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Insulin in Amyotrophic Lateral Sclerosis: Impairment, Tests and Treatment

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23 January 2023

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24 January 2023

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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

Introduction

ALS is a disease of unknown etiology involving the degeneration of motor neurons (MTNs) [1,2]. There are two variants, sporadic ALS (sALS), which affects 80-90% of the patients, and familial ALS (fALS), usually associated with gene mutations. There is strong comorbidity with frontotemporal dementia (FTD), mainly its behavioral variant (bvFTD) [3,4]. The few approved treatments have only a marginal benefit [5,6,7], and death usually occurs two to five years after diagnosis.
Here I point to a promising immediately available therapy, which, although based on strong existing evidence, is not recognized by the medical community. I highlight wide evidence that insulin function is impaired in a large subset of ALS patients, and explain why it is usually not detected and why insulin-based therapy (insulin itself or drugs promoting its secretion) should provide benefit. The account is supported by wide epidemiological data on the relationship between ALS and diabetes mellitus (DB) and body mass index (BMI), studies showing that DB drugs are associated with decreased ALS risk, imaging and molecular evidence in ALS, and other preclinical results.

Method

An extensive manual examination of the relevant literature has been conducted over several years. Papers were identified via searches of Google Scholar and PubMed between 1950 and November 2022, and references from and citations of relevant articles. The search terms used were ALS, FTD, glucose, insulin, diabetes, AMPK, cellular stress, unfolded protein response, oxidative stress, glutathione, TDP-43, and calcium. Hundreds of thousands of papers were examined, with over 35,000 papers thoroughly read.
Note that although the methodology used is similar to that used for reviews, this paper is not a review. It reports novel results, which are based on previously reported empirical evidence.

Known ALS Pathophysiology

The etiology of ALS is not known, but much is known about its pathophysiology. Both sALS and fALS cells show clear cellular stress and stress responses, including endoplasmic reticulum (ER) stress [8,9,10,11], unfolded protein and heat shock responses (UPR, HSR) [12,13,14,15,16,17,18,19,20], oxidative stress [9,21] with reduced glutathione (GSH) [22,23] and increased lipid peroxidation [24,25,26,27,28,29,30], and immune reactivity [31,32]. Indeed, almost all patients show pathological accumulation of the TDP-43 protein, which is associated with stress responses [33]. ALS cell stress involves excitotoxicity, with much evidence pointing to calcium overload [34,35,36,37,38,39,40]. Mitochondria are impaired, with reduced oxidative phosphorylation [9,41,42,43,44,45] and permeability pore opening [46].
These phenomena are widely recognized and comprise the logical foundation of the drugs approved for ALS and of almost all clinical trials done over the years [47].

Insulin Is Impaired in ALS

A thorough search and examination of the literature revealed that ALS exhibits an additional strong pathophysiology, insulin impairment. Twenty one papers published during the last sixty years have reported the results of explicit glucose tolerance or insulin tests (mainly using the oral glucose tolerance test (OGTT)) in ALS patients who were not previously diagnosed with diabetes. Of these, eighteen reported impaired insulin secretion [48,49,50,51,52,53] or signaling [54,55,56,57,58,59,60,61,62,63,64,65], and one reported an inverse correlation between gluocse disposal rate and disease severity [66]. Only two early papers reported normal glucose tolerance, one using only neurological patients as controls [67], and one not using controls at all [68]. Another paper found increased plasma and CSF alpha-hydroxybutyrate (a pre-diabetes marker) [69], and another reported insulin resistance (IR) in bvFTD [70].
In other words, almost anybody who has ever tested insulin function in ALS has found it to be impaired in patients not previously diagnosed with diabetes (at the group level). We can conclude that insulin is impaired in a significant subset of ALS patients.
In addition to these results, there are strong epidemiological data pointing to a link between ALS and DB. Studies examining whole-country registers in England, Sweden, Taiwan, and Denmark have shown that early DB (diagnosed before the age of 50 in Sweden and Denmark or 65 in Taiwan) is associated with increased ALS risk [71,72,73,74,75]. In addition, high HbA1c (indicating high blood glucose levels over a time period) is significantly associated with higher ALS mortality [76].
Indirect support for insulin impairment in ALS comes from BMI data. Low BMI is a known marker of severe insulin impairment (see also below), and pre-onset low BMI is strongly associated with increased risk [77,78,79,80,81,82,83,84,85].
These data might suggest that type-2 DB (DB2) would be associated with increased ALS risk. However, there is strong country, regional, and single clinic evidence that late age DB is associated with decreased ALS risk [72,74,75,86,87,88,89,90,91], delayed onset [85,92,93,94], and longer survival [92,93]. We explain this apparent paradox further below.
These results are generally not mentioned at all, or mentioned very little, in relation to ASL, both in reviews in leading forums [2,95,96], and even in reviews focusing on metabolism [97,98]. The vast majority of researchers and clinicians are thus probably not aware of these strong ALS-DB links and of insulin impairment in ALS.

