Hormones Receptors and Signal Transduction MCB 720 Oct

Hormones, Receptors, and Signal Transduction MCB 720 Oct 15, 2015 John J. Kopchick, Ph. D.

Hormone -Receptor Interactions Hormone stems from a Greek term meaning “to spur on. ”

General principles Ø Ø Ø Higher organisms, from the fruit fly to humans, are comprised of cells. The cells often unite to form tissue which come together to form organs which together make up the organism. Cells of an organism do not live in isolation. The communication between cells ultimately controls growth, differentiation, and metabolic processes within the organism. Communication between cells is often by direct cell to cell contact. Communication frequently occurs between cells over short and long distances.

General principles cont. . . Ø Ø Ø In cases of short and long distance communication, a substance may be released by one cell and recognized by a different target cell. In the target cell, a specific response is induced. Cells use an amazing number of signaling chemicals. Some of these signaling molecules are termed “hormones. ” The ability of a hormone to induce a response in a target cell is usually mediated by a hormone receptor on, or in, the target cell.

General characteristics of hormones Ø Ø Ø Hormones are molecules synthesized by specific tissue. Classically these tissue were called glands. Hormones are secreted directly into the blood which carries them to their sites of action. Hormones are present at very low levels in the circulatory system. Hormones specifically affect or alter the activities of the responsive tissue (target tissue). Hormones act specifically via receptors located on, or in, target tissue.

Hormone/Receptor Interaction Secondary Signals

Hormone Range of possible pathways Receptor Mediator Protein Effectors H 1 R 1 G 1 E 1 H 2 R 2 G 2 E 2 Possible pathways of transmission of hormonal signal. Each hormone can work through one or more receptors; each hormone-receptor complex can work through one or more mediator proteins (either G proteins or other signaling mechanism), and each mediating protein or enzyme activated by hormone-receptor complexes can affect one or more effectors functions.

The four primary arenas of hormone action Growth & Development Reproduction Hormones Maintenance of internal environment Energy production, utilization & storage

Definitions Endocrine - Refers to the internal secretion of biologically active substances. Exocrine - Refers to secretion outside the body, for example, through sweat glands, mammary glands, or ducts lead to the gastrointestinal. Hormone - Substances released by an endocrine gland transported through the bloodstream to another tissue where it acts to regulate functions in the target tissue (classic definition). Paracrine - Hormones that act locally on cells that did not produce them. Autocrine - Hormones that act on cells that produced them. Receptors -Hormones bind to receptors molecules on cells. A receptor must specifically recognize the hormone from the numerous other molecules in the blood and transmit the hormone binding information into a cellular specific action.

Endocrine Blood vessel Hormone secretion into blood by endocrine gland Distant target cells Paracrine Secretory cell Adjacent target cell Autocrine Receptor Hormone or other extra cellular signal Target sites on same cell

Actions of hormones & neurotransmitters & their interrelationships (H, hormone; R, receptor; N, neurotransmitter. )

Examples of Hormones and glands that produce them

Selected hormones & their functions Hormone Source Principal functions Insulin Pancreas Controls blood-sugar level and storage of glycogen. Glucagon Pancreas Stimulates conversion of glycogen to glucose; raises blood sugar level. Oxytocin Pituitary gland Stimulates contraction of the uterine muscles and secretion of milk by the mammary glands. Vasopressin Pituitary gland Controls water excretion by the kidneys; stimulates contraction of the blood vessels. Growth hormone Pituitary gland Stimulates growth. Adrenocorticotrophic Pituitary gland Stimulates the adrenal cortex, which, in turn, releases hormone (ACTH) several steroid hormones. Prolactin Pituitary gland Stimulates milk production by the mammary glands after birth of baby. Epinephrine Adrenal glands Stimulates rise in blood pressure, acceleration of heartbeat, decreased secretion of insulin, and increased blood sugar.

