the brains of Parkinson's disease patients, even in those without diabetes. This raises the possibility that defective insulin signalling pathways may contribute to the development of the pathological features of Parkinson's disease, and thereby suggests that the insulin signalling pathway may potentially be a novel target for disease modification. Given these growing links between PD and Type 2 diabetes it is perhaps not unsurprising that drugs used the treatment of T2DM are amongst the most promising treatments currently being prioritised for repositioning as possible novel treatments for PD and several clinical trials are under way. In this review, we will examine the underlying cellular links between insulin resistance and the pathogenesis of PD and then we will assess current and future pharmacological strategies being developed to restore neuronal insulin signalling as a potential strategy for slowing neurodegeneration in Parkinson's disease.
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                Author and article information

                Contributors
                makung@catholic.ac.kr
                Journal
                NPJ Parkinsons Dis
                NPJ Parkinsons Dis
                NPJ Parkinson's Disease
                Nature Publishing Group UK (London )
                2373-8057
                27 January 2023
                27 January 2023
                2023
                : 9
                : 11
                Affiliations
                [1 ]GRID grid.263765.3, ISNI 0000 0004 0533 3568, Department of Statistics and Actuarial Science, , Soongsil University, ; Seoul, 06978 Korea
                [2 ]GRID grid.411947.e, ISNI 0000 0004 0470 4224, Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, , The Catholic University of Korea, ; Seoul, 06591 Korea
                [3 ]GRID grid.411947.e, ISNI 0000 0004 0470 4224, Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, , The Catholic University of Korea, ; Seoul, 07345 Korea
                Author information
                http://orcid.org/0000-0003-3205-9114
                Article
                462
                10.1038/s41531-023-00462-8
                9883517
                36707543
                d9f0d5b0-d1cf-4c59-bdc6-088d42d2542c
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 October 2022
                : 19 January 2023
                Categories
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                Custom metadata
                © The Author(s) 2023

                risk factors,epidemiology
                risk factors, epidemiology

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