Tagged: diabetes

Thyme to look east: Baicalein

 

Recently I wrote a post about research investigating an interesting compound called Epigallocatechin gallate (or EGCG – click here for that post). Several eagle-eyed readers, however, noted something interesting in the details of one of the research reports that was discussed in that post.

The study in question had used EGCG as a positive control for evaluating the ability of other compounds for their ability to inhibit the clustering of Parkinson’s-associated protein alpha synuclein.

But there was also a second positive control used in that study.

It is called baicalein.

In today’s post, we will discuss what baicalein is and what research has been done on it in the context of Parkinson’s.

 


Lake Baikal. Source: Audleytravel

Once upon a thyme, in a far away land, there was a mysterious little flowering plant.

The “far away land” was the southern parts of eastern Siberia.

And the flowering plant is Scutellaria baicalensis – which is more commonly referred to as Baikal skullcap.

What is Baikal skullcap?

Baikal skullcap is a perennial herb that is indigenous to Southern Siberia, China and Korea. For centuries, traditional Chinese medicine has used the dried roots – which is called huángqín (Chinese: 黄芩 or golden root) – for a variety of ailments.

Baikal skullcap. Source: Urbol

The plant grows to between 1-4 feet in height, with lance head-shaped leaves and blue-purple flowers. Baikal skullcap belongs to the same family of flowering plants (Lamiaceae) as thyme, basil, mint and rosemary.

For traditional Chinese medicinal use, the roots are usually collected in spring or autumn once the plant is more than 3-4 years old. They are dried and then used to treat hypertension, to reduce “fire and dampness”, and to treat prostate & breast cancers.

And one of the key constituents of Baikal skullcap (and huángqín) is a compound called baicalein.

What is baicalein?

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Monthly Research Review – April 2018

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during April 2018.

The post is divided into five parts based on the type of research (Basic biology, disease mechanism, clinical research, other news, and a new feature: Review articles/videos). 


So, what happened during April 2018?

In world news:

  • April 4–15th – The 2018 Commonwealth Games were held in Gold Coast, Queensland, Australia (New Zealand came 5th in the medals tally… not bragging, just saying).

Source: Vimeo

  • April 27th – Kim Jong-un crosses into South Korea to meet with President Moon Jae-in, becoming the first North Korean leader to cross the Demilitarised Zone since its creation in 1953. In initial small steps towards reconciliation, South Korea said it would remove loudspeakers that blare propaganda across the border, while North Korea said it would shift its clocks to align with its southern neighbour.

BFFs? Source: QZ

Source: Plus

  • And finally the city of Trier in Germany is already struggling to keep up with demand for ‘0-euro’ notes, bearing the face of its most famous son and communism’s creator Karl Marx. Sold for 3 euros each, the notes are part of celebrations for his 200th birthday (5th May 1818).

You get what you pay for. Source: DDR

In the world of Parkinson’s research, a great deal of new research and news was reported:

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Diabetes and Parkinson’s

A reader recently asked for an explanation of some recent research regarding diabetes and Parkinson’s.

You see, a significant proportion of the Parkinson’s community have glucose intolerance issues and some live with the added burden of diabetes. That said, the vast majority of diabetics do not develop PD. Likewise, the vast majority of people with Parkinson’s do not have a diagnosis of diabetes.

There does appear to be a curious relationship between Parkinson’s and diabetes, with some recent research suggests that this association can be detrimental to the course of the condition. 

In today’s post we will look at what what diabetes is, consider the associations with Parkinson’s, and we will discuss the new research findings.


Foreman and Ali. Source: Voanews

1974 was an amazing year.

On October 30th, the much-hyped heavyweight title match – the ‘Rumble in the Jungle’ – between George Foreman and Muhammad Ali took place in Kinshasa, Zaire (Democratic Republic of the Congo).

Stephen King. Source: VanityFair

A 26-year-old author named Stephen King published his debut novel, “Carrie” (April 5, with a first print-run of just 30,000 copies).

