Pulsatile insulin, sometimes called metabolic activation therapy, or cellular activation therapy describes in a literal sense the intravenous injection of insulin in pulses versus continuous infusions. Injection of insulin in pulses mimics the physiological secretions of insulin by the pancreas into the portal vein which then drains into the liver. In healthy, non-diabetic individuals, pancreatic secretions of insulin correspond to the intake of food. The pancreas will secrete variable amounts of insulin based upon the amount of food consumed (basically speaking, the more food that is consumed, the more insulin the pancreas will secrete) among other factors. The majority of available experimental evidence suggests a more potent hypoglycemic effect of pulsatile insulin in comparison to continuous insulin infusion. Continuous exposure to insulin and glucagon is known to decrease the hormones’ metabolic effectiveness on glucose production in humans due to the body developing an increased tolerance to the hormones. Down-regulation at the cellular level may partially explain the decreased action of steady-state levels of insulin, while pulsatile hormone secretion may allow recovery of receptor affinity and numbers for insulin. Intermittent intravenous insulin administration with peaks of insulin concentrations may enhance suppression of gluconeogenesis and reduce hepatic glucose production.
Dr. Thomas Aoki, former Head of Metabolism Research at the Joslin Diabetes Center in Boston, Massachusetts, and a former Professor of Medicine at the University of California, Davis, was the pioneer of using pulsatile insulin in the treatment of diabetes. Dr. Aoki’s work focused on the role of liver dysfunction in diabetic metabolism. He theorized that end organ damage in diabetes is caused by abnormal hepatic glucose metabolism, inadequate insulin delivery, and insulin resistance. His approach consisted of an ever-increasing baseline of insulin using Respiratory Quotient to determine the efficiency of treatment (US Patent 4,826,810). The treatment has now been changed from the Aoki approach and made to work more effectively. There are a number of clinics currently using a modified approach to achieve normalized carbohydrate metabolism levels, with patients from many clinics receiving outcomes which are not expected with other therapies. By Administrative Law Determination, following a lengthy trial, the State of California CalPers was ordered to pay for the treatment as it was adjudicated not to be experimental, investigational and was medically necessary for those patients who appealed. That order was not appealed and became final. In addition, CMS was also ordered to pay (Florida appeal).
Pulsatile Insulin and the Liver
Normally, insulin is secreted from the pancreas in pulses into the portal vein which brings blood into the liver in variable amounts, closely related to ingestion of meals. For induction and maintenance of insulin-dependent enzymes essential for glucose metabolism in the liver (e.g. hepatic glucokinase, phosphofructokinase, and pyruvate kinase), the hepatocytes require a defined insulin level (200-500 µU/ml in the portal vein) concomitant with high glucose levels (which acts as a bimolecular signal). In non-diabetic subjects, portal insulin concentrations are twofold to threefold greater than those in the peripheral circulation. During the first pass through the liver, 50% of the insulin is removed, strongly insinuating that the liver is the principal metabolic target organ of the gastrointestinal tract and the pancreas. The insulin retained by the hepatocytes may itself be essential for the long-term effects of insulin on hepatic glucose metabolism as well as growth and de novo enzyme synthesis. Following oral glucose intake, the liver accounts for an equal or greater portion of total net glucose uptake compared to the periphery. Insulin exerts pivotal control of glucose levels through its ability to regulate hepatic glucose production directly or indirectly. The traditional subcutaneous (S.C.) insulin administration regimens used by diabetic patients a) fails to capture the pulsatile nature of natural insulin secretion and b) does not reach high enough insulin concentrations at the hepatocyte level (e.g., 10 U regular insulin injected S.C. produce a peak systemic circulation concentration of 30-40 µU/ml and an even lower portal vein concentration of 15-20 µU/ml).
Reviews on efficacy
The body of information on this approach is increasing greatly. There is some disagreement about whether this therapy benefits patients. Some insurers refuse to cover the treatment. Several literature reviews by insurers conclude that there is insufficient evidence of efficacy.
To date, there are no treating physicians or clinic personnel who do not assert significant beneficial outcomes from the treatment, particularly as it has now been improved. The detractors are criticized as not having first hand information, and base their opposition on insufficient data.
A number of insurance company reviews have claimed that there are no physiologic benefit from pulsatile delivery. However, none of these insurance company claims have ever gone to hearing before an impartial reviewer, and recently, there now exists virtual unity of agreement from all clinical trials and reviewing papers citing pulsed or burst insulin, that burst insulin delivery mimics normal pancreatic insulin.
In every hearing and cases where a judge has heard evidence, insurance companies have been ordered to pay for that patient. For example, a trial with CalPERS resulted in a decision ordering Blue Cross and other insurance providers to pay for the therapy as to those parties. There has never been a hearing where the patient was not successful in requiring payment.
- "Hepatic Activation Therapy". Anthem Blue Cross. Retrieved 6 July 2010.
- "Clinical Policy Bulletin: Intermittent Intravenous Insulin Therapy". Aetna. Retrieved 6 July 2010.
- "Outpatient Intravenous Insulin Therapy (OIVIT)". Blue Regence. Retrieved 6 July 2010.
- "Intermittent Intravenous Insulin Therapy". UnitedHealthcare. Retrieved 28 April 2011.
- Grubert, J. M. (1 August 2005). "Impact of continuous and pulsatile insulin delivery on net hepatic glucose uptake". AJP: Endocrinology and Metabolism 289 (2): E232–E240. doi:10.1152/ajpendo.00567.2004.
- Courtney, CH; Atkinson, AB; Ennis, CN; Sheridan, B; Bell, PM (August 2003). "Comparison of the priming effects of pulsatile and continuous insulin delivery on insulin action in man.". Metabolism: clinical and experimental 52 (8): 1050–5. doi:10.1016/s0026-0495(03)00156-2. PMID 12898472.