ScienceWeek

MEDICAL BIOLOGY: ON INSULIN SIGNALING

The term "hormone" was first used in 1902 by William Bayliss (1860-1924) and Ernest Starling (1866-1927) to describe the action of secretin, a hormone produced by the mammalian duodenum and which stimulates the secretion of pancreatic juice. Based more on physiological effects than on chemical structure, subsequent use of the term "hormone" led to the definition of hormones as signal molecules, products of glandular cells, with the signal molecules secreted into the internal milieu, most frequently into the blood. Acting on target cells, these chemical messengers coordinate activities of different parts of the body. Target cells, in turn, respond according to their degree of differentiation, age, and functional and nutritional status, the target cells integrating many hormonal and neuronal regulatory stimuli. The target cell "receptor" is a specific chemical structure required for target cells to receive and recognize a hormone messenger. In general, hormone receptors transduce the external chemical signals provided by hormones and are responsible for the initiation of the first cellular responses to hormones, this first response usually involving a cascade of specific biochemical reactions inside the cell.

The disease diabetes mellitus has a long history, but it was only in 1869 that Paul Langerhans (1847-1888) identified a new type of cell in the pancreas, cells apparently glandular in character, and histological groups of these cells came to be called "islets of Langerhans". In 1889, von Mering and Minkowski demonstrated that diabetes mellitus, characterized in its most evident form by permanent high blood sugar (hyperglycemia) and glucose in the urine (glycosuria; glucosuria) could be induced experimentally in the dog by total removal of the pancreas. This demonstrated the essential role of the pancreas in the regulation of glucose balance (glucose homeostasis). The hormone responsible for this action was called "insulin", and was finally isolated from the pancreas in 1922 by Frederick Banting (1891-1941) and Charles Best (1899-1978). This discovery had an enormous impact in physiology, biochemistry, and medicine. The discovery had an extremely beneficial effect on the prognosis and therapy of insulin-dependent diabetes, allowing a specific replacement treatment for endogenous insulin deficiency, which if untreated is potentially fatal. The arrival of the insulin era was also of major importance in protein chemistry. Insulin was one of the first proteins to be crystallized (Abel 1926), and its primary structure was the first to be elucidated (Sanger 1953). Partial synthesis was accomplished between 1964 and 1966, and total synthesis was completed in 1974. Human insulin, available commercially, is currently prepared by a modification of pork insulin or by a biosynthetic process involving genetic engineering.

The insulin molecule consists of two polypeptide chains connected by two disulfide bridges, with a third disulfide bridge linking parts of one chain. This two-chain structure has evidently been present throughout evolution, but major variations in the amino acid sequences are observed between species. Various mammalian insulins usually have similar potencies in all mammals, including humans; fish insulin has considerable potency in mammals. It is evidently the 3-dimensional structure of insulin, and not the primary sequence of amino acid residues, which is responsible for its potency across different species: variations in amino acid sequence are still potent, provided the specific 3-dimensional structure is maintained.

Insulin apparently exerts its glucose-lowering effects by stimulating glucose uptake in tissues such as skeletal muscle, suppressing fatty acid release from fat (adipose) tissue, and inhibiting production of glucose by the liver. Muscle, liver, and fat, therefore, are widely viewed as the principal insulin-sensitive tissues in the body. The brain, in contrast, has historically been considered insulin-insensitive because its ability to use glucose does not require insulin. Because of this, the idea that insulin participates in the central nervous system control of food intake and body weight was received with skepticism when it was first proposed more than 20 years ago. Since then, however, support for this hypothesis has steadily accumulated, including the demonstration that insulin is transported across the blood-brain barrier, that it is effective in suppressing food intake when given directly into the brain, and that insulin receptors are concentrated in brain areas involved in energy homeostasis.

The following points are made by Morris F. White (Science 2003 302:1710):

1) "How long will the patient live?" was the only question to ask until a series of discoveries beginning with the description by Paul Langerhans (1847-1888) of pancreatic islets changed the lives of people with diabetes (1). Twenty years later, in 1889, pancreatic secretions were shown to control blood sugar levels; however, it took another 30 years until insulin was purified from the islets before patients could ask about the "quality of their life with insulin."

2) For the next 50 years clinicians and scientists revealed the system-wide effects of insulin in liver, muscle, and adipose tissues, and recent work reveals insulin's effect on longevity and the central nervous system. In the 1970s, the insulin receptor was discovered, and 10 years later the demonstration of its tyrosine kinase activity pointed us toward the mechanism of signal transduction (2). Remarkably, this steady progress has not stemmed the worldwide diabetes epidemic that will take a huge toll in premature morbidity and mortality in this new century (3).

3) Diabetes mellitus is a complex disorder that arises from various causes, including dysregulated glucose sensing or insulin secretion (maturity-onset diabetes of the young, MODY), autoimmune-mediated beta-cell destruction (type 1), or insufficient compensation for peripheral insulin resistance (type 2). Type 2 diabetes afflicts 18.2 million Americans. It usually occurs in middle age, but is appearing in young people owing to the close association with obesity. The signaling pathways linking obesity, peripheral insulin action, and beta-cell function are important to understand.

4) The insulin receptor is the prototype for a family of homologous integral membrane proteins composed of an extracellular insulin-binding domain that controls the activity of an intracellular tyrosine kinase. A 150-kb gene on chromosome 19 composed of 22 exons encodes the human pro-receptor. During translation, two homologous pro-receptors form a disulfide-linked dimer that is cleaved to form a tetramer of two alpha-beta dimers. Insulin binds to the extracellular alpha subunits to activate the tyrosine kinase on the intracellular portion of the transmembrane beta subunits. The activated receptor recruits and phosphorylates cellular substrates to initiate signal transduction.

5) In summary: The signaling pathways used by insulin have been identified. Now our challenge is to understand how the failure of these signals is associated with obesity and the progressive failure of pancreatic beta cells that leads to diabetes. Whether better management of chronic inflammation can improve insulin action is an important area of investigation. Drugs that stimulate IRS2 (insulin receptor substrate protein 2) synthesis or signaling might be a good starting point. This knowledge will lead to rational strategies that prevent or cure diabetes.

References (abridged):

1. M. Bliss, The Discovery of Insulin (Univ. of Chicago Press, Chicago, IL, 1982)

2. M. Kasuga et al., Nature 298, 667 (1982)

3. P. Zimmet et al., Nature 414, 782 (2001)

4. M. White, Insulin Signaling Pathway, Sci. STKE (Connections Map, as seen November 2003), http://stke.sciencemag.org/cgi/cm/cmp_12069

5. F. Frasca et al., Mol. Cell. Biol. 19, 3278 (1999)

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