Lucy. Source: Youtube

The fossil remains of a 3.2 million years old hominid skeleton was discovered in Ethiopia (November 24th). It was named ‘Lucy’ – after the song “Lucy in the Sky with Diamonds” by The Beatles which was played repeatedly in the expedition camp the evening after the team’s first day of work on the site (Source).

And Richard Nixon becomes the first US president to resign from office (August 9th).

President Richard Nixon. Source: Fee

In addition to all of this, in December of 1974, a small study was published in the Journal of Chronic Diseases.

It dealt with Parkinson’s and it presented a rather startling set of findings:

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Reduce your RAGE as you AGE

An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.

Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditionsAGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.

RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant. 

In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.


The wonder of ageing. Source: Club-cleo

NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.


Ageing means different things to different people.

For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?

Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!

George Carlin. Source: Thethornycroftdiatribe

Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.

Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.

What do we know about the biology of ageing?

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Self monitoring: there’s something in your eye

Self tracking/monitoring has become a popular habit for the general population with the introduction of products like Fitbit and Apple watch.

It is particularly useful for groups like the Parkinson’s community though, who are tired of having just one hour per year of assessments with their neurologist.

In today’s post, we will look at some new tracking/monitoring technologies that are being developed that could have important implications for not only how we assess Parkinson’s disease, but also for how we treat it.



Homo deus. Source: RealClearLife

I have recently finished reading ‘Homo Deus‘ by Yuval Noah Harari – the excellent follow-up to his previous book ‘Sapiens‘ (which is an absolute MUST READ!). The more recent book provides an utterly fascinating explanation of how we have come to be where we will be in the future (if that makes any sense).

In the final few chapters, Harari discusses many of the technologies that are currently under development which will change the world we live in (with a lot of interesting and cautionary sections on artificial intelligence – the machines that will know vastly more about us than we know about ourselves).

Of particular interest in this part of the book was a section on the Google-Novartis smart lens.

What is the Google-Novartis smart lens?

In 2014, a company called Alcon, which is a wholly owned subsidiary of Novartis formed a collaboration with the Google offshoot Verily Life Sciences that would focus on developing smart lens.

The initial project is rather ambitious: develop and take to the clinic a glucose-sensing contact lens for people with diabetes. The idea has been particularly championed by Google founder Sergey Brin (a prominent figure within the Parkinson’s community with his significant contributions to Parkinson’s research each year).

People with diabetes have to keep pricking their finger over the course of a day in order to check the levels of insulin in their blood. A less laborious approach would be welcomed by the diabetic world (an estimated 415 million people living with diabetes in the world).

This is what the lens may eventually look like:

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DPP-4: Not a Star Wars character

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Dipeptidyl peptidase-4 (or DPP-4) is an enzyme that breaks down the protein (GLP-1) that stimulates insulin release in your body. 

Inhibitors of DPP-4 are used in the treatment of Type 2 diabetes, because they help increase insulin levels in the body.

Recently some Swedish researchers noticed something curious about DPP-4 inhibitors: They appear to reduce the risk of developing Parkinson’s disease.

In today’s post, we will review what DPP-4 inhibitors do and look at how this could be reducing the risk of Parkinson’s disease.


januvia

Sitagliptin. Source: Diabetesmedicine

Last year an interesting research report about a class of medications that could possibly reduce the risk of developing Parkinson’s disease was published in the journal Movement disorders:

SWeds

Title: Reduced incidence of Parkinson’s disease after dipeptidyl peptidase-4 inhibitors-A nationwide case-control study.
Authors: Svenningsson P, Wirdefeldt K, Yin L, Fang F, Markaki I, Efendic S, Ludvigsson JF.
Journal: Movement Disorders 2016 Jul 19.
PMID: 27431803

In this study, the investigators used the Swedish Patient Register, to find the medical records of 980 people who were diagnosed with Parkinson’s disease but also had type 2 diabetes. Importantly, all of the subjects had been treated with Type 2 diabetes medication for at least 6 months prior to the date of Parkinson’s being diagnosed.

