Protective Properties Of GLP-1 And Associated Peptide Hormones in Neurodegenerative Disorders Part 1

Type 2 diabetes mellitus and the associated desensitisation of insulin signalling has been identified as a risk factor for progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and others. 

Diabetes is a chronic disease that has adverse effects on our physical health. However, many people do not know that diabetes can also affect our memory. According to research, people with diabetes often experience symptoms of memory loss.

However, this does not mean that diabetes is the culprit for memory loss. On the contrary, if we take appropriate preventive measures in time, diabetes will not become an obstacle that limits memory. For example, maintaining a good blood sugar level can help slow down the rate of memory loss. At the same time, we can also protect our brain function by exercising and maintaining a healthy lifestyle and eating habits.

It is important to remember that even if we are diagnosed with diabetes, we must not lose faith and courage in life. We can still make changes to keep our bodies and brains healthy. Therefore, let us deal with diabetes with a positive attitude, take control of our health, and continue to live a healthy, happy and fulfilling life. It can be seen that we need to improve our memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc., which can promote brain health in many ways.

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Glucagon-like peptide 1 (GLP-1) is a hormone that has growth factor-like and neuroprotective properties. Several clinical trials have been conducted, testing GLP-1 receptor agonists in patients with Alzheimer's disease, Parkinson's disease or diabetes-induced memory impairments. 

The trials showed clear improvements in Alzheimer's disease, Parkinson's disease and diabetic patients. Glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) is the 'sister' incretin hormone of GLP-1. 

GIP analogues have shown neuroprotective effects in animal models of disease and can improve the effects of GLP-1. Novel dual GLP-1/GIP receptor agonists have been developed that can enter the brain at an enhanced rate. 

The improved neuroprotective effects of these drugs suggest that they are superior to single GLP-1 receptor agonists and could provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients.

LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary).

KEYWORDS

Alzheimer's, brain, epilepsy, incretins, inflammation, Parkinson's, stroke.

1 | INTRODUCTION

Type 2 diabetes mellitus is one of the risk factors for neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. 

Numerous patient cohort studies have demonstrated that people with type 2 diabetes mellitus are at a much higher risk of developing Alzheimer's disease (Akimoto et al., 2020; An et al., 2018; Kellar & Craft, 2020; Liu, Hu, et al., 2015) or Parkinson's disease (Athauda & Foltynie, 2016; Hu et al., 2007; Kuan et al., 2017; Rhee et al., 2020; Sergi et al., 2019; Svenningsson et al., 2016) later on in life. 

As one of the drivers behind this observation, impaired insulin signalling in the brains of people with Alzheimer's disease or Parkinson's disease has been identified (Athauda & Foltynie, 2016; Cheong et al., 2020; Craft, 2005; Freiherr et al., 2013; Hölscher, 2011; Moroo et al., 1994; Steen et al., 2005; Talbot et al., 2012). 

As early as the 1970s, Hoyer and colleagues described impaired glucose metabolism and energy turnover as a key feature of Alzheimer's disease, but it had been ignored as the finding did not fit in with the amyloid hypothesis that dominated Alzheimer's disease research until recently (Hoyer, 1998, 2004; Hoyer et al., 1988). 

Importantly, insulin-signalling impairments in the brain have also been described in people who do not have type 2 diabetes mellitus (Craft, 2005; Steen et al., 2005; Talbot, 2014). 

An important driver of insulin desensitisation in these cases is most likely the chronic inflammation response that is always present in the brains of people with Alzheimer's disease (Akiyama et al., 2000; Clark & Vissel, 2014), Parkinson's disease (Hirsch & Hunot, 2009; Tansey & Goldberg, 2010), stroke (Endres et al., 2008), epilepsy (Varvel et al., 2016), Huntington chorea (Ghasemi, Dargahi, et al., 2013) and others. 

During the chronic inflammation response, microglia will release pro-inflammatory cytokines, which downregulate growth factor signalling (Clark et al., 2012; Hölscher, 2020b; Santos & Ferreira, 2018). 

In the brain, insulin acts as a growth factor and is critical for energy metabolism, gene expression, cell growth, cell repair, synaptic activity, inhibition of apoptosis and other key processes that keep neurons healthy and functional (Frolich et al., 1999; Ghasemi, Haeri, et al., 2013; Hölscher, 2014; Schubert et al., 2003; Talbot et al., 2012). 

