The Role of Insulin

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The history of insulin is fascinating and has been told especially well by Michael Bliss in The Discovery of Insulin.18

In 1889, Minkawski and Von Mering, in Strasbourg found that dogs subjected to pancreatectomy became diabetic. One account of the finding was that the technician raised the suspicion of sugar in the urine to Minkawski, by observing flies settling in large numbers on the puddles of urine passed by the diabetic dogs, in contrast to their relative lack of interest in the urine of normal dogs.

In 1869 Paul Langerhans, a medical student writing his thesis, observed microscopic islands of different structure to the main mass of digestive enzyme secreting pancreas. This seminal observation, perhaps the most perspicacious of any medical student, led to intense study of the islets. They are miniature organs embedded within the pancreas in most creatures, but constituting separate independent organs in some fish. Each islet consists of approximately 1000 cells of four distinct types each with its own secretion task:

a cells producing glucogon

^ cells producing insulin. They constitute 60-80% of the cells in the islets, i.e. 6-800 cells/islet

8 cells producing somatostatin pp cells producing pancreatic polypeptide.

There is a delicate and profuse capillary network and nerve connections in the islet, somewhat resembling the renal glomerulus. The capillaries of the islets anastomose with the main pancreatic vasculature which may facilitate signaling between endocrine and exocrine pancreatic cells. The interaction of cytokines between the individual cell types may be important attributes that would be lost to separated islets or surrogate ^ cells. The pancreas contains one million islets and therefore 6-8 x 108 ^ cells. The endocrine secretions of the islets enter the portal blood and the first organ they reach is the liver. Insulin is partially metabolized by the liver, which converts glucose to glycogen.

In the 1920s, the connection between removal of the pancreas and diabetes was established, but various oral preparations of pancreas did not ameliorate diabetes. The young orthopedic surgeon, Frederick Banting, working in Toronto, was convinced that an extract of pancreas injected would provide the vital substance missing in diabetes. With the technical assistance and a major intellectual contribution from a medical student, Charles Best, the two rather low profile researchers produced an extract of pancreas that lowered the blood sugar of diabetic dogs and eventually in 1922, they persuaded clinical colleagues to try a similar extract in diabetic patients. Some but not all of the early clinical cases responded, but first the help of a protein chemist, James Collip was needed. There was much opposition from conservative clinicians, but eventually the concept was accepted that a substance from the pancreatic islets called "insulin" could be used as a treatment for diabetic patients. It soon became apparent that a large commercial pharma company, with deep pockets and prepared to accept a risky project, would be required to produce enough of the substance in relative purity to provide lifelong treatment. The Eli Lilly Company stepped in, rose to this challenge, and the lives of diabetics were transformed, albeit with the reservations of the diabetic way of life and the risk of complications to which I have referred.

The molecular structure of the complicated protein insulin was determined in Cambridge in the 1950s at the Laboratory of Molecular Biology by Frederick Sanger in the course of his first Nobel Prize work. The physiology of insulin and the control of glucose metabolism is complex. Before active insulin is available, a non-active molecule called C-peptide must be cleaved from the parent molecular proinsulin. There is an important basal secretion of insulin, but on the intake of food, insulin granules, stored in the P cells, are released in a pulsatile manner simultaneously from a number of P cells, in amounts relating to the ambient blood glucose concentration in the islets. The timing is critical. If released too early or too late, high insulin blood levels will cause inappropriate, possibly dangerous, hypoglycemia. If not enough insulin is available at the appropriate time, normal glucose metabolism cannot take place and the blood sugar level will rise. There is a considerable reserve of P cell function, so after even a large meal not all the P cells exhaust their supply of secreted insulin from within their cell membranes. There is a slow turnover of P cells, perhaps around 5% per annum in man, from progenitor cells present in the islets and/or in the ducts of the exocrine pancreas. In rodents the turnover is much greater.9

The chemistry of insulin secretion varies in different species. In man an inactive pro-insulin is the first main synthetic step and this becomes cleaved into the inactive C-peptide, a marker of insulin synthesis and insulin. In mice there are two active insulins, I and II. In diabetic patients, the level of glycosolated hemoglobin rises. The interactions between insulin, gluco-gon and other endocrine secretions are complicated and in some patients, microangiopathy develops in the retinae, glomeruli, and small blood vessels throughout the body associated with serious complications.

First passage of insulin through the liver is physiological, but release of insulin directly into the caval venous system appears to be well tolerated following vascularized pancreatic transplants.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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