Pulsatile Insulin
Encyclopedia
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.
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.
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).
A number of investigators have found no physiologic benefit from pulsatile delivery.
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.
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
in pulses versus continuous infusions. Injection of insulin in pulses mimics the physiological secretions of insulin by the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
into the portal vein which then drains into the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. 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
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
is known to decrease the hormones’ metabolic effectiveness on glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
production in humans due to the body developing an increased tolerance to the hormones. Down-regulation at the cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
level may partially explain the decreased action of steady-state levels of insulin, while pulsatile hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
secretion may allow recovery of receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
affinity and numbers for insulin. Intermittent intravenous insulin administration with peaks of insulin concentrations may enhance suppression of gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
and reduce hepatic glucose production.
Background
Dr. Thomas Aoki, former Head of MetabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
Research at the Joslin Diabetes Center
Joslin Diabetes Center
Joslin Diabetes Center is the world’s largest diabetes research center, diabetes clinic, and provider of diabetes education. It is located in the Longwood Medical and Academic Area in Boston, Massachusetts, USA. Among the Harvard Medical School Affiliated institutions, Joslin is unique in its sole...
in Boston
Boston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
, Massachusetts
Massachusetts
The Commonwealth of Massachusetts is a state in the New England region of the northeastern United States of America. It is bordered by Rhode Island and Connecticut to the south, New York to the west, and Vermont and New Hampshire to the north; at its east lies the Atlantic Ocean. As of the 2010...
, and a current Professor of Medicine at the University of California, Davis
University of California, Davis
The University of California, Davis is a public teaching and research university established in 1905 and located in Davis, California, USA. Spanning over , the campus is the largest within the University of California system and third largest by enrollment...
, was the pioneer of using pulsatile insulin in the treatment of diabetes. Dr. Aoki’s work focused on the role of liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
dysfunction in diabetic metabolism. He theorized that end organ
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
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 ingestionIngestion
Ingestion is the consumption of a substance by an organism. In animals, it normally is accomplished by taking in the substance through the mouth into the gastrointestinal tract, such as through eating or drinking...
of meals. For induction and maintenance of insulin-dependent enzymes essential for glucose metabolism in the liver (e.g. hepatic glucokinase, phosphofructokinase
Phosphofructokinase
Phosphofructokinase-1 is the most important regulatory enzyme of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors...
, and pyruvate kinase
Pyruvate kinase
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding one molecule of pyruvate and one molecule of ATP.-Reaction:The reaction with 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.A number of investigators have found no physiologic benefit from pulsatile delivery.
In some cases, insurance companies have been ordered to pay for that patient. For example, a trial with CalPERS
CalPERS
The California Public Employees' Retirement System or CalPERS is an agency in the California executive branch that "manages pension and health benefits for more than 1.6 million California public employees, retirees, and their families"...
resulted in a decision ordering Blue Cross and other insurance providers to pay for the therapy as to those parties.