Why Insulin Impairment Is Not Detected

We saw that explicit testing of insulin function in ALS points to an impairment. However, if this is the case, ALS patients should have been routinely diagnosed with late DB, which is not the case. How can this be explained?
Here I present a novel answer to this question: ALS involves excessive insulin-independent glucose uptake (IIGU), which in most patients masks their insulin problem. Since DB2 is normally discovered when blood glucose levels are abnormally high, when glucose levels seem normal, deeper tests of insulin function (e.g., OGTT) are usually not done.
Insulin induces glucose uptake mainly by stimulating the translocation of the Glut4 glucose transporter to the plasma membrane [99]. However, Glut4 translocation is also stimulated independently of insulin, including by AMPK [100], (nor)epinephrine [101,102], and calcium [103,104]. Contraction-induced glucose uptake is a major and well-known skeletal muscle mechanism [103], and so is glucose-induced uptake (‘glucose effectiveness’) [105]. Even calcium concentrations that are below the contraction threshold trigger glucose uptake [106]. Note that Glut4 expression is not limited to skeletal muscle but occurs in brain motor areas as well, including in MTNs [107,108].
Insulin-independent glucose uptake can be excessive in ALS due to several causes. As noted above, calcium overload is one of the major phenomena of ALS. AMPK is activated by ATP deficiency, which can in turn be induced by two of the major ALS phenomena, mitochondria dysfunction (since mitochondria normally produce most of the cell’s ATP) and calcium overload (since the plasma membrane and ER calcium pumps consume ATP [109]). A complete theory of ALS that explains why IIGU occurs is presented in a companion paper.
There is very strong evidence supporting this masked IIGU account. Hypermetabolism identified via FDG-PET clearly occurs in skeletal muscle and low brain motor areas in ALS [110,111,112,113,114,115]. When added to the widespread evidence for increased resting energy expenditure in ALS detected via indirect calorimetry (including in early-stage patients) [116,117,118,119,120,121,122,123], hypermetabolism is one of the major documented ALS phenomena. While indirect calorimetry does not point to a specific mechanism, FDG-PET directly points to excessive transporter-mediated glucose uptake. ALS patients also show cortical hypometabolism that correlates with gray matter atrophy [124,125,126], which may point to glucose deficiency due to excessive glucose uptake by the motor system. Frontal hypometabolism is also a core feature of FTD [127,128,129,130,131].
At least some of this excessive glucose uptake in ALS is insulin-independent, as shown by increased activated AMPK in patient MTNs [132,133], early increased sympathetic activity [134,135,136,137,138], and chronic intracellular MTN calcium [34,139]. The increased sympathetic activity in skeletal muscle is not correlated with ALS disability, duration, or prognosis, showing that it is a core characteristic of the disease [140,141]. In the large subset of patients with impaired insulin function, most of the excessive Glut4-mediated uptake would be insulin-independent.
The existence of a chronic energy consuming process in ALS is also supported by the fact that patients exhibit severe weight loss that is not fully accounted for by reduced food intake [142,143,144].
Readers might still wonder why such a gross dysregulation in glucose homeostasis is so commonly not detected. The answer has two parts here. Regarding hyperglycemia, IIGU is normally responsible for more than half of skeletal muscle glucose uptake [101], so excessive IIGU can mask partially or even fully impaired insulin. Regarding hypoglycemia, there are specific mechanisms to protect from it, counter-regulatory responses (CRRs). Our account implies that as long as insulin is partially functional, CRRs should be moderately hyperactivated. Indeed, all of the CRR components (sympathetic activation (cited above), growth hormone, glucagon, cortisol) are mildly increased in ALS [65,145,146,147,148,149]. Thus, the combination of excessive IIGU and CRRs makes glucose levels seem at around the normal range.