Selected hormones & their functions cont. . . Hormone Source Cortisone Adrenal glands Thyroxine & Triiodothyronine Thyroid gland Calcitonin Thyroid gland Parathyroid Principal functions Helps control carbohydrate metabolism, salt and water balance, formation and storage of glycogen. Increases the metabolic rate of carbohydrates and proteins. Prevents the rise of calcium and phosphate in the body. Parathyroid gland Regulates the metabolism of calcium and phosphate in hormone in the body. Gastrin Stomach Secretin Estrogen Duodenum Ovaries Progesterone Ovaries Testosterone Testes Stimulates secretion of gastric juice. Stimulates secretion of pancreatic juice. Stimulates development and maintenance of female sexual characteristics. Stimulates female sexual characteristics and maintains pregnancy. Stimulates development and maintenance of male sexual characteristics.

“Generic” Hormone/Receptor Interactions

Regulation of transcription by hormones that act on the cell surface.

Types of Hormones Ø Catecholamines Hormones and Thyroid Small and derived from amino acids (epinephrine, thryoxine. ) Ø Steroid Hormones and Vitamin D Relatively small and derived from cholesterol Ø Prostaglandin's Relatively small and derived from fatty acids Ø Proteins or Polypeptides relatively large and derived from translation of hormone specific m. RNA (growth hormone, insulin)

Thyroid Hormones Ø Ø Ø Ø Synthesized solely in the thyroid gland ( T 4; 3’, 5’, 3, 5 -Ltetra-iodothyronine). Majority of the active form, T 3 (3’, 3, 5 -L-triiodothyronine), is produced in the peripheral tissues through deiodination of T 4. Thyroid gland cells concentrates iodine for thyroid hormone synthesis. Iodine is attached to tyrosine residues on a protein, termed thyroglobulin. Tyrosine residues are then coupled together to yield thyronines. Proteolytic digestion of thyroglobulin then yields T 4 and T 3 in a 10: 1 ratio. Helps in the metabolism of sugars. The half life of T 4 is 7 days and that of T 3 is 1 day.

Tyroxine [Tetra-iodothyronine (T 4)] I I NH 3+ O HO I CH 2 C H COO Thyroid Hormones I Tri-iodothyronine (T 3) I I NH 3+ HO O CH 2 I C H COO - Increase of oxidation of sugars by most body cells; induction of some enzymes

T 4 T 3 T 3 T 4 T 3 Regulation of transcription by thyroid hormones. T 3 and T 4 are tri-iodotyronine and tyroxine, respectively.

Steroid Hormones Ø Ø Ø Produced in the adrenals, ovaries, testes, and placenta. Derived from cholesterol. Enzymes in the various glands control the final product. For example, cytochrome P 450 c 11 which is located in the adrencortical cells, is involved in coritsol production. This enzyme is lacking in the gonads, that do not produce cortisol or aldosterone. Gonads, however, can produce dihydroxytestosterone, estradiol, or progesterone depending upon the enzymes present in the gonadal tissue. Over 50 different steroid metabolites have been described.

Cholesterol Metabolism

Steroid Hormones

Regulation of transcription by steroid hormones

Catecholamines Ø Ø Ø Are synthesized in nervous tissues from which the adrenal medulla is derived. Adrenal medulla is the major source for circulating epinephrine. Synthesized from tyrosine which is converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylases. Subsequent conversions to dopamine and then to nor epinephrine which is released by most catecholamineproducing cells of the body. In the adrenal medulla and a few other tissue, nor epinephrine is converted to epinephrine. The half life is 1 -2 minutes. Flight, fright, or fight!

Prostaglandins and Leukotrienes Ø Ø Ø They can be produced by most cells depending upon lipid and enzyme content of the cells. Arachidonic acid, which is derived from lipid metabolism, is the precursor compound. Depending upon the lipoxygenase present in the cell, either, HETE, prostaglandin (G 2) or leukotrienes Cyclooxygenase (involved in PGG 2 synthesis) is widely distributed throughout the body and is inhibited by aspirin, indomethacin, and other nonsteroidal and antiinflammatory agents. Several COX inhibitors!! - Problems The half-life is a few seconds.