For comparative sake, they selected 5 controls (non-Parkinsonian) with Type 2 diabetes (n = 4,900) for each of their Parkinsonian+diabetes subjects. They next looked at whether GLP-1R agonists (such as Exenatide), Dipeptidyl peptidase-4 (or DPP-4) inhibitors, or any other oral Type 2 diabetic medication can influence the incidence of Parkinson’s disease.

Now, if all things are considered equal, then when looking at each diabetes medication there should be 1 person in the Parkinson’s disease + Type 2 diabetes for every 5 people in the Type 2 diabetes control group taking each medication right? That is because there are almost 1000 people in the first group and 5000 in the second group.

But this is not what the researchers found.

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Exenatide: An editorial

editorial

In my previous post, we briefly reviewed the results of the phase II double-blind, randomised clinical trial of Exenatide in Parkinson’s disease. The study indicates a statistically significant effect on motor symptom scores after being treated with the drug.

Over the last few days, there have been many discussions about the results, what they mean for the Parkinson’s community, and where things go from here, which have led to further questions.

In this post I would like to address several matters that have arisen which I did not discuss in the previous post, but that I believe are important.


bydureon

I found out about the Exenatide announcement – via whispers online – on the afternoon of the release. And it was in a mad rush when I got home that night that I wrote up the post explaining what Exenatide is. I published the post the following evening however because I could not access the research report from home (seriously guys, biggest finding in a long time and it’s not OPEN ACCESS?!?!?) and I had to wait until I got to work the next day to actually view the publication.

I was not really happy with the rushed effort though and decided to follow up that post. In addition, there has been A LOT of discussion about the results over the weekend and I thought it might be good to bring aspects of those different discussion together here. The individual topics are listed below, in no particular order of importance:

1. Size of the effect

There are two considerations here.

Firstly, there have been many comments about the actual size of the effect in the results of the study itself. When people have taken a deeper look at the findings, they have come back with questions regarding those findings.

And second, there have also been some comments about the size of the effect that this result has already had on the Parkinson’s community, which has been considerable (and possibly disproportionate to the actual result).

The size of the effect in the results

The results of the study suggested that Exenatide had a positive effect on the motor-related symptoms of Parkinson’s over the course of the 60 week trial. This is what the published report says, it is also what all of the media headlines have said, and it sounds really great right?

The main point folks keep raising, however, is that the actual size of the positive effect is limited to just the motor features of Parkinson’s disease. If one ignores the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and focuses on the secondary measures, there isn’t much to talk about. In fact, there were no statistically significant differences in any of the secondary outcome measures. These included:

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Exenatide: One step closer to joblessness!

bydureon

The title of today’s post is written in jest – my job as a researcher scientist is to find a cure for Parkinson’s disease…which will ultimately make my job redundant! But all joking aside, today was a REALLY good day for the Parkinson’s community.

Last night (3rd August) at 23:30, a research report outlining the results of the Exenatide Phase II clinical trial for Parkinson’s disease was published on the Lancet website.

And the results of the study are good:while the motor symptoms of Parkinson’s disease subject taking the placebo drug proceeded to get worse over the study, the Exenatide treated individuals did not.

The study represents an important step forward for Parkinson’s disease research. In today’s post we will discuss what Exenatide is, what the results of the trial actually say, and where things go from here.


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Last night, the results of the Phase II clinical trial of Exenatide in Parkinson’s disease were published on the Lancet website. In the study, 62 people with Parkinson’s disease (average time since diagnosis was approximately 6 years) were randomly assigned to one of two groups, Exenatide or placebo (32 and 30 people, respectively). The participants were given their treatment once per week for 48 weeks (in addition to their usual medication) and then followed for another 12-weeks without Exenatide (or placebo) in what is called a ‘washout period’. Neither the participants nor the researchers knew who was receiving which treatment.

At the trial was completed (60 weeks post baseline), the off-medication motor scores (as measured by MDS-UPDRS) had improved by 1·0 points in the Exenatide group and worsened by 2·1 points in the placebo group, providing a statistically significant result (p=0·0318). As you can see in the graph below, placebo group increased their UPDRS motor score over time (indicating a worsening of motor symptoms), while Exenatide group (the blue bar) demonstrated improvements (or a lowering of motor score).

graph

Reduction in motor scores in Exenatide group. Source: Lancet

This is a tremendous result for Prof Thomas Foltynie and his team at University College London Institute of Neurology, and for the Michael J Fox Foundation for Parkinson’s Research who funded the trial. Not only do the results lay down the foundations for a novel range of future treatments for Parkinson’s disease, but they also validate the repurposing of clinically available drug for this condition.