Why Insulin Is Impaired in ALS

The papers cited earlier reporting insulin impairment in ALS have raised various possible explanations for their results, including reduced glucose uptake by wasted skeletal muscle, physical inactivity inducing IR, stress opposition of insulin signaling via cortisol and (nor)epinephrine, and malnutrition (‘starvation diabetes’). However, it has also been acknowledged that these explanations cannot account for the overall pattern of results, which include reduced insulin secretion and receptor expression.
Moreover, these accounts do not address the relationship between ALS and DB1, and the strong association of low pre-onset BMI with increased risk. Since this datum applies for patients many years pre-onset, it is not due to post-onset muscle wasting, inactivity, stress or mulnutrition. In addition, ALS patients do not show hidden pre-onset muscle wasting or inactivity but rather the opposite, since ALS is associated with higher pre-onset physical capacity [77,84,150,151].
Here I propose a novel answer to this question: the core pathological processes that damage MTNs in ALS can also damage insulin secretion and/or signaling, directly or indirectly. As noted above, intracellular calcium toxicity is known to be a major underlying process in ALS. It is clearly possible that the impaired calcium-related proteins are expressed in beta cells, such that the harmful underlying processes occur also in beta cells1. Calcium is fundamental to beta cell function, where its acute entry via voltage-gated calcium channels triggers insulin secretion [99]. Hence, calcium toxicity can directly impair beta cells. In addition, chronic calcium can yield chronic insulin secertion, leading to hyperinsulinemia and IR that eventually damage beta cells.

Insulin Protection in ALS

  • Insulin should be protective in ALS. Insulin promotes glucose uptake and protein synthesis [99]. As part of these role, it streamlines cellular energy production and health in a variety of ways. It opposes oxidative stress by promoting GSH synthesis [152,153], opposes with GSH the apoptosis-promoting effects of H2O2 [154], acts as an anti-inflammatory agent in the immune system [155], promotes mitochondria health, oxidative phosphorylation, ATP production, and protein synthesis [156,157], promotes synaptic plasticity [158], and opposes calcium overload and toxicity [159,160,161,162,163,164,165,166]. Insulin promotes the production of N-Acetylglucosamine (GlcNAc) [167], whose use in O-GlcNAcylation decreases intracellular Ca2+ load [168], H2O2 production, and permeability pore opening [169]. The insulin-induced GSH inhibits stress-induced formation of stress granules [170], which are strongly associated with TDP-43 accumulation [33]. Conversely, chronic intracellular calcium [171,172] and mitochondria impairment [173,174] induce insulin resistance. Beta cell stress and IR are associated with unfolded proteins [175,176,177,178,179,180], permeability pore opening [181], and calcium toxicity [171,172,179,182,183,184]. In other words, insulin is an essential component of the stress compensatory mode, and its impairment may lead to decompensation.
In summary, insulin opposes all of the detrimental phenomena that clearly occur in ALS, and these in turn impair insulin signaling.
  • Insulin-based DB drugs are indeed protective in ALS. No clinical trials have been done using insulin therapy for ALS. However, several large studies (including all Medicare and a large Swedish population) have found that usage of DB drugs is specifically associated with decreased risk of developing ALS [185,186,187]. In an all-Taiwan study, moderate insulin use for DB was associated with decreased risk specifically for patients taking non-oral DB drugs [87].
A single clinical trial for ALS using a DB drug, pioglitazone, has been conducted (as an add-on to riluzole) [188]. No benefit has been shown, and the treatment may have even accelerated progression. Pioglitazone does not act directly on the insulin path. It reduces blood glucose levels (thereby sensitizing insulin) mainly by reducing glucose production by the liver, not via direct improvement of insulin signaling. Reducing liver glucose production is not a good strategy in ALS, because ALS cells need glucose for protein synthesis and for opposing oxidative stress, as explained above. Pioglitazone is known to be ineffective and possibly harmful in DB1, and what is harmful for DB1 is also harmful for ALS (see below).
  • Why DB2 is associated with decreased risk. DB2 involves reduced insulin function, so it could be expected to increase ALS risk. However, it is associated with reduced risk (see references above). There are three possible explanations to this apparent paradox.
First, DB2 is diagnosed when blood glucose is elevated. This normally indicates that insulin function is impaired, but it also indicates that insulin-independent glucose uptake, which is directly induced by the underlying disease processes, is not that excessive. In this account, DB2 is not protective per se, but reflects a reduced effect or risk of the core cause of ALS.
Second, the main pathophysiology in DB2 is IR. IR involves higher blood insulin, which, although promoting further IR, can also induce some insulin signaling, especially in initial or mild DB2. Although weak, this insulin signaling should be protective in ALS.
Finally, many DB2 patients are treated with insulin-based drugs (GLP-1 agonists or insulin itself), which should again oppose the core ALS mechanisms2. Here, it is DB2 treatment that opposes the development of ALS. Evidence supporting this account was cited above.
In the second and third accounts, insulin is directly protective in ALS.