Hormone Antagonists

Examples of hormone antagonists used in therapy Antagonist to Use Growth Hormone Acromegaly, Diabetes Progesterone Contraceptive, abortion Glucocorticoid Spontaneous Cushing’s Syndrome Mineralo-corticoid Primary and secondary mineralocorticoid excess Androgen Prostate cancer Tamoxifin Estrogen Breast cancer Gn. RH Prostate cancer -Adrenrgic Hypertension, hyperthyroidism Prostaglandin Acute and chronic inflammatory disease

Hormone Receptors and Signal Transduction

Hormone Receptors Nuclear receptors estrogens Cytoplasmic receptors Most steroid and thyroid hormones Cell surface membrane receptors Polypeptide hormones and catecholamines

A general model for the action of peptide hormones, catecholamines, and other membrane-active hormones. The hormone in the extra cellular fluid binds to the receptor and activates associated effector(s) systems, that may or may not be in the same molecule. This activation results in generation of an intracellular signal or second messenger that, through a variety of common and branched pathways, produces the final effects of the hormone on metabolic enzyme activity, protein synthesis, or cellular growth and differentiation.

Receptors that span the membrane Seven times

c. AMP: synthesis and degradation

c. AMP

Amino acid Phosphorylation is very important in intracellular signal transduction ATP S Serine Protein Kinases – transfer terminal Phosphate groups from ATP to Serine, Threonine, or Tyrosine residues in proteins Result in activation or inactivation of the recipient protein !

S Serine Amino acids that can be phosphorylated Threonine Y Tyrosine

GPCR Pathway G a G P C R G AC a -S GTP 13 GTP 12/ G a -I G P C R G Pax GTP illin a G P C R G -Q P YK 2 G P C R ab g bg G Grow Fact th ors R T K s SOS G G GDP G Src Crk FAK GTP GRB 2 SHC Ras GEFs PI 3 K Raf 1 PLC-b c. AMP GEFs A S K 1 EPAC PKA CDC 42 Rac Rap 1 LARG MEKs PKC IKKs MEKs PDZRho. GEF DAG Akt/ PKB ERKs BIMP 1 PAK BRaf MKKs IP 3 R JNK p 115 Rho. GEF IKKs p 38 MEKs P Caln NF-k. B CREB BCL 10 Calm Ca 2+ NFAT Ca 2+ ERKs NFAT Rho ROCK CREB SRF 2009 Protein. Lounge. com SRF lk--11 EElk c-Jun C-Fos c-Fos STATs Ts NFAT -KB F N-k. B NF C Gene Expression NF-k. B P P Ik. Bs Degradation

Peptide hormone receptors

Huising, et. al. J. Endo. 2006. 189: 1 -25

Michael Brown – 1985 – LDL Receptors Joseph Goldstein – 1985 – LDL Receptors J. Michael Bishop – 1989 – Cellular Oncogenes Harold E. Varums, 1989 – Cellular Oncogenes Alfred G. Gilman – 1994 – G Proteins Stanley B. Prusiner – 1997 – Prions Ferid Murad – 1998 – Nitric oxide signaling Richard Axel -2004 - Odorant Receptors Robert J. Lefkowitz – 2012 - G Protein-coupled Receptors

General View of Metabolism

Levels of blood sugar (glucose) regulate secretion of hormones from the pancreas Pancreas secretes insulin when glucose levels are high Insulin binds to insulin receptors on fat and muscle and “promotes” glucose uptake Overall effect: blood glucose levels return to normal

Glucose Tolerance Test

The Insulin Receptor Ø Responsible for clearance of glucose Ø In addition to binding insulin, it possesses a tyrosine kinase activity Ø It is involved in many cellular activities

Glucose Transporter Intracellular Trafficking

Insulin Receptor Tyrosine kinase

Insulin-mediatedglucosetransportsignalingpathway Insulin IR a a b Cell membrane b P IRS PI 3 K Glut 4 Akt P Xiao Chen

Insulin-mediated glucose transport signaling pathway IR glucose a Insulin a b b Cell membrane P IRS PI 3 K Akt P Xiao Chen

Insulin Signaling Pathways by C. Hooper http: //www. abcam. com/index. html? pageconfig=resource&rid=10602&pid=7

Cartoon of Intracellular Signaling System Used By Many Peptide Hormones and Growth Factors l For example – Insulin – EGF

Tyrosine kinase receptors are a family of receptors with a similar structure. They each have a tyrosine kinase domain (which phosphorylates proteins on tyrosine residues), a hormone binding domain, and a carboxyl terminal segment with multiple tyrosines for autophosphorylation. When hormone binds to the extra cellular domain the receptors aggregate.

