Insulin

Insulin

insulin

Insulin is synthesised in humans and other mammals within the beta cells (B-cells) of the islets of Langerhans in the pancreas. Within the islets of Langerhans, beta cells constitute 60-80% of all the cells.

Insulin is built from 51 amino acids and is one of the smallest proteins known. Beef (bovine) insulin differs from human insulin in two amino acid residues, and pork insulin in one residue. Fish insulin is also close enough to human insulin to be effective. Insulin is produced as a prohormone molecule (pro-insulin), that is later transformed into the active hormone.

Insulin is the primary effector in carbohydrate homeostasis (blood sugar regulation); it specifically catalyses glucose into glycogen. However, insulin also takes part in the metabolism of fat (triglycerides) and proteins. It has very anabolic properties; it is quoted as being the most anabolic hormone known for a human. Glucagon has the opposite effect to insulin; it turns glycogen into glucose.

Two types of tissues are most strongly influenced by insulin: muscle cells (myocytes) and fat cells (adipocytes). Myocytes are important because of their central role in movement, breathing, circulation, etc, and adipocytes because they accumulate excess calories against future needs (give you a “fuel tank”). Together, they account for about 2/3 of all cells in a typical human body.

Insulin and Diabetes Mellitus
Insulin is used medically in some forms of diabetes mellitus. Patients with Type 1 diabetes mellitus depend on exogenous insulin (injected subcutaneously) for their survival because of an absolute deficiency of the hormone; patients with Type 2 diabetes mellitus have either relatively low insulin production or insulin resistance, and occasionally require insulin administration if other medications are inadequate in controlling blood glucose levels.

Summary of the Actions of Insulin on Cells
1) Increased glycogen synthesis: insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen. Lowered levels of insulin cause liver cells to convert glycogen to glucose and dump it into the blood; hence “homeostasis” (regulation of blood sugar).

2) Increased fatty acid synthesis: insulin forces fat cells to take in glucose which is converted to fatty acids. Lack of insulin causes the reverse

3) Increased esterification of fatty acids: forces adipose tissue to make fats (ie, triglycerides) from fatty acid esters. Lack of insulin causes the reverse

4) Decreased proteinolysis: forces reduction of protein degradation. Lack of insulin increases protein degradation. So, one can appreciate how important insulin is if attempting to build muscle or conserve muscle tissue.

5) Decreased lipolysis: forces reduction in conversion of fat cell lipid stores into blood fatty acids. Lack of insulin causes the reverse.

6) Decreased gluconeogenesis: decreases production of glucose from various substrates in liver. Lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.

7) Increased amino acid uptake: forces cells to absorb circulating amino acids. Lack of insulin inhibits absorption. Again, one can appreciate how important insulin is if attempting to build muscle or conserve muscle tissue.

8) Increased potassium uptake: forces cells to absorb serum potassium. Lack of insulin inhibits absorption.

9) Arterial muscle tone: forces arterial wall muscle to relax increasing blood flow, especially in “micro arteries”. Lack of insulin reduces flow by allowing these arterial wall muscles to contract.

Genetics
Both Type 1 and Type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by infection, stress, or environmental factors (e.g. exposure to a causative agent). There is a genetic element in the susceptibility of individuals to some of these triggers which has been traced to particular HLA genotypes (i.e. genetic ‘self’ identifiers used by the immune system). However, even in those who have inherited the susceptibility, Type 1 diabetes mellitus seems to require an environmental trigger.

There is an even stronger inheritance pattern for Type 2 diabetes; those with Type 2 ancestors or relatives have very much higher chances of developing Type 2. It is also often connected to obesity, which is found in approximately 85% of (North American) patients diagnosed with that form of the disease, so inheriting a tendency toward obesity seems also to contribute. Age is also thought to be a contributing factor, as most Type 2 patients in the past were older. The exact reasons for these connections are unknown.

Regulatory Action on Blood Glucose
Human blood glucose levels normally remain within a narrow range. In most humans this varies from person to person from about 70 mg/dl to 110 mg/dl. After eating, especially if eating high glycemic index foods, your blood sugar level increases. Conversely, prolonged periods of not eating cause stored glucose (glycogen) to be released into bloodstream. This homeostatic process is the result of many factors, but hormone regulation is the most important.

There are two groups of hormones affecting blood glucose levels:
1) Hyperglycemic hormones (such as glucagon, growth hormone, and adrenaline), which increase blood glucose level

2) A hypoglycemic hormone, insulin, which as you’ll have learned by now, decreases blood glucose level.

It is far less dangerous to have too much glucose in the blood than too little. Mechanisms which restore too low blood glucose (hypoglycemia) must be quick and effective because of serious consequences of insufficient glucose.

