Targeting insulin at the liver where it should be – Hepatocyte-Delivered Vesicle for Insulin

Targeting insulin at the liver where it should be – Hepatocyte-Delivered Vesicle for Insulin
Targeting insulin at the liver where it should be – Hepatocyte-Delivered Vesicle for Insulin

Whilst we are on the subject of novel diabetes treatments, I recently came across Hepatocyte Directed Vesicle Insulin from Diasome, and this one is a really exciting, watch this space treatment for me as it’s a really interesting idea and would, in theory allow injectable insulin to function more effectively, and remove things like the pizza effect. But I may be a bit of a Diabetes Tech nerd…


Firstly a bit of background. As most people know, in a normal, functioning human, Insulin is formed in the pancreas and delivered directly into the hepatic portal vein which means that the majority of the action is undertaken on the Liver in terms of managing glucose, as per the slide below. Note that all slides are taken from an interview with Robert Geho, from Diasome, which came up with HDV.

In insulin dependent diabetics, this isn’t the case and almost no insulin reaches the Liver. Given  normal biomechanics, this seems wrong, and yet, as his slide says, exogenous insulin focuses on glucose uptake in the muscle. That’s why Diasome has been researching a mechanism to get at least some of the insulin to the liver. It should have an impact on post-prandial blood glucose levels.

Diasome came up with HDV, but what is it? It is described in the patent as “This invention is a chemically structured delivery system for targeting drugs , hormones, biologicals or diagnostic materials to the hepatocyte. [liver cell]“.

It is basically a specifically tuned liposome that binds to insulin with a molecule in the outer layer that causes the body to recognise that the payload (insulin) is aimed at liver cells (hepatocytes). Once the targeted molecule reaches the liver in the blood, the liver cells extract the insulin and use it directly. Effectively, it is protected from use by the rest of the body by doing this. The HDV-modified insulin used in trials had a concentration of 99% free insulin, 1% HDV-bound insulin.

The idea is that HDV is mixed with a phial of insulin once, and then does its magic.

What are the effects of HDV when used with Insulin?

In the trials undertaken on dogs by Diasome, the glucose response to an oral glucose tolerance test showed an interesting response:

Astonishingly, the glucose response in the Diabetic dogs treated with regular insulin and added HDV (HDV-I) was almost the same as that of a non-diabetic dog (the green and red lines on the chart above).

In addition, the overall glycaemic control improved:

The stand out point for me from this slide is the massive reduction in the number of Hypoglycemic events that were noted. I understand that this is due to the liver, now receiving more insulin, building up a larger store of glycogen and therefore being able to react to blood glucose levels dropping more effectively. The other interesting factor is the reduction in mean daily plasma levels, by about 100 points, or in UK terms 5.5mmol/l. That would show up in your Hba1C result!

But this is all dogs. What about Humans? There is some available data for Humans, although the Phase II data isn’t so easily accessible:

Once again, this is very interesting. The glucose test that was undertaken was the same as you’d see from a GP, but the interesting factor for me was the response of the HDV-I versus the regular insulin without HDV. remember, the insulin is the same in both cases, one just has HDV added.

The increase in blood glucose with regular insulin was around 140mg/dl (7.8mmol/l) whereas with the HDV modified insulin, it was roughly 90 mg/dl (5 mmol/l). It is making the glucose extraction in the body roughly 36% more efficient. And that’s massive.

What does this mean?

There are a couple of takeaways from these phase II trials. The first is that by engaging the liver, it seems that exogenous insulin can be made much more efficient, leading to a requirement for much less insulin. This is probably for two reasons. The first is that it allows the liver to store glycogen. The second is that, by enabling the insulin to reach the liver, it allows the insulin to block the effects of glucagon. 
For me though, it’s the implications of the second that are much greater. Theoretically, if there is more insulin having an effect on the liver directly events like the Pizza Effect and Chinese Meal Effect could become a thing of the past, as glucagon action on the liver should be reduced. It’s a very exciting thing to see.

When can I get it?

Not yet, unfortunately. HDV-I has the go-ahead from the FDA for Phase 3 trials, and these typically take a good 12 months to complete. The are also working with the Joslin Foundation, so we can expect some more news from that area. The current status is:
 It’s looking interesting on both the injected and oral front. Based on the usual process for these types of work, we’re probably looking at a minimum of two years before this is available on the market, if all the trials go successfully. And that will be an interesting spot in two years. If anyone at Diasome is reading, I’d be very interested in any UK phase three trials that take place!
And best of all, Diasome is not a public company, which means there are no short selling sharks out there needing to somehow depress the share price to make a killing.

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