When the receptors aggregate, the tyrosine kinase domains phosphorylate the C terminal tyrosine residues.

This with This phosphorylation produces binding sites for proteins SH 2 domains. GRB 2 is one of these proteins. GRB 2, SOS bound to it, then binds to the receptor complex. causes the activation of SOS.

SOS is a guanyl nucleotide-release protein (GNRP). When this is activated, it causes certain G proteins to release GDP and exchange it for GTP. Ras is one of these proteins. When ras has GTP bound to it, it becomes active.

Activated ras then causes the activation of a cellular kinase called raf-1.

Raf-1 kinase then phosphorylates another cellular kinase called MEK. This cause the activation of MEK.

Activated MEK then phosphorylates another protein kinase called MAPK causing its activation. This series of phosphylating activations is called a kinase cascade. It results in amplification of the signal.

Adapted from: Dr. Donald F. Slish, Biological Sciences Department, Plattsburgh State University, Plattsburgh, NY. Among the final targets of the kinase cascade are transcriptions factors (fos and jun showed here). Phosphorylation of these proteins causes them to become active and bind to the DNA, causing changes in gene transcription.

Examples of therapeutics developed based on these types of receptors and the associated tyrosine kinase signaling system Erbitux – Imclone Iressa - Astra. Zeneca Gleevec – Novartis Herceptin - Genentech

EGF Receptor Signal Transduction Pathway SIGMA-ALDRICH Tyrosine kinase Cell Proliferation

Epidermal Growth Factor Receptor EGF Cysteine Rich Domain Receptor EGF Dimerization Cell Membrane Tyrosine Kinase Domain * * * P P * * * Signal Transduction

EGFR Family n n n The epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four receptors, Erb. B 1 (EGFR) Erb. B 2 (Her/Neu) Erb. B 3 (HER 3) Erb. B 4 (HER 4).

Non-small cell lung cancer n n Non-small cell lung cancer comprises over 75% of all lung cancers. ~400, 00 cases of the disease are diagnosed in the seven major pharmaceutical markets. High unmet needs of therapy still persist for this tumor type. The overall survival of NSCLC patients remains below 12 months. The EGFR is expressed on these cells.

Epidermal Growth Factor Receptor in Non–Small-Cell Lung Carcinomas: Correlation Between Gene Copy Number and Protein Expression and Impact on Prognosis Fred R. Hirsch, Marileila Varella-Garcia, Paul A. Bunn, Jr, Michael V. Di Maria, Robert Veve, Roy M. Bremnes, Anna E. Barón, Chan Zeng, Wilbur A. Franklin Journal of Clinical Oncology, Vol 21, 2003: 3798 -3807, 2003 • The percentage of EGFR positive tumor cells per slide (0% to 100%) was multiplied by the dominant intensity pattern of staining (1, negative or trace; 2, weak; 3, moderate; 4, intense); therefore, the overall score ranged from 0 to 400 (Fig 1). Specimens with scores 0 to 200, 201 to 300, and 301 to 400 were respectively classified as having negative or low, intermediate, and high levels of expression.

Influence of histological type, smoking history and chemotherapy on survival after first-line therapy in patients with advanced non-small cell lung cancer Itaya , Yamaoto, Ando, Ebisawa, Nakamura, Murakami, Asai, Endo and Takahashi Cancer Science Volume 98, Page 226, 2007 • For overall survival, smoking history and histology were significant prognostic factors. The 2 -year overall survival rates were as follows: smokers, 17%; non-smokers, 52%, P < 0. 0001;

Iressa (gefitinib tablets) Astra. Zeneca. IRESSA is indicated as monotherapy for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies.

