Pulsatile insulin

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.

Background

Dr. Thomas Aoki, former Head of Metabolism Research at the Joslin Diabetes Center in Boston, Massachusetts, and a current 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.

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).

Controversy about efficacy

There is disagreement about whether this therapy benefits patients. Many insurers refuse to cover the treatment. Several literature reviews by insurers conclude that there is no evidence of efficacy.^{[1][2][3] [4]}

A number of investigators have found no physiologic benefit from pulsatile delivery.^{[5] [6]}

In some cases, 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.

Notes

1. ^ "Hepatic Activation Therapy". Anthem Blue Cross. http://www.anthem.com/medicalpolicies/policies/mp_pw_a050507.htm. Retrieved 6 July 2010. 
2. ^ "Clinical Policy Bulletin: Intermittent Intravenous Insulin Therapy". Aetna. http://www.aetna.com/cpb/medical/data/700_799/0742.html. Retrieved 6 July 2010. 
3. ^ "Outpatient Intravenous Insulin Therapy (OIVIT)". Blue Regence. http://blue.regence.com/trgmedpol/medicine/med96.html. Retrieved 6 July 2010. 
4. ^ "Intermittent Intravenous Insulin Therapy". UnitedHealthcare. https://www.oxhp.com/secure/policy/intermittent_iv_insulin_therapy_411.html. Retrieved 28 April 2011. 
5. ^ 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. 
6. ^ Courtney, CH; Atkinson, AB, Ennis, CN, Sheridan, B, Bell, PM (2003 Aug). "Comparison of the priming effects of pulsatile and continuous insulin delivery on insulin action in man.". Metabolism: clinical and experimental 52 (8): 1050–5. PMID 12898472.