In this post we will review what we know thus far. And to do that, let’s start at the very beginning with the obvious question:

So what is Exenatide?

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George H and Vascular Parkinsonism

george-hw-bush

During Super Bowl 51, ex-president George HW Bush was visibly wheel chair bound. He has in fact been using motorised scooters and wheelchairs since 2012.

His doctors have indicated that he suffers from Vascular Parkinsonism.

In today’s post we will discuss what Vascular Parkinsonism is and how it differs from Parkinson’s disease.


gettyimages-173500627

During a visit to the White house. Source: Heavy

An important concept to understand about the subject matter here:

Parkinsonism is a syndrome, while Parkinson’s is a disease.

A syndrome is a collection of symptoms that characterise a particular condition, while a disease is a pathophysiological response to internal or external factors. The term ‘Parkinsonism’ is an umbrella term that encompasses many conditions which share some of the symptoms of Parkinson’s disease.

There are many different types of Parkinsonism, such as:

  • Idiopathic Parkinson’s disease (the most common type of parkinsonism)
  • Progressive Supranuclear Palsy (PSP)
  • Corticobasal Degeneration (CBD)
  • Multiple System Atrophy (MSA)
  • Essential tremor
  • Vascular Parkinsonism
  • Drug-induced Parkinsonism
  • Dementia with Lewy bodies
  • Inherited Parkinson’s disease
  • Juvenile Parkinson’s disease

All of these conditions fall under the syndrome title of ‘Parkinsonism’, but are all considered distinct/separate diseases in themselves.

So what is Vascular Parkinsonism?

Vascular Parkinsonism was first described in 1929 by Dr Macdonald Critchley (King’s College Hospital, London).

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Macdonald Critchley. Source: Npgprints

vascularpd

Title: Arteriosclerotic Parkinsonism.
Author: Critchley, M.
Journal: Brain (1929) 52, 23–83
PMID: N/A                                (this article is accessible by clicking here)

It is estimated that approximately 3% to 6% of all cases of Parkinsonism may have a vascular cause. Vascular (or Arteriosclerotic) Parkinsonism is results from a series of small strokes in the basal ganglia area of the brain and can lead to the appearance of symptoms that look like Parkinson’s disease: slow movements, tremors, difficulty walking, and rigidity.

Walking problems are particularly prominent with Vascular Parkinsonism, as the lower half of the body is usually more affected than the upper half. Another sign of Vascular Parkinsonism can be a poor or no response to L-dopa treatment, as production of dopamine is not the problem. Using brain scanning techniques we can see that some people with Vascular Parkinsonism will have a normal Dopamine transporter (DAT) scan – which demonstrates appropriate levels of dopamine being released and reabsorbed in the striatum (the red-white areas in the image below).

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DAT-scan and MR images of 62-y-old male  with Vascular Parkinsonism (A) and 62-y-old male with Parkinson’s disease (B). Source: JNM

The brain scans above are from a person with Vascular Parkinsonism (A) and another person with Parkinson’s disease (B). Firstly, note the reduced levels of red-white areas in the image (B) – this reduction is due to less dopamine is being released and reabsorbed in the striatum in Parkinson’s disease (as there are less dopamine fibres present). Compare that with the relatively normal levels of red-white areas in the image (A), indicating normal levels of dopamine turnover (suggesting dopamine fibres are still present). Next, look at the black and white image in panel (A) and you will see a red arrow pointing at damaged areas (darkened regions) of the striatum – indicative of mini strokes. A dopamine receptor scan may show a reduction in the levels of dopamine receptors as a result of the strokes, meaning that the released dopamine will not be having much effect.

Do we know what can cause the strokes associated with Vascular Parkinsonism?