Iressa (gefitinib tablets) Astra. Zeneca. • Mechanism of Action • The mechanism of the clinical antitumor action of gefitinib is not fully characterized. • Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). • EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to gefitinib. Gefitinib is an anilinoquinazoline with the chemical name 4 Quinazolinamine, N-(3 -chloro-4 - fluorophenyl) -7 -methoxy-6[3 -4 -morpholin) propoxy] C 22 H 24 Cl. FN 4 O 3

• PRODUCT MONOGRAPH • IRESSA® • gefitinib tablets • 250 mg • Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor

Zactima Tyrosine Kinase Inhibitor for Treatment of Lung Cancer • • Zactima (ZD 6474) is an orally available Tyrosine Kinase Inhibitor (TKI) under development by Astra. Zeneca for the treatment of solid tumours. Following promising results in early clinical trials, Zactima has now progressed to phase III development in Non-Small Cell Lung Cancer (NSCLC), its primary indication. If phase III trials prove successful, analysts believe Zactima could be on the market by 2008 and help to fill the void left by recent setbacks with Iressa (gefitinib), its first TKI for lung cancer. At the beginning of the year, Astra. Zeneca withdrew its marketing application for Iressa in Europe. This followed the release of new longterm data that showed it to be no better than placebo in prolonging patients' lives. Meanwhile, in the US Iressa will soon be available only to existing NSCLC patients who have already shown treatment benefit and will not be prescribed to new patients. While Iressa has stalled in Europe and the US, it is approved in more than 30 countries elsewhere. http: //www. drugdevelopment-technology. com/projects/zactima/ Astra. Zeneca

Zactima or Vandetanib - 2008 New ´biologic´ drug made by Astra. Zeneca. It is an oral targeted therapy that targets VEGF and EGFR pathways. It is being hailed as a treatment for non-small cell lung cancer and costs roughly 6, 500 pounds or $10, 000 US a month. The mean increased survival time in research was 4 months. As with all biologics, some people may survive considerably longer. In Phase III Clinical trials it was tested with chemotherapy agents docetaxel, (Zodiac), and pemetrexed, (Zeal), and on its own, (Zest). All with non-small cell lung cancer. It performed best in the first trial, Zodiac, and reduced symptoms of the cancer better than chemotherapy alone. It is reported to perform similarly to Tarceva. A fourth trial (Zephyr) was conducted against an oral inhibitor of EGFR and a placebo and did not appear to do very well. T The overall results of these trials has been described by some experts (see GRACE http: //cancergrace. org/lung/2010/08/17/zephyr-trial-final-results/) as ´debatable´ or ´marginal´. Vandetanib was the first drug to be approved by FDA (April 2011) for treatment of latestage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery. Vandetanib was first initially marketed without a trade name, and is being marketed under the trade name Caprelsa since August 2011.

BCR-ABL • • • The exact chromosomal defect in Philadelphia chromosome is translocation. Parts of two chromosomes, 9 and 22, swap places. The result is that part of the BCR ("breakpoint cluster region") gene from chromosome 22 (region q 11) is fused with part of the ABL gene on chromosome 9 (region q 34). Abl stands for "Abelson", the name of a leukemia virus which carries a similar protein. The result of the translocation is a protein of p 210 or sometimes p 185 weight (p is a weight fraction of cellular proteins in k. Da). The fused "bcr-abl" gene is located on the resulting, shorter chromosome 22. Because abl carries a domain that can add phosphate groups to tyrosine residues (tyrosine kinase) the bcr-abl fusion gene is also a tyrosine kinase. (Although the bcr region is also a serine/threonine kinase, the tyrosine kinase function is very relevant for therapy, as will be shown. ) The fused bcr-abl protein interacts with the interleukin 3 beta(c) receptor subunit. The bcr-abl transcript is constitutively active, i. e. it does not require activation by other cellular messaging proteins. In turn, bcr-abl activates a number of cell cycle-controlling proteins and enzymes, speeding up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML. (Chronic myelogenous leukemia)

Gleevec (imatinib mesylate, aka STI-571) FDA APPROVES GLEEVEC FOR LEUKEMIA TREATMENT The Food and Drug Administration today announced the approval of Gleevec (imatinib mesylate, also known as STI-571), a promising new oral treatment for patients with chronic myeloid leukemia (CML) -- a rare life-threatening form of cancer. FDA reviewed the marketing application for Gleevec in less than three months under its "accelerated approval" regulations. Novartis, May 10, 2001 Used in the treatment of Chronic Myeloid Leukemia (CML) and Gastrointestinal Stromal Tumors (GIST)

Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. In colony formation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows inhibition of Bcr-Abl positive colonies from CML patients. In vivo, it inhibits tumor growth of Bcr-Abl transfected murine myeloid cells as well as Bcr-Abl positive leukemia lines derived from CML patients in blast crisis. Gleevec (Novarits) In vitro studies demonstrate imatinib is not entirely selective; it also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF mediated cellular events

