Insulin is a peptide hormone produced by beta cells in the islets of Langerhans, which comprise the endocrine pancreas. Unlike most other hormones, which directly or indirectly elevate blood glucose, insulin is one of the few hormones that lowers blood sugar levels in addition to promoting anabolism of amino acids into proteins and free fatty acids into storage as triacylglycerol.
The main trigger for insulin release is a rise in blood glucose, which occurs minutes to hours after a meal (depending on whether or not the food contained a significant amount of simple sugar). The beta cells that manufacture insulin sense blood sugar levels via a receptor called GLUT-2 (Glucose Transporter-2).
When blood glucose exceeds a certain concentration (approx.120 mg/dL in normoglycemic people), the GLUT-2 receptors transport glucose inside the beta cell, leading to a burst of ATP production. This spike in ATP leads to the closure of potassium (K+ ) channels and opening of calcium (Ca++) channels, resulting in the depolarization of the beta cell membrane and exocytosis of insulin in a manner analogous to neurotransmitter release from a neuron following an action potential.
As with all endocrine glands, the beta cells release insulin directly into the bloodstream, where it acts on numerous tissues, esp. the liver, skeletal muscle, and adipose (fat) tissue. Insulin remains active for 15-30 minutes, after which most is degraded by cells in the liver and kidneys.
Insulin’s mechanism of action was not understood until recently, and elucidating the effects of this hormone remains an intense area of research. Like other peptide hormones, insulin cannot cross cell membranes so it must exert its effects by binding to a cell surface receptor. The insulin receptor is known as a receptor tyrosine kinase (RTK). It is a homodimeric protein, meaning it consists of two identical subunits.
When insulin binds to its receptor, the two subunits move close together and several tyrosine residues on each subunit become phosphorylated. At this point, the RTK is activated. In this activated state, the RTK adds phosphate groups to nearby proteins including one called Insulin Receptor Substrate (IRS). Somehow, the phosphorylated form of IRS induces the movement of glucose transport channels (e.g. GLUT-3, GLUT-4) to the cell surface. This allows the liver hepatocytes, skeletal muscle cells, adipocytes, etc. to take up glucose from the extracellular fluid and utilize it for energy.
Insulin’s effects on protein and fat metabolism are also anabolic, but the signal transduction pathways involved are less well understood. There is a time delay of several hours between insulin binding to a target cell and an increase in protein or lipid synthesis. This suggests that insulin’s long term effects involve alterations in gene transcription. Changes in gene expression may occur via several pathways, including PKA/CREB, Ras/MAP Kinase, PI3 Kinase and others.
Deranged glucose metabolism, in the form of the disease diabetes mellitus (DM), is a leading cause of morbidity and mortality in the industrialized world today. The hallmark symptoms of diabetes include malaise, fatigue, polydypsia (excessive thirst), polyphagia (excessive hunger), and polyuria (excessive urination, sometimes in excess of two gallons of urine in a day).
The complications of untreated diabetes are well known: retinopathy leading to blindness; neuropathy and gangrene of the extremities, a general susceptibility to infections; poor wound healing; and kidney failure.
Traditionally, diabetes was classified as Type I/Insulin dependent/Juvenile onset DM vs. Type II/Non-insulin dependent/Adult onset DM. Although the usefulness of this scheme has been called into question, it remains helpful in understanding the onset and progression of most cases of diabetes.
Type I diabetes is believed to be an autoimmune disease, in which the beta islet cells are destroyed, leading to an absolute insulin deficiency. Type I DM represents about 10% of all diabetes cases. Most cases occur sporadically, meaning they do not show a clear hereditary pattern. Most Type I DM patients come to medical attention by adolescence. For unclear reasons, the incidence of Type I DM is on the rise in many countries in the world.
A life threatening complication in people with Type I DM is a condition called Diabetic Ketoacidosis (DKA). In DKA, the body acts as though it were starving in the midst of plenty. Although blood glucose levels may exceed 500 mg/dL, the liver converts proteins into acetoacetate and B-hydroxybutyrate, collectively known as ketone bodies. This metabolic pathway normally kicks in during periods of prolonged starvation. Out of control production of ketone bodies overwhelms the body’s ability to maintain blood pH at 7.4. The person’s blood turns acidic, leading to nausea, vomiting, and sometimes seizures and coma. Untreated DKA is generally fatal.
The treatment for Type I DM is insulin injections, which have become more manageable thanks to the development of Lantus insulin, administered once a day. Future therapies are likely to involve islet cell transplants and creation of durable islet cells from stem cell progenitors.
In contrast to Type I DM, patients with Type II DM tend to be overweight adults who also suffer from high blood pressure and high cholesterol. Type II DM is not caused by insufficient insulin production; rather, it results from end organ insensitivity to insulin. Basically, the liver, muscles, and fat tissue ignore insulin and fail to take up blood glucose.
A life threatening complication in Type II diabetics is called non-ketotic hyperosmolar coma. NKHC occurs due to a combination of physiological stress and lack of access to water. Blood glucose levels may exceed 1000 mg/dL, and the person becomes progressively dehydrated until s/he slips into a coma.
Treatment of early stage Type II DM consists of one or more oral medications. Over time, 25% or more of Type II diabetics require insulin injectiuons.
An especially effective drug in managing Type II DM is metformin (Glucophage), which decreases glucose production in the liver. Other drugs, e.g. the sulfonylureas, act as secretagogues that promote insulin release from the pancreas. Still other drugs such as acarbose block glucose uptake in the small intestine.
In the 1990’s a new class of diabetes drugs came on the market. These were the thiazolidinediones (TZDs) which act as insulin sensitizers in the liver and other tissues. Unfortunately two of these drugs, rezulin and avandia, were linked to liver failure and heart attacks, respectively, and ultimately withdrawn from the market. One TZD called actos remains on the market, but, predictably, its use has declined.