The symptoms of Vascular Parkinsonism tend to appear suddenly and generally do not progress, unlike Parkinson’s disease. We don’t know for sure what causes the mini strokes associated with Vascular Parkinsonism, and it probably varies from person to person, In general, however, doctors believe that high blood pressure and diabetes are the most likely causal factors (heart disease may also play a role).

What does it all mean?

Some people of Parkinson’s disease may actually have Vascular Parkinsonism, which can result from mini strokes in the basal ganglia region of the brain. They will usually be unresponsive to L-dopa and have more motor issues with their lower half of the body.

While Ex-President George HW Bush’s situation is extremely unfortunate, it reminds us that not all forms of Parkinsonism are Parkinson’s disease – an important factor to keep in mind when considering treatment regimes. We have posted this information here to make the Parkinson’s community more aware of this form of Parkinsonism. Later in the year we will discuss another form of Parkinsonism.


The banner for today’s post was sourced from Ew

A drug from Kalamazoo

diabetes60systemreview-1024x683

Last week a research report was published in the prestigious journal Science Translational Medicine (that means that it’s potentially really important stuff). The study involved a new drug that is being clinically tested for diabetes.

In last week’s study, however, the new drug demonstrated very positive effects in Parkinson’s disease.

In today’s post we will review the new study and discuss what it means for Parkinson’s.


Diabetic patient doing glucose level blood test

Diabetic checking blood sugar levels. Source: Gigaom

FACT:  One in every 19 people on this planet have diabetes (Source: DiabetesUK).

It is expected to affect one person in every 10 by 2040.

Diabetes (or ‘Diabetes mellitus’) is basically a group of metabolic diseases that share a common feature: high blood sugar (glucose) levels for a prolonged period. There are three types of diabetes:

  • Type 1, which involves the pancreas being unable to generate enough insulin. This is usually an early onset condition (during childhood) and is controlled with daily injections of insulin.
  • Type 2, which begins with cells failing to respond to insulin. This is a late/adult onset version of diabetes that is caused by excess weight and lack of exercise.
  • Type 3, occurs during 2-10% of all pregnancies, and is transient except in 5-10% of cases.

In all three cases inulin plays an important role.

What is insulin?

Insulin is a chemical (actually a hormone) that our body makes, which allows us to use sugar (‘glucose’) from the food that you eat.

Glucose is a great source of energy. After eating food, our body releases insulin which then attaches to cells and signals to those cells to absorb the sugar from our bloodstream. Without insulin, our cells have a hard time absorbing glucose. Think of insulin as a “key” which unlocks cells to allow sugar to enter the cell.

What does diabetes have to do with Parkinson’s disease?

So here’s the thing: 10–30% of people with Parkinson’s disease are glucose intolerant (some figures suggest the percentage may be as high as 50%).

Why?

We do not know.

Obviously, however, this ratio is well in excess of the 6% prevalence rate in the general public (Source:DiabetesUK). We have discussed the curious relationship between diabetes and Parkinson’s disease in a previous post (click here to read it).

And the relationship between Parkinson’s disease and diabetes is not a one way street: A recent analysis of 7 large population studies found that people with diabetes are almost 40% more likely to develop Parkinson’s disease that non-diabetic people (Click here for more on this).

EDITORIAL NOTE HERE: We would like to point out that just because a person may have diabetes, it does not necessarily mean that they will go on to develop Parkinson’s disease. There is simply a raised risk of developing the latter condition. It is good to be aware of these things, but please do not panic.

We have no idea why there is an association between diabetes and Parkinson’s disease, but each month new pieces of research are published that support the connection between Parkinson’s and diabetes, and this all provides encouraging support for an ongoing clinical trial (which we will discuss below).

So what research has been done?

Well, just this year alone there have been some interesting studies reported. The first piece of research deals with a drug that is used for treating type-2 diabetes:

Metformin

Title: Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons.
Author: Bayliss JA, Lemus MB, Santos VV, Deo M, Davies JS, Kemp BE, Elsworth JD, Andrews ZB.
Journal: PLoS One. 2016 Jul 28;11(7):e0159381.
PMID: 27467571       (This article is OPEN ACCESS if you would like to read it)

Metformin (also known as Glucophage) has been one of the most frequently prescribed drugs for the treatment of type 2 diabetes since 1958 in the UK and 1995 in the USA. The mechanism by which Metformin works is not entirely clear, but it does appear to increase the body’s ability to recognise insulin.

