The Physiology and Clinical Pharmacology of Insulin in Relation to its Application in Insulin Potentiation Therapy     <Back to Articles page.>

        by SGA, M.D.   Unpublished article, 1990.  52 references.

Following is a brief summary by Chris Duffield.  
The original article resides on Dr. SGA's website.

Roles of insulin in the cell.  Insulin affects transport of glucose and other substances across cell membranes in many kinds of cells in many different tissues.  Substances for which  transport is regulated include some amino acids and fatty acids, potassium and magnesium, and some monosaccharides.  Insulin also mediates cell formation of macromolecules with many cell functions, and stimulates lipogenesis, proteogenesis, glycogenolysis, and nucleic acid synthesis, glucose oxidation, and magnesium-activated sodium-potassium ATPase mechanisms.  

Insulin receptor .  General description of receptor structure and function.   When insulin binds to the receptor, the combined complex is endocytosed (pulled inward) into the cell where insulin and/or receptor stimulate cellular events.

Blood glucose lowering appears to be regulated by insulin-stimulated deployment of glucose transport proteins to the cell surface.

Insulin receptors are found in most cells and cell types.  More are found in some cancer cells, and some such cells secrete their own insulin.  This could be a way for cancer cells to  stimulate their own growth and use glucose at the expense of healthy cells.

Insulin receptors are found on the blood-brain barrier (BBB) and glial cells.  The BBB has a different system for glucose transport, which up- or down-regulates to counter chronic hypoglycemia or hyperglycemia.  Insulin receptors, as well as similar receptors for insulin-like growth factors I and II and other factors, may be for transporting these molecules into the brain for action on brain cells.  The roles of insulin in brain function are still poorly understood.

Insulin can potentiate the actions of drugs in tissues, such as the brain, that have insulin receptors.  This effect is probably due to increased transport of the drugs across membranes.  Such increased transport was demonstrated in an experiment [by Dr. SGA] showing a 33 percent increase in accumulation of radiolabeled AZT in rats prepared with insulin.  

The mechanisms for this drug transport are unclear.  One possibility is by receptor-mediated endocytosis, demonstrated in experiments in human muscle cells, human lymphocytes, and rat fibroblasts, where the drug or peptide is bound to insulin.  But the transport also increases for free, unbound drugs.

Some cancer cells, especially of breast and colon, have more insulin receptors than normal cells.  This could increase transport of drugs like methotrexate into the cells, perhaps explaining the huge increase of toxicity of methotrexate observed in breast cancer cell cultures in the presence of insulin.

Insulin may also affect lipid metabolism, resulting in increased cell membrane fluidity and permeability to drugs.

By increasing transport of drugs into cells, insulin potentiation can allow drugs to be given in lower doses, for increased safety and effectiveness.

Insulin and IGF-I work together to promote cancer cell growth, the latter stimulating growth and the former stimulating fuel availability.  Insulin can also stimulate growth by cross-reacting with IGF-I receoptors, which, like insulin receptors, are more concentrated on many cancer cells.  It could be that insulin given in IPT recruits cancer cells into the S-phase of the cell growth cycle, in which they are more sensitive to anticancer drugs.  Normal cells, with fewer receptors, may absorb less drug and may be less likely to be in S-phase, thus being relatively spared the toxic effects.

Insulin-induced hypoglycemia in IPT:  Typical insulin dose is 0.1-0.4 U/kg body weight, given as a single bolus IV.  0.4 U/kg is the most common dose; lower doses are for people who are more sensitive to the effects of insulin.  Preferred insulin is Humalog (Lilly), for faster action and faster recovery.  Other insulins work slower but just as well.  Close observation of the patient is important for safety during IPT.

Insulin-induced hypoglycemia triggers counterregulation mechanisms, including release of glucagon, epinephrine, growth hormone, cortisol, and norepinephrine.  Glucagon most strongly restores glucose level, with some help from epinephrine.  Cortisol, growth hormone, and norepinephrine do not have this effect.

Patients with type I diabetes, decreased cortisol secretion, or taking beta blocker medication may overreact to insulin, and should be started at 0.1U/kg insulin dose, increasing by 0.05 U/kg with each treatment until the appropriate level of response is reached.

Experience shows that during IPT, hypoglycemic symptoms begin about 25 to 30 minutes after insulin injection IV.  Treatment timing should be based on symptoms, not the clock.  Symptoms can include sweating and tachycardia.  At this point, drugs are administered, followed by 25  cc of 50 percent hypertonic glucose IV.

Safety.  Such glucose injection has been found to consistently end hypoglycemia and avoid any dangerous symptoms of deeper hypoglycemia.  With an IV tube attached, glucose can be quickly administered if a patient has a fast or deep reaction to insulin.

Glucometer readings taken before insulin, at the appropriate level of hypoglycemic symptoms, and after recovery show  typical values of 80-100, 35-40, and 80-100 mg%, respectively.

CNS reactions to hypoglycemia may vary depending on the habitual glucose level in the patient's blood, due to the level of expression of the insulin-dependent glucose transport protein expressed on the BBB.  Patients with undiagnosed or poorly controlled type II diabetes may have stronger hypoglycemic symptoms for a given level of blood sugar.