|
ScienceWeek
MEDICAL BIOLOGY: ON INSULIN RESISTANCE
The following points are made by M. Montminy and S-H. Koo (Nature 2004 432:958):
1) Type II diabetes affects some 5% of adults in most developed countries, and a far higher proportion of the population exhibits insulin resistance, a condition that predisposes individuals to diabetes. The mechanisms leading to insulin resistance are unclear, although the abnormal accumulation of certain fats in the liver (hepatic steatosis) is a contributing factor. Stoffel et al[1] demonstrate that the inactivation of a protein called Foxa2 promotes steatosis and contributes to the development of diabetes in insulin-resistant animals. The results have implications for the design of new drugs to treat insulin resistance and diabetes.
2) Energy balance in mammals resembles today's hybrid cars -- we use a variable mix of glucose and fat as energy substrates, depending on food intake. During waking and feeding hours, we use glucose as an efficient source of energy, and under fasting conditions, during sleep for example, we burn primarily fat. Fat stores, called triglycerides, are converted to circulating fatty acids, and are further broken down in a process known as fatty-acid oxidation. In the fasting state, the liver also maintains normal circulating levels of glucose (which is essential for brain function) by synthesizing glucose anew, in a process known as gluconeogenesis.
3) The capacity of the liver to synthesize glucose and burn fat is governed by a set of ignition switches, called transcription factors, that operate in the nucleus to turn genes on and off[2]. These switches respond to changes in circulating hormones --principally insulin and glucagon -- that allow the liver cell to change gears between feeding and fasting metabolism. In response to feeding, insulin triggers the activation of a cascade of proteins inside the cell, each transmitting the feeding signal to the next through a chemical modification known as phosphorylation. In insulin-resistant states, the orderly phosphorylation of certain proteins in response to insulin is damaged, preventing insulin from correctly regulating glucose and fat metabolism[3]. As a consequence, insulin-resistant individuals exhibit hyperglycaemia (high blood glucose), partly because of elevated gluconeogenesis in the liver.
4) Despite this inability to inhibit glucose production in diabetes, insulin still seems to be capable of shutting off the switch that normally promotes fat burning (fatty-acid oxidation) during fasting. This phenomenon, known as mixed insulin resistance, implies that the insulin signal is transmitted preferentially to the fatty-acid-oxidation switch rather than the glucose switch, the unfortunate consequence being that insulin-resistant individuals are not only hyperglycaemic but also accumulate triglycerides in the liver rather than breaking them down.[2-4]
References (abridged):
1. Wolfrum, C., Asilmaz, E., Luca, E., Friedman, J. M. & Stoffel, M. Nature 432, 1027-1032 (2004)
2. Spiegelman, B. M. & Heinrich, R. Cell 119, 157-167 (2004)
3. Saltiel, A. & Kahn, C. R. Nature 414, 799-806 (2001)
4. White, M. Mol. Cell. Biochem. 182, 3-11 (1998)
Nature http://www.nature.com/nature
--------------------------------
Related Material:
MEDICAL BIOLOGY: ON INSULIN SIGNALING
Notes by ScienceWeek:
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)
Science http://www.sciencemag.org
--------------------------------
Related Material:
INSULIN RESISTANCE IS A POOR PREDICTOR OF TYPE 2 DIABETES IN INDIVIDUALS WITH NO FAMILY HISTORY OF DISEASE
The following points are made by A.B. Goldfine et al (Proc. Nat. Acad. Sci. 2003 100:2724):
1) Both insulin resistance and insulin deficiency are components of the pathogenesis of type 2 diabetes. However their temporal relationships in the disease process remains unclear (1). Hyperglycemia, per se, induces defects in both insulin secretion and in insulin action (2). Thus, it is not possible to distinguish the role of either in the development of diabetes in persons already affected with disease. To elucidate the predictive values of these parameters on the occurrence of type 2 diabetes, studies must be performed in normoglycemic individuals. However there are few prospective studies evaluating normoglycemic subjects to determine their contribution to the pathogenesis of type 2 diabetes. Individuals with a family history of type 2 diabetes are at greater risk of developing the disease than people who have no family history of disease. Insulin sensitivity (SI) and the acute insulin response to glucose (AIRg) exhibit familial clustering, suggesting these are inherited traits (3,4).
2) Several studies have shown that insulin resistance (or hyperinsulinemia) predate glucose intolerance and type 2 diabetes in normoglycemic individuals at high risk of developing diabetes, including ethnic Mexican American (5) and Pima Indian groups and Caucasians. In a longitudinal study of nondiabetic Caucasian offspring of two type 2 diabetic parents, the authors found both low SI and low glucose effectiveness (SG), but not low first-phase insulin secretion, were associated with development of type 2 diabetes one to two decades later. Euglycemic insulin-clamp studies have also shown early defects in glucose metabolism with decreased total-body glucose metabolism and impaired nonoxidative glucose metabolism (primarily glycogen storage) in persons at risk for type 2 diabetes, including normoglycemic first-degree relatives of patients with type 2 diabetes.
3) Other studies have focused on the role of insulin secretion in the development of type 2 diabetes and demonstrated reduced cell function. Although fasting insulin levels may appear normal or elevated in patients with type 2 diabetes, other studies have shown that islet function testing at matched glucose levels in patients with type 2 diabetes is impaired in both basal and stimulated states.
4) In summary: In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (SI) and low insulin-independent glucose effectiveness (SG) predict the development of diabetes one to two decades later. The authors report that to determine whether low SI, low SG, or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964-82. During 25 ± 6 years follow-up, comprising 2,758 person years, the FH cohort (54 ± 9 years) had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of SI and SG derived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH vs. FH+ individuals with low SI and low SG. The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of SI, i.e., the glucose disposition index.
5) The authors suggest these data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low SI and low SG , both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH individuals.
References (abridged):
1. DeFronzo, R. A. (1988) Diabetes 37, 667-687
2. Rossetti, L., et al (1990) Diabetes Care 13, 610-630
3. Warram, J.H., et al (1988) Adv. Exp. Med. Biol. 246, 175-179
4. Watanabe, R.M., et al (1999) Hum. Hered. 49, 159-168
5. Haffner, S.M., et al (1986) N. Engl. J. Med. 315, 220-224
Proc. Nat. Acad. Sci. http://www.pnas.org
ScienceWeek http://scienceweek.com
|