Insulin Trajectories, DB1, and BMI in ALS

Insulin function normally decreases with aging [190,191], but in ALS, several trajectories are possible. The main factors that distinguish between the different scenarios is whether and when beta cell impairment and insulin hypersecretion occur. Here I discuss the possible lifetime trajectories of insulin in ALS and their effect on patient metabolism, body mass index (BMI), symptoms, and the association with DB1. This includes an account of why higher pre-onset BMI can be associated with both decreased and increased ALS risk.
A brief summary of insulin’s relationship with BMI is in order. Acute insulin promotes glucose uptake by the motor system, and quick insulin clearance from blood allows lipolysis and reduces lipogenesis. Conversely, chronic lower-grade insulin yields chronic insulin signaling, which channels more glucose towards visceral adipose tissue, opposes lipolysis, and promotes lipogenesis and higher BMI [189]. Severely impaired insulin secretion, or severe desensitization of insulin signaling by its prolonged hypersecretion, stronly impair lipogenesis and promote fat-based metabolism (which induces lipolysis) to compensate for cellular glucose deficiency. This results in lower BMI.
  • Normal secretion with late impairment. In the first scenario, insulin secretion capacity is not affected by the disease until it is normally reduced with aging. Since both insulin and IIGU promote glucose uptake, and since ALS involves excessive IIGU, overall pre-onset glucose uptake in this scenario should be higher, and glucose levels should be on the lower side. Indeed, in a large study in Sweden, ALS was associated with lower blood glucose from 20 years pre-onset to onset [192].
In this scenario, skeletal muscle and other cells uptake and utilize more glucose than they normally do, so less glucose is available for muscle and adipose tissue storage. Moreover, decreased blood glucose levels imply reduced insulin secretion even though secretion capacity is intact (as assumed in this scenario). Reduced secretion diminishes energy storage and stimulates fat-based energy production and lipolysis. As a result, the person is expected to be leaner than the average. Indeed, in both country-wide and single clinic studies, low pre-onset BMI was found to be strongly associated with increased ALS risk [77,78,79,80,81,82,83,84,85].
Here, the aging-related reduction in insulin (and possibly in other protective agents, e.g., steroids) is a trigger for the appearance of disease symptoms. Higher BMI is associated with decreased risk in these studies and with longer survival in a meta-analysis [193] because it indicates weaker core disease processes (as in the DB2 account), and because it is contrasted with low BMI, which is a characteristic of the present scenario.
  • Increased secretion with late impairment. In a second scenario, insulin secretion is chronically higher than normal most life. This can be ALS-independent, or driven by ALS processes (e.g., chronically high beta cell calcium). As explained above, this scenario eventually leads to both IR and impaired secretion, each of which can trigger the disease symptoms.
Unlike in the previous scenario, the chronically increased insulin secretion in the present one can induce higher pre-onset BMI and visceral fat. This accords with the Swabia cohort in which ALS was associated with high BMI 20 to 70 years pre-onset [194]. Moreover, a recent Michigan cohort was reported to show BMI gain 10-15 years pre-onset, followed by BMI loss 5 years pre-onset [195]. This is precisely the pattern predicted here: the initial BMI gain is due to chronic secretion possibly followed by mild IR, while the subsequent BMI loss is due to the collapse of insulin function and the core disease processes.