Metformin treatment has previously been found to be neuroprotective. The researchers in this study wanted to determine if a protein called ‘AMPK’ was involved in that neuroprotective effect. They generated cells that do not contain AMPK and grew dopamine neurons – the brain cells badly affected by Parkinson’s disease.

In both cell cultures and in mice, the researchers found that Metformin was neuroprotective both in normal conditions and in the absence of AMPK. The study could not explain how the neuroprotective potential of Metformin was working, but it adds to the accumulating pile of evidence that some diabetes treatments may be having very positive effects in Parkinson’s disease.

A second piece of research from early this year goes even further:

SWeds

Title: Reduced incidence of Parkinson’s disease after dipeptidyl peptidase-4 inhibitors-A nationwide case-control study.
Authors: Svenningsson P, Wirdefeldt K, Yin L, Fang F, Markaki I, Efendic S, Ludvigsson JF.
Journal: Movement Disorders 2016 Jul 19.
PMID: 27431803

Using the Swedish Patient Register, the researchers of this study identified 980 people with Parkinson’s disease who were also diagnosed with type 2 diabetes between July 1, 2008, and December 31, 2010. For comparative sake, they selected 5 controls (non-Parkinsonian) with type 2 diabetes (n = 4,900) for each of their Parkinsonian+diabetic subjects. Their analysis found a significant decrease in the incidence of Parkinson’s disease among individuals with a history of DPP-4 inhibitor intake.

DPP-4 inhibitors work by blocking the action of DPP-4, which is an enzyme that destroys the hormone incretin. Incretin helps the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. By blocking DPP-4, we are increasing the production of insulin.

Authors concluded that ‘clinical trials with DPP-4 inhibitors may be worthwhile’ in people with Parkinson’s disease.

So what was published last week?

Metabolic Solutions Development is a Kalamazoo (Michigan)-based company that is developing a new drug (MSDC-0160) to treat type 2 diabetes. Last week, Prof Patrik Brundin and colleagues from the Van Andel Institute in Grand Rapids published a research report that suggested MSDC-0160 may have very beneficial effects in Parkinson’s disease:

brundin-title

Title: Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease.
Authors: Ghosh A, Tyson T, George S, Hildebrandt EN, Steiner JA, Madaj Z, Schulz E, Machiela E, McDonald WG, Escobar Galvis ML, Kordower JH, Van Raamsdonk JM, Colca JR, Brundin P.
Journal: Sci Transl Med. 2016 Dec 7;8(368):368ra174.
PMID: 27928028

The drug from Kalamazoo, MSDC-0160, functions by reducing the activity of a recently identified protein that carries pyruvate into mitochondria.

What does this mean?

Pyruvate is a very important molecule in our body. The body can make glucose from pyruvate through a process called gluconeogenesis, which simply means production of new glucose. Thus, pyruvate is essential in providing cells with fuel to create energy (for more on pyruvate, click here for a good review article).

Pyruvate is carried into the power house of the cell – the mitochondria – by a protein called mitochondrial pyruvate carrier (MPC). The drug from Kalamazoo, MSDC-0160, is a blocker of MOC. It reduces the activity of MPC.

MPC also has other functions. It is known to be a key controller of certain cellular processes that influences mammalian target of rapamycin (mTOR) activation. mTOR responds to signals to nutrients, growth factors, and cellular energy status and controls the cells response. For example, insulin can signal to mTOR the status of glucose levels in the body. mTOR also deals with infectious or cellular stress-causing agents, thus it could be involved in a cells response to conditions like Parkinson’s disease.

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Things that activate mTOR. Source: Selfhacked

Given the interaction with mTOR, the researchers in Michigan hypothesised that MSDC-0160 might reduce the neurodegeneration of dopaminergic neurons in animal models of Parkinson’s disease.