Beta cells in the islets of Langerhans are sensitive to variations in blood glucose levels because of the presence of glucokinase, which responds to glucose concentrations. If that level increases, more insulin from beta cell stores is released into the blood, and beta cell insulin production increases. When the glucose level comes down to its normal level, insulin release slows or stops. And, before the level of glucose drops dangerously low, hyperglycemic hormones come into play, forcing release of glucose into the blood from cellular stores.

The Brain and Hypoglycemia
Though other cells can use other fuels for a while (most prominently fatty acids), neurons are dependent on glucose as a source of energy in the non-starving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue, and they have very small internal stores of glycogen. Thus, a sufficiently low glucose level first and most dramatically manifests itself in impaired functioning of the central nervous system; dizziness, speech problems, even loss of consciousness, are common. This phenomenon is known as hypoglycemia or, in cases producing unconsciousness, hypoglycemic coma (insulin shock).

Causes of hypoglycemia include:
1) oral hypoglycemic agents (eg, sulfonylureas, or similar drugs) which increase insulin release from beta cells in response to a particular blood glucose level)

2) external insulin (usually injected subcutaneously).

Considerations when using Insulin:
There are several difficulties with the use of insulin, both as a clinical treatment for diabetes and for those choosing to use it to increase mass/performance (which is more common than perhaps people realise):

1) method of administration
2) selecting the ‘right’ dose and timing
3) selecting an appropriate insulin preparation (typically on ‘speed of onset and duration of action’ grounds)
4) adjusting dosage and timing to fit food amounts and types
5) adjusting dosage and timing to fit exercise undertaken
6) adjusting dosage, type, and timing to fit other conditions as for instance the increased stress of illness

Diabetics (and those choosing to use it) give themselves insulin, usually via subcutaneously hypodermic injection. This is both non-physiologic (the pancreas releases insulin (and C-peptide) gradually into the portal vein instead of subcutaneously) and simply a nuisance for patients to inject themselves once or several times a day. Also, it is dangerous in case of mistake (especially too much insulin)

Unlike many medicines, insulin cannot (yet) be taken orally. It is treated in the gastrointestinal tract precisely as any other protein; that is, reduced to its amino acid components ( so all insulin activity is lost). There are research efforts underway to develop methods of protecting insulin from the digestive tract so that it can be taken orally; Inhaled insulin is under active investigation as are several other techniques.

Insulin Types
Medical preparations of insulin (Eli Lilly and Novo Nordisk or from any other) are never just ‘insulin in water’. Clinical insulins are specially prepared mixtures of insulin plus other substances. These delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on. Some recent insulins are not even precisely insulin, but so called insulin analogues. The insulin molecule in an insulin analogue is slightly modified so that they are: 1) absorbed rapidly enough to mimic real beta cell insulin (Lilly’s ‘lispro’ and Novo Nordisk’s ‘aspart’). 2) steadily absorbed after injection, instead of having a ‘peak’ followed by a more or less rapid decline in insulin action all while retaining insulin action in the human body.

The management of choosing insulin type and dosage/timing should be done by an experienced medical professional.

Exapmles of Insulins
The following semi-comprehensive list gives examples of the different types of insulin availiable.

Product Manufacturer Form

Rapid acting (onset less than 15 minutes)
Humalog (insulin lispro) Lilly Human
Humalog Cartridge (3 ml and 1.5 ml) Lilly Human
Humalog Prefilled Pen (3 ml, packets of 5) Lilly Human
NovoLog PenFill (insulin aspart) (3 ml) Novo Nordisk Human
NovoLog (insulin aspart) Novo Nordisk Human

Short acting (onset 0.5–2 hours)
Humulin R (regular) Lilly Human
Iletin II Regular Lilly Pork
Novolin R (regular) Novo Nordisk Human
Novolin R PenFill (3 ml) Novo Nordisk Human
Novolin R (regular) Novo Nordisk Human

Intermediate acting (onset 2–4 hours)
Humulin L (lente) Lilly Human
Humulin N (NPH) Lilly Human
Humulin N Prefilled Pen (3 ml, 5 pack) Lilly Human
Iletin II NPH Lilly Pork
Novolin L (lente) Novo Nordisk Human
Novolin N (NPH) Novo Nordisk Human
Novolin N PenFill (3 ml) Novo Nordisk Human
Novolin N (NPH) Novo Nordisk Human

Long acting
Humulin U (ultralente) (onset 4–6 hours) Lilly Human
Lantus (insulin glargine) (onset 1.1 hours) Aventis Human

Mixtures
Humulin 50/50 Lilly Human
Humulin 70/30 Lilly Human
Humulin 70/30 Prefilled Pen Lilly Human
Humalog Mix 75/25 Lilly Human
Humalog Mix 75/25 Prefilled Pen Lilly Human
Novolin 70/30 Novo Nordisk Human
Novolin 70/30 PenFill Novo Nordisk Human
NovoLog Mix 70/30 Novo Nordisk Human
Novolin 70/30 Novo Nordisk Human