Body composition studies provide abundant evidence for this scenario in ALS. Reported results include increased visceral as opposed to subcutaneous fat at onset, even when total body fat is similar to controls [196], higher fat mass with lower fat-free mass [118], loss of lean mass and BMI and gain of fat mass with disease progression [197,198], and a lower/higher percentage of muscle/fat mass, respectively [199].
In this scenario, insulin impairment again seems to be the specific event that triggers the appearance of ALS symptoms.
In a third scenario, insulin secretion is increased as in the second scenario, but ALS symptoms appear before IR does. This is possible when the core problem or IR affect MTNs faster than they affect beta cells.
  • Early impairment (early DB, DB1). In a fourth scenario, insulin secretion is reduced at an early age, due to ALS processes or independently. In this case, the protection that insulin provides is not present, resulting in increased ALS risk. This explains increased ALS risk with early DB (cited above), which is usually insulin-dependent (DB1).
DB1 patients normally receive insulin treatment, which should delay ALS onset or maybe even prevent it altogether. There are two reasons why insulin does not always prevent the disease. First, it is notoriously difficult to balance insulin treatment, so patients commonly undergo episodes of low insulin levels, during which their cells are exposed to damage. This might be why in the all-Taiwan study cited above of ALS in DB [87], high insulin use, indicating a prolonged severe damage to insulin function, showed a non-significant association with increased risk.
Second, insulin treatment is calibrated by glucose levels, but due to the excessive IIGU in ALS, seemingly normal glucose levels do not indicate that a sufficient amount of glucose is used by the insulin path (which is essential for protein synthesis, opposing oxidative stress, etc.). In other words, these comorbid patients probably do not receive enough insulin, and their insulin treatment only brings them to a state similar to that of the first scenario.
  • No impairment. Finally, it is still possible for insulin secretion and signaling to be intact throughout life, including during disease appearance and initial progression. In this scenario, the disease is completely driven by its core causes and aging. For example, steroids also decline with aging, and are generally protective by reversing the aging-related increase in brain calcium currents [200]. However, since chronic intracellular calcium induces IR [171,172,179,201,202], this scenario is less likely than the other ones.
In summary, there are several possible patterns of insulin secretion, IR, glucose levels, and BMI in ALS. In the more likely scenarios, the impairment of insulin function is a direct trigger of disease symptoms. The severe weight loss shown in ALS is caused not only by dysphagia and energy-consuming core processes (see above), but also by strongly impaired insulin. This explains the association of low BMI and DB1 with increased risk, and that of high BMI with decreased risk. However, in a common scenario, impaired signaling can be preceded by chronically higher secretion, explaining why higher BMI can be associated also with increased risk.