And this is exactly what they found.

The researchers reported that MSDC-0160 protected dopamine neurons in a mouse model of Parkinson’s disease. It also protected human midbrain dopamine neurons grown in cell culture when they were exposed to a toxic chemical. In addition, it demonstrated neuroprotective effects in a worm (called Caenorhabditis elegans) that produces a lot of the parkinson’s related protein alpha synuclein. MSDC-0160 even slowed the cell loss observed in a genetically engineered mouse that exhibits a slow loss of dopamine neurons. Basically, treatment with MSDC-0160 protected the cells from whatever the researcher threw at them.

How did it do this?

The researchers found that MSDC-0160 was reducing mTOR activity and also initiating a process called autophagy (which is the garbage disposal system of the cell). By kick starting the rubbish removal system, the cells were healthier. In addition, treatment with MSDC-0160 resulted in less inflammation – or activation of the immune system – in the brain.

Sounds very interesting. When do clinical trials start?

We’re not sure. They will most likely be in the planning stages though. If MSDC-0160 is approved for diabetes, it will be easier to have it approved for Parkinson’s disease as well.

Other diabetes drugs, however, are currently being tested in clinical trials for Parkinson’s disease. Of particular interest is Exenatide, which is just finishing a placebo-controlled, double blind phase 2 clinical trial. We are expecting the results for that trial early next year. Previous clinical studies suggested very positive results for Exenatide:

 

diabetes

Title: Exenatide and the treatment of patients with Parkinson’s disease.
Authors: Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T.
Journal: J Clin Invest. 2013 Jun;123(6):2730-6.
PMID: 23728174     (This study is OPEN ACCESS if you would like to read it)

The researchers running this clinical study gave Exenatide to a group of 21 patients with moderate Parkinson’s disease and evaluated their progress over a 14 month period (comparing them to 24 control subjects with Parkinson’s disease). Exenatide was well tolerated by the participants, although there was some weight loss reported amongst many of the subjects (one subject could not complete the study due to weight loss). Importantly, Exenatide-treated patients demonstrated improvements in their clinician assessed PD ratings, while the control patients continued to decline. Interestingly, in a two year follow up study – which was conducted 12 months after the patients stopped receiving  Exenatide – the researchers found that patients previously exposed to Exenatide demonstrated a significant improvement (based on a blind assessment) in their motor features when compared to the control subjects involved in the study.

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Exenatide. Source: Diatribe

The results of that initial clinical study were intriguing and exciting, but it is important to remember that the study was open-label: the subjects knew that they were receiving the drug. This means that we can not discount the placebo effect causing some of the beneficial effects reported.

And Exenatide is not the only diabetes drug being tested

Pioglitazone is another licensed diabetes drug that is now being tested in Parkinson’s disease. It reduces insulin resistance by increasing the sensitivity of cells to insulin. Pioglitazone has been shown to offer protection in animal models of Parkinson’s disease (click here and here for more on this). And the drug is currently being tested in a clinical trial.

So what does it all mean?

People with diabetes appear to be more vulnerable than the general population to developing Parkinson’s disease, and many people with Parkinson’s disease have glucose processing issues. It would be very interesting to better understand the link between Parkinson’s disease and diabetes. Why is it that so many people with Parkinson’s disease are glucose intolerant? And why do so many people with diabetes go on to develop Parkinson’s? Answering either of these questions might provide further insight into how both conditions function. And given that drugs associated with one appear to help with the other only strengthens the curious association.

As mentioned above, 2017 will bring the results of Exenatide clinical trial, upon which a lot of hope is riding. If it provides positive benefits, then we will finally have a treatment that can slow the progression of the disease. In addition, we will be able to delve more deeply into how Exenatide is causing it’s effect. Positive outcomes for Exenatide will also open the flood gates for many of the other clinically approved diabetes medications which could be trialled on people with Parkinson’s disease.

So despite how you may be feeling about 2017 (based on the events of 2016), we here at the SoPD believe that there is a lot to look forward to in the new year.


The banner for today’s post was sourced from Diabetes60systems