It is therefore easy to see why continuous impairment of insulin signalling in the brain will increase the risk for developing neurodegenerative disorders.

2 | NASAL APPLICATION OF INSULIN IMPROVES SYMPTOMS IN ALZHEIMER'S DISEASE

To test the hypothesis that normalising insulin signalling in the brain has beneficial effects in the brain in Alzheimer's disease, Craft and colleagues conducted a series of clinical trials in which patients were given insulin via a nasal spray (Kellar & Craft, 2020). 

The rationale behind this is that it is not possible to give insulin i.v. or subcutaneously (s.c.) to non-diabetic people, which would reduce peripheral glucose levels and cause a hypoglycaemic shock. 

To avoid this, the insulin is applied by a nasal spray and enters the brain via nasal epithelia with little reaching the peripheral bloodstream (Freiherr et al., 2013). 

A range of pilot studies consistently showed that insulin or long-acting insulin analogues improve memory, cognition and uptake of glucose in the brain as shown by 18FDG-PET imaging, reduced Alzheimer's disease biomarkers in the central nervous system and more (Freiherr et al., 2013; Hölscher, 2020a; Kellar & Craft, 2020). 

For example, in a 4-monthlong placebo-controlled trial of 104 patients with mild to moderate Alzheimer's disease patients, intra-nasal treatment with 20 IU of insulin daily improved memory and both doses of insulin (20 and 40 IU) preserved general cognition as assessed by the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) score and functional abilities as assessed by the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. 

The decrease in 18FDG-PET uptake in brain scans seen in placebo-treated patients over time was not visible in the drug-treated patients. Two months after drug treatment had stopped, the improvements in memory were still present (Craft et al., 2012). 

Biochemical analyses of exosomes that originate from the brain showed that in patients treated with 20 IU insulin, biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were improved and showed strong positive correlations with ADAS-Cog changes (Mustapic et al., 2019). 

This result is a proof of concept that overcoming insulin resistance in the brain does indeed reduce disease progression in Alzheimer's disease and that this is a viable target for research.

3 | INSULIN SIGNALLING IS IMPAIRED IN THE BRAINS OF PARKINSON'S DISEASE PATIENTS

Type 2 diabetes has been identified as a risk factor for Parkinson's disease, too. A large-scale cohort analysis of patient databases showed that the presence of diabetes increased the risk of Parkinson's disease regardless of co-morbidities such as cardiovascular, cerebrovascular and chronic kidney diseases (Rhee et al., 2020). 

In a meta-analysis of available studies, it was found that type 2 diabetes mellitus can increase progression and likelihood of developing motor and cognitive impairments (Chohan et al., 2021) (see also Cheong et al., 2020; Sergi et al., 2019). 

The analysis of exosomes derived from the brain demonstrated impaired insulin signalling and treatment with exendin-4 improved this (Athauda et al., 2019). 

Measurements of insulin desensitisation in brain tissue showed that in the striatum of Parkinson's disease brains, insulin signalling was found to be impaired (Talbot, 2021). 

Importantly, a pilot study testing the effects of nasally applied insulin in Parkinson's disease patients showed improvement in Parkinson's disease severity as measured by the modified Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale (UPDRS)- Motor (Part III) tests (Novak et al., 2019).

4 | ARE ALL DRUGS THAT ARE SENSITTO IVE INSULIN SIGNALLING NEUROPROTECTIVE?

Treating Alzheimer's disease patients with insulin is not a sensible approach as it can enhance insulin desensitisation and eventually accelerate Alzheimer's disease disease progression. 

A clinical trial using nasal insulin did show worsening of disease progression in a subgroup, indicating that there is a threshold after which insulin no longer improves disease progression (Claxton et al., 2015). 

In addition, studies of cohorts of patients taking different medications for treating type 2 diabetes mellitus showed that prolonged use of insulin increased the risk of developing Alzheimer's disease (Bohlken et al., 2018). This effect mirrors the observations made in type 2 diabetes mellitus patients who are treated with insulin. Prolonged treatment will eventually lead to insulin desensitisation (Dailey, 2007). 