Tests and Treatment

  • Therapy. There are several lines of ALS treatment implied by the analysis here, the main one being insulin-based DB drugs. Since insulin opposes the main ALS processes and its impairment is directly associated with the appearance of symptoms, insulin-based drugs might slow down disease progression. In MTNs whose axons have only started degenerating, treatment may even reverse the process.
The specific insulin-based treatment to be used depends on beta cell insulin secretion capacity. In cases where endogenous insulin secretion is possible (as in most DB2 patients), GLP-1 agonists are currently preferred over insulin, due to reduced risk of hypoglycemia [203]. However, if beta cells are already damaged to the extent that endogenous insulin secretion in meaningful amounts is not possible, exogenous insulin should be used.
To reduce hypoglycemia risk, therapy can be combined with a hypercaloric carb diet (HCD). Such a diet should have additional benefits in ALS, since additional glucose would relieve cellular stress, promote protein folding, and provide raw material for lipogenesis, countering the tissue wasting shown in ALS. Indeed, HCD (without insulin) showed better results than a control diet in a small ALS clinical trial [204].
  • Tests. Using insulin-based therapy for all ALS patients would require clinical trials and an approval process. However, such a therapy is already justified in patients with demonstrated insulin dysfunction. As part of ALS diagnosis, patients should undergo DB classification tests focusing on insulin function.
The simplest test is the oral glucose tolerance test, but there are several additional options (intravenous glucose, insulin or glucagon tolerance tests, with or without clamps). A highly informative test is a glucose clamp with somatostatin infusions to suppress endogenous insulin secretion [105]. This test isolates the insulin-independent component of glucose uptake, and can directly alert that it is excessive. Thus, it might be capable of identifying many of the cases where insulin secretion and insulin-stimulated glucose uptake are low but are still within the ‘normal’ range, along with seemingly normal glucose levels.
In many patients, the test results would show insulin impairment at levels standardly defined as DB or pre-DB, justifying DB therapy. In these cases, insulin-based rather than other DB drugs should be preferably used, because they are expected to have a greater benefit in ALS (see pioglitazone discussion above). Metformin reduces hepatic glucose production and thus alleviates IR, but it also activates AMPK [205], which might stimulate the excessive glucose uptake shown in ALS 3.
It is not clear whether patients showing increased insulin secretion at diagnosis (the third scenario above, where symptoms appear before insulin diminishes) should be treated with insulin. On one hand, they already have too much basal insulin. On the other hand, their current insulin levels have not managed to protect their MTNs (symptoms have already appeared), and exogenous insulin may both protect their MTNs and relieve the pressure off their beta cells.
It is reassuring that a systematic review has found no evidence of DB drugs being associated with higher ALS risk [207].
  • Other treatment. Insulin-based therapy can be combined with other drugs. Calcium channel blockers, which reduce calcium load, are associated with reduced ALS risk [186,187]. Clinical trials using nimodipine alone did not help in ALS [208,209], but daily oral use of verapamil, with insulin treatment, improved beta cell function in adult recent onset DB1 in a human phase II clinical trial [210]. Anti-oxidative stress agents such as the drugs currently approved for ALS might also help, but it is not clear that using them would be cost-effective.

