Update on insulin

Sissinghurst, June 2012

Another outing to the local Diabetes UK group, with its primary focus on fundraising and unfriendliness. It turns out that the positive interaction in the last meeting was an aberration caused by the lack of a speaker - this time they were back on form, and completely ignoring me once more. I am tempted to write to the Chair just to let them know how off-putting their meetings are to someone who's not one of their particular friends.

The reason I attended (and didn't leave) was because the speaker was the doctor who had previously provided the update on treatments for Type 2 Diabetes a year ago. This time his subject was insulin, and here is what I learned.

Just to recap - insulin is a protein, constructed from two crosslinked peptides made of 51 amino acids. It is secreted by the pancreas into the bloodstream, stimulated by glucose from digested food, and transported along with the glucose to liver, muscle, and fat cells. Insulin is the facilitator, the key to the door that allows glucose to enter the cell and to fuel metabolism. As an aside, nerve and brain cells also use glucose as fuel, but they don't need insulin to facilitate entry.

Insulin has some other functions in the body, as well as allowing the uptake of blood sugar. It inhibits the breakdown of fat in adipose tissue, stimulates the uptake of amino acids that form the protein in our bodies, and also stimulates the passage of potassium from the blood into cells. It is an anabolic hormone.

The diagnosis of Diabetes Mellitus relies on measurement of blood sugar being above a particular threshold, which could be for a number of reasons. In Type 1 Diabetes, blood sugar is high because the pancreas has stopped producing insulin, so there is none in the bloodstream, and the circulating glucose therefore can't be admitted to cells. For Type 2 Diabetes, blood sugar is high because despite the presence of insulin in the bloodstream (sometimes large amounts of insulin), the cells have become resistant to its action. After a period of time, people with Type 2 Diabetes sometimes stop producing enough insulin, and then will need insulin injections. People with Type 1 Diabetes generally need insulin injections immediately on diagnosis.

So the main substance of the short lecture was all about types of insulin. There are two main types: Human and Analogue. In the past, bovine and porcine insulin was sourced from the pancreases of animals, but very few people use these now. Since the invention of genetic manipulation techniques, insulin that is indistinguishable from human insulin is made by bacteria - this, obviously, is Human insulin, and its peak of action is within 6 to 8 hours from injection (Actrapid, Humulin S).

Real human insulin secreted by a pancreas into the bloodstream acts within 30 minutes - the different profile of the same molecule when injected is due to that mode of delivery - into subcutaneous fat, which delays things a great deal. For this reason, the insulin molecule has been tinkered with to create Analogue insulin, which has a slightly different sequence of amino acids, or has had additional atoms or strings of atoms attached to it, to change its action profile. Short acting Analogue insulin can work within 2 to 4 hours (Novorapid, Humalog, Apidra), which is nearer the profile of pancreatic insulin (but still slower than the real stuff).

The aim with all these developments in injectable insulin is to try to mimic the action of insulin secreted by the pancreas in the non-diabetic person. As well as the spurt of insulin that is triggered by carbohydrate being turned into blood glucose, there is a particular profile to the way that the supply of insulin tails off after a meal, and also a background trickle of insulin that is released into the bloodstream steadily for 24 hours a day. For this reason, other insulins have been developed. The first product combined insulin with zinc. Six insulin molecules grouped around the zinc atom forming a hexamer, and slowed the release of insulin to provide a longer-lasting hit. Nowadays, this is achieved by the addition of protamine, and these medium-acting insulins are called Isophane or NPH insulins (Insulatard, Humulin I).

There are also pre-mixed insulins, both Human (Humilin M3) and Analogue (Novomix 30, Humalog Mix 25 and Humalog Mix 50) that contain some short- and some medium-acting insulin. The number indicates the proportion of short-acting (25, 30 or 50%) to long-acting (75, 70 or 50%) insulin. And to replicate the trickle of background insulin, two analogue insulins have dominated the market for some time (Lantus/Glargine, Detemir/Levemir). Neither is perfect, they still have mild peaks of action rather than being flat through the day, and Levemir doesn't quite last 24 hours so some people have to inject it twice a day.

The speaker also brought news of new developments not yet available. There is a new insulin (Linjeta) that may act almost as quickly as human insulin by including EDTA, which binds to zinc and prevents the formation of the hexamer, allowing the insulin to diffuse into the bloodstream more quickly. [At this point I asked why zinc was included at all, and the speaker thought it was necessary to ensure the stability of the product in storage before injection.] Another new insulin (Degludec) is hoped to provide the desired flat profile of background insulin by attaching a fatty acid side chain to the insulin. And a third development (Insupatch) is intended to speed up the release of insulin for people using insulin pumps by including a small heating element around the cannula, which increases the blood flow through the insulin-containing area of subcutaneous fat.

I'll have to go to the next local meeting, unfortunately, because being pre-Christmas, the speaker is a Dietitian. I'm not yet sure whether I'll mention the unfriendly nature of the meetings to any of the committee, of whom there are several present, wearing badges. They show no more inclination to talk to me than anyone else in the room.