Different drugs to treat type 2 diabetes mellitus that can improve insulin sensitivity are on the market. Metformin is a widely prescribed drug that has been tested for its potential to reduce the risk of developing Alzheimer's disease. 

The results from preclinical studies are mixed (Hölscher, 2020b) and a Phase II clinical trial that tested metformin in Alzheimer's disease patients showed no improvement (Luchsinger et al., 2016). 

Another very popular and effective drug class is the glucagon-like peptide 1 (GLP-1) receptor agonist group that currently has several different drugs on the market for the treatment of type 2 diabetes mellitus (Dhillon, 2018; Müller et al., 2019; Schmidt et al., 2014). 

Activating the GLP-1 receptor can desensitise insulin signalling (Campbell & Drucker, 2013; Hölscher, 2019; Long-Smith et al., 2013; Madsbad et al., 2011; Zhou et al., 2019). 

In addition, GLP-1 analogues do not affect blood glucose levels in normoglycemic people (Wadden et al., 2013) and therefore can be safely given to non-diabetic patients with chronic neurodegenerative disorders.

5 | GLUCAGON-LIKE PROTEIN 1

GLP-1 is a peptide hormone containing 30–31 amino acids. It plays important physiological signalling roles to control cell metabolism and energy utilisation (Baggio & Drucker, 2007). The G-protein-coupled GLP-1 receptor belongs to the Class B receptor family. 

The other receptors for glucagon, the GLP-2 receptor and the glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) receptor belong to the same group. 

Agonist binding to the receptor activates an adenylyl cyclase, increases IP3 levels and activates the associated classic growth factor second messenger signalling pathways (see Figure 1) (Baggio & Drucker, 2007; Doyle & Egan, 2007; Hölscher, 2020a). The GLP-1 receptor is expressed on neurons and found in most areas of the brain, indicating that GLP-1 plays a key signalling role (Cork et al., 2015; Darsalia et al., 2012, 2013; During et al., 2003; Graham et al., 2020; Hamilton & Holscher, 2009; Lee et al., 2011; Li et al., 2009; Merchenthaler et al., 1999; Mora et al., 1992; Teramoto et al., 2011). 

The receptor is normally not expressed in glial cells at a high level, but receptor densities increase after an inflammation response is triggered in the brain, indicating that it plays a role in controlling inflammation (Chowen et al., 1999; Lee et al., 2011; Ohshima et al., 2015). GLP-1 is expressed in glial cells and has anti-inflammatory properties. 

GLP-1 is considered to be an anti-inflammatory cytokine and reduces the release of pro-inflammatory cytokines (Iwai et al., 2006; Kappe et al., 2012). 

In patients with type 2 diabetes mellitus, the GLP-1 mimetic exendin-4 (exenatide) reduced levels of reactive oxygen species (ROS) and nuclear factor-κB (NF-κB) and the mRNA expression of the pro-inflammatory cytokines TNF-α and IL-1ß in mononuclear cells in the blood (Chaudhuri et al., 2012).

FIGURE 1 GLP-1 and GIP-induced second messenger cell signalling pathways, which control energy utilisation, mitogenesis, mitophagy, gene expression, autophagy, inhibition of apoptosis, modulation of ion channels, cell growth and repair and the cellular response to oxidative stress. Neuronal function and synaptic activity as well as the inflammation response by microglia is influenced by these processes. 

Adapted from (Hölscher, 2018). Abbreviations: GLP-1R, glucagon-like peptide 1 receptor; GIPR, glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide receptor; PKA, protein kinase A; PLC, phospholipase C; PI3K, phosphoinositide 3 kinase; PKB, protein kinase B; AC, adenylate cyclase; EPAC, exchange proteins directly activated by cAMP; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; ERK, extracellular signal-regulated kinase; CREB, cyclic AMP response element binding protein; P90RSK, ribosomal S6 kinase; PPAR, peroxisome proliferator-activated receptor family; MEK1/2, MAPK or ERK kinases; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1-α; c-Raf, rapidly accelerated fibrosarcoma (Raf) proto-oncogene serine/threonine-protein kinase Mcl1, myeloid cell leukaemia protein-1; Casp-9, caspase 9; Casp-3, caspase 3; Bax, Bik, Bcl2-interacting killer.

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