Discussion

In this paper I analyzed the existing ALS literature to conclude that
  • Insulin opposes all of the salient pathophysiological phenomena identified in ALS, and these in turn oppose insulin signaling.
  • Insulin secretion and/or signaling have been found to be impaired in non-DB ALS in almost all of the studies that have explicitly tested for them.
  • Insulin impairment is usually not diagnosed, most likely because it is masked by excessive insulin-independent glucose uptake.
  • Different insulin impairment trajectories can explain why early/late DB are associated with increased/decreased risk of ALS, respectively, and the BMI data in ALS.
  • DB drugs including insulin-based therapy have been found to be protective in ALS in several large retrospective studies.
The analysis is supported by very strong existing evidence that is not recognized by most of the research and medical communities. This paper is the first to point to the wide extent of the problem, and provides novels accounts of the seeming paradoxical glucose and DB phenomena.
Insulin impairment is not the core cause of ALS, which is most likely calcium overload. However, insulin impairment strongly facilitates ALS and is a major trigger of ALS symptoms. Insulin-based therapy would not be able to reverse MTN death or total axonal degeneration, but it has a good chance of considerably slowing disease progression if started early enough.
Almost anybody who has ever examined insulin signaling in ALS has found that it is impaired at the group level. DB2, which involves higher blood insulin and in many cases insulin-based drugs, is associated with reduced risk. DB drugs have been independently found to be associated with reduced risk. These three data points alone, even without the new theoretical analysis presented here, justify DB screening tests in ALS patients, followed by DB treatment if positive.
All of the professional infrastructure for insulin-based therapy in ALS is already in place. The OGTT and other related tests are standard tests routinely administered in medical centers. If test results show that the patient has DB according to standard norms, treatment using DB drugs is fully justified. Treating patients for DB does not require new clinical trials, even if the analysis here shows that the treatment actually targets their ALS. The only non-standard recommendation made here is that treatment would not start with metformin or other non-insulin-based drugs (or life-style changes), but immediately with insulin-based therapy.
Whether insulin manages to help or not is an empirical question. ALS is diagnosed when the NMJ has accumulated enough damage to interfere with muscle function. It is possible that at this point, exogenous insulin cannot slow down the negative chronic processes within MTNs, which include mutually enforcing calcium toxicity, oxidative stress, inflammation, and the apoptosis arms of cellular stress responses. If it helps, it would probably help only patients who were diagnosed early enough.
Most of the evidence brought here is from sALS4. Although the etiologies of sALS and fALS are probably different, they show a converging pathophysiology. Thus, our conclusions may be applicable to fALS as well. This should be corroborated in future research.
The analysis here applies to FTD patients showing ALS symptoms, so at least to behavioral variant FTD. Unlike in ALS, the link between dementia and IR is well-known [211,212], to the extent that some forms of dementia are thought to be ‘type-3 diabetes’ [213]. FTD patients were specifically shown to have DB much more than controls [214]. Thus, insulin-based therapy is a natural direction in FTD.
The scenario in which insulin secretion is impaired early (the fourth one) explains comorbidity with DB1. It also raises the interesting possibility that at least some cases of DB1 have the same underlying cause as ALS, but do not show ALS symptoms because their insulin treatment is successful.
A companion paper presents a complete theory of ALS according to which ALS is an autoimmune disease that targets calcium channels. That paper also points to the precise protein whose impairment causes the disease. The presentation here only assumes that calcium toxicity is a major phenomenon in ALS (which is consensual) and is otherwise independent of that theory.
I hope that this paper will contribute to reducing the suffering of ALS patients and their families and caretakers.

Acknowledgments

I thank Professors Marc Gotkine (MBBS), Gil Leibowitz (MD), and Roger Kornberg for their helpful comments on a related paper draft, and Yair Safrai and Yoav Lorch for their continued support. Error and omissions, if present, are solely mine.

Conflicts of Interest

The author declares no conflicts of interest.

Abbreviations

ALS amyotrophic lateral sclerosis.
AMPK AMP-activated protein kinase.
ATP adenosine triphosphate.
BMI body mass index.
CRR counter-regulatory response.
CSF cerebrospinal fluid.
DB diabetes mellitus.
DB1, DB2 type 1, type 2 diabetes mellitus.
ER endoplasmic reticulum.
fALS familial ALS.
FDA food and drug administration.
FTD frontotemporal dementia.
GLP-1 glucagon-like peptide 1.
Glut4 glucose transporter type 4.
GSH glutathione.
H2O2 hydrogen peroxide.
HCD hypercaloric carb diet.
IIGU insulin-independent glucose uptake.
IR insulin resistance.
MTN motor neuron.
OGTT oral glucose tolerance test.
sALS sporadic ALS.
SOD superoxide dismutase.
TDP-43 TAR DNA-binding protein 43.

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1
A theory of ALS presented in a companion paper points to a specific calcium channel protein as the core cause of ALS, and this protein is indeed expressed in beta cells.
2
See below why this argument is less valid for DB1.
3
Metformin was also harmful to females in the SOD1 mouse ALS model [206].
4
Although it is possible that the early OGTT results had included some fALS patients.
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