Monoclonal Antibody Therapy

Antibody to EGF R binds and blocks EGF from binding EGF Erbitux, Imclone Cell Membrane Tyrosine Kinase Domain Therefore, no tyrosine kinase activity and no intracellular signaling

Herceptin is the first humanized antibody approved for the treatment of HER 2 -positive metastatic breast cancer. Herceptin is designed to target and block the function of HER 2 protein over expression. Genentech HER 2 = Human Epidermal Growth Factor Receptor 2

Herceptin, a monoclonal antibody, binds to HER 2 and ultimately results in destruction of the cell

So two targets to inhibit EGF/EGFR signaling 1 EGF Receptor Dimerization EGF Cell Membrane Tyrosine Kinase Domain P P Signal Transduction 2 Colored slide: D-88

Diabetes - from the Greek word, diabetes, meaning “a crossing over or passing through”. Any of several metabolic disorders marked by excessive discharge of urine and persistent thirst. (The American Heritage Dictionary). Diabetes mellitus - a chronic disease of pancreatic origin, characterized by insulin deficiency, subsequent inability to utilize carbohydrates, excess sugar in the blood and urine, excessive thirst, hunger, and urination, weakness, emaciation, imperfect combustion of fats resulting in acidosis, and, without injection of insulin, results in coma and death. (The American Heritage Dictionary).

Diabetes, con’t. Ø Ø Type I or Insulin Dependent Diabetes Mellitus (IDDM) – Also called juvenile diabetes - lack of insulin Type II or Non Insulin Dependent Diabetes Mellitus (NIDDM) – Also called adult onset diabetes - insulin present but cells do not respond that is they are“insulin resistant”.

Facts: (Diabetes 1996 Vital Statistics, ADA) 16 -20 million Americans have diabetes. 385, 000 diabetes die each year. 625, 000 new cases each year. Every minute of every day, someone new is diagnosed with diabetes. 127, 000 children (younger that age 20) have diabetes. 11% of the U. S. population, age 65 -74, has diabetes.

Diabetes, con’t. Diabetic eye disease (retinopathy): by 15 years after diagnosis of diabetes, retinopathy is present in 97% of insulin users and 80% of non-insulin users. About 20% of people with diabetes have kidney disease (nephropathy). 40% of the deaths associated with diabetes are due to heart disease.

Types of diabetes mellitus (Diabetes 1996 Vital Statistics, ADA) Type I or insulin-dependent diabetes mellitus (IDDM) - Low or absent levels of endogenous insulin. Dependent on insulin therapy to prevent ketoacidosis and sustain life. Onset predominantly before age 30 but can occur at any age. Onset is usually abrupt and patients are usually thin. Cause appears to be a combination of genetic and environmental determinants. Pancreatic islet cells are destroyed. Type II or non-insulin dependent diabetes mellitus (NIDDM) - Normal to High insulin levels characterize most patients, indicating insulin resistance in tissues. Often see development of low insulin levels as the disease progresses. Patients are not prone to ketoacidosis during normal circumstances. Although not dependent on insulin therapy for survival, many require it for adequate blood glucose control. Onset is predominantly after age 40, particularly in whites, and often asymptomatic; most patients are obese. Cause appears to be a combination of genetic and environmental lifestyle determinants. Drugs are available to promote insulin release from the pancreas or to allow cells to be more sensitive to insulin action.

Types of diabetes, con’t. Gestational Diabetes Mellitus (GDM) - Glucose intolerance that has its onset or recognition during pregnancy. Associated with older age, obesity, and family history of diabetes. Risk for subsequent NIDDM is increased. Newborn offspring often have macrosomia and may also be at increased risk for developing NIDDM. Diabetes insipidus - Caused by the total or partial lack of the hormone vasopressin, also called antidiuretic hormone. Blood glucose is normal, but increased urine output with accompanying thirst. Other types of diabetes - Diabetes secondary to other conditions with hyperglycemia at a level diagnostic of diabetes. Impaired Glucose Tolerance (IGT) - Blood glucose levels that are higher than normal but not diagnostic for diabetes mellitus. Risk for subsequent NIDDM is increased.