Pulsatile insulin
Pulsatile insulin describes in a literal sense the 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. Aokis 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 U/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 U/ml and an even lower portal vein concentration of 15-20 U/ml).
A relative deficiency of insulin at the hepatocyte level leads to an impaired capacity to process incoming dietary glucose. With the liver functioning as the target organ of the pancreas, it can be concluded that the purpose of giving pulsatile insulin to a diabetic patient should not be limited to the control of blood glucose levels but rather the normalization of hepatic metabolism. Furthermore, these same hepatic enzymes are found in all glucose-utilizing bodily systems, suggesting a synchronous effect by insulin and glucose.
It has been shown that the diabetic patients capacity to oxidize and store exogenous carbohydrates is markedly impaired. In the resting, post-absorptive, non-diabetic subject, the energy requirement is met primarily through fat oxidation reflected by indirect calorimetry in the form of a respiratory quotient (RQ), (volume CO2 /volume O2) of 0.7-0.8. After glucose administration, CO2 production and consequently the RQ increases to a range of 0.9-1.0, indicating that glucose has become the primary source of energy. Conversely, in the patient with diabetes mellitus on conventional insulin therapy, no such increase in RQ or CO2 production is observed after glucose administration. 
The possible fates of ingested glucose are a) oxidation (liver, brain, muscle), b) conversion to fat (liver, muscle, adipose tissue), c) storage as glycogen (liver, muscle), or d) transamination of intermediary metabolites to form amino acids (e.g. alanine). Only the first two processes generate the CO2 requisite for an increase in the RQ. Liver and muscle appear to be the most active tissues for glucose oxidation. In 1985, Meistas, et al, showed in non-diabetic post-absorptive men that resting muscle is not the source of the increased CO2 production after ingestion of a 100-gram glucose meal.
It is postulated that if hepatic activation was achieved and maintained in patients with diabetes through treatment with pulsatile insulin, that the frequency of hypoglycemic reactions should decrease.

# Bibliography
1. Vinik AI, Mehrabyan A, Diabetic Neuropathies, Med Clin N Am 88:947-999, 2004.
2. Koury CB, ADA Releases Diabetic Neuropathies Statement, Diabetic Microvascular Complications Today, 2:18-20, 2005.
3. Vinik AI, Emley MS, Megerian JT, Gozani SN, Median and Ulnar Nerve Conduction Measurements with the Symptoms of Diabetic Peripheral Neuropathy Using the NC-Stat System, Diabetes Technology and Therapeuticss, 6; 816-24, 2004.
4. Zinman LH, Bril V, Perkins BA, Cooling Detection Thresholds in the Assessment of Diabetic Sensory Polyneuropathy, Diabetes Care 27:1674-79, 2004.
5. Curtis BM, O Keefe JH, Autonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight, Mayo Clin Proc 77: 45-54, 2002.