Preprint Article Version 3 Preserved in Portico This version is not peer-reviewed

Insulin in Amyotrophic Lateral Sclerosis: Impairment, Tests and Treatment

Version 1 : Received: 14 December 2022 / Approved: 16 December 2022 / Online: 16 December 2022 (08:04:09 CET)
Version 2 : Received: 19 December 2022 / Approved: 20 December 2022 / Online: 20 December 2022 (08:49:21 CET)
Version 3 : Received: 23 January 2023 / Approved: 24 January 2023 / Online: 24 January 2023 (10:25:55 CET)

How to cite: Rappoport, A. Insulin in Amyotrophic Lateral Sclerosis: Impairment, Tests and Treatment. Preprints 2022, 2022120297. https://doi.org/10.20944/preprints202212.0297.v3 Rappoport, A. Insulin in Amyotrophic Lateral Sclerosis: Impairment, Tests and Treatment. Preprints 2022, 2022120297. https://doi.org/10.20944/preprints202212.0297.v3

Abstract

Background. Amyotrophic Lateral Sclerosis (ALS) is a devastating disease involving motor neuron degeneration. The few drugs approved for treatment have at most a marginal benefit, and death usually occurs 2-5 years after diagnosis. Methods. A thorough manual examination of the relevant literature, covering over 35,000 papers. Results. Two major phenomena that are generally not known to clinicians were found. First, insulin signaling is impaired in ALS even in patients not diagnosed with diabetes (DB). Almost all studies that have explicitly tested insulin function in non-DB ALS patients using glucose tolerance tests (18 out of 20, 1964-2022, different groups) have found it to be impaired. Second, there is strong evidence for excessive insulin-independent glucose uptake (IIGU) in ALS. In addition, (i) early/late diabetes are associated with increased/decreased risk, respectively; (ii) insulin-based diabetes drugs are protective in ALS in large retrospective human studies; and (iii) strong animal and human evidence shows that insulin opposes all of the major pathological processes in ALS. Conclusion. Most ALS patients have insulin impairment, yet this is commonly not diagnosed, likely because excessive IIGU normalizes glucose levels. The impairment promotes disease progression. Late diabetes is associated with decreased risk because high glucose levels indicate non-excessive IIGU, and because diabetes drugs are protective. Insulin-based treatment (e.g., GLP1 agonists, insulin) is beneficial and can be disease-modifying in ALS and in frontotemporal dementia variants comorbid with ALS. ALS patients should be routinely tested for insulin function and treated if test results are positive.

Keywords

ALS; frontotemporal dementia; insulin; diabetes

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Comments (1)

Comment 1
Received: 24 January 2023
Commenter: Ari Rappoport
Commenter's Conflict of Interests: Author
Comment: This version has an expanded description of insulin trajectories and BMI in ALS.
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