to Vaccine? From Viper Venom

Description

14 Jun 2008 – graduate students, post-doctoral and clinical fellows to discuss ... and practice, tips on choosing a post-doc, advice on setting up a private practice .... President-Elect. [e-mail] ... http://www.endo-society.org/membership/election.cfm. New this year! ...... coworkers investigated Vpr's effect on the ...

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• Publié par: paul.vallen
• Nombre de lectures: 21
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Trends & Insi hts for the Endocrine Community

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H ertension Treatment: From Viper Venom 

Steroid & Growth Hormone Abuse in Youth Minorities in cal Research

cu e Neuropathy & Diabetes

EndocrinE TrainEE day

June 14, 2008 8:00 AM – 6:00 PM San Francisco, California

nmt dele:   Febu 15, 2008

The Endocrine Trainee Day was created by The Endocrine Society to further meet the needs of endocrine trainees. The full-day event will provide a unique opportunity for graduate students, post-doctoral and clinical fellows to discuss the breadth of endocrinology with their peers and the leaders in the field.

The program includes sessions targeted to basic researchers as well as to pediatric and adult endocrine clinical fellows. Leading endocrinologists will present perspectives on the diagnosis and treatment of endocrine disorders, new technologies in research and practice, tips on choosing a post-doc, advice on setting up a private practice, job opportunities and strategies for achieving a healthy balance between career and personal life and much more. The nomination deadline is February 15, 2008 .

Trainees selected to attend the workshop will receive compli - mentary registration to ENDO 08 and a $500 travel award.

For up-to-date information, visit www.endo-society.org .

January 2008 Vol. 33 No.1 content TrendsandInsightsfortheEndocrineCommunity

pg. 12

Features

Hypertension Trea c t ov m er e st n o t r : y  12 From Viper Venom to Vaccine? Steroid & Growth Hormone 17 Abuse in Youth Minorities in Clinical Research 20 Spotlight on Policy

Acute Neuropathy & Diabetes 23 Practice Resources

Departments 02 Viewpoint 03 Editor’s Page 04 Trends & Insights 11 Smart Moves  20 S tlight on Policy po 22 Research Briefs 23 Practice Resources 27 Society Update/Calendar 30 Classified s 36 A Look Back

pg. 19

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V IEWPOINT

Dear Colleagues: designed to introduce a select group of clinical fel lows to career options in hypothesis-driven or translational In previous letters, I have research. This workshop focuses on fi nding a mentor, highlighted The Endocrine Society’s obtaining research funding, and discovering options for focus on trainees and trainee pro- clinical research careers. grams. In this letter, I would like The Endocrine Society generously supports trainee to detail some of the ways in which participation through its grants and awards program. the Society welcomes, values, and Typically, the Society is able to make grants to more supports trainees and young profes- than 400 trainees to help with the cost of attending our Margaret Shupnik, Ph.D. sionals. A strong commitment to programs, such as ENDO, and to recognize outstanding our fledgling endocrinologists is a prominent part of the achievement. This continues to be of the highest priority, Society’s recently revamped (June 2006) strategic plan, and we will look for ways to expand our fi nancial support stemming from our conviction that endocrinology is and for trainees. must continue to be an attractive fi eld for those consid- Of course, many other Endocrine Society programs are of ering careers in research and medicine. particular value to trainees and early career professionals, One result of the Council’s including the annual Board Re- development of a new strategic Th Endocrine view Course, Clinical Endocrinol- plan is that our bylaws were e ogy Update, and the Endocrine modified in March 2007, with Society generously Self-assessment Program. The the approval of the member- job fair at ENDO and our Web- ship, so that The Endocrine based career center are certainly Society is one of the few sci- supports trainee useful to those just beginning entific or professional societies their endocrinology careers, and in which trainees can both participation through improvements to the Society’s its grants and vote and serve on committees. new Web site are being planned Trainees are welcome to partici- awa d with trainees in mind. pate in the leadership of the The Endocrine Society has a Society by serving on commit- r s program . major role to play in supporting tees—and we are committed to the scientific, professional, and increasing their opportunities to help shape the Society’s career development of students, research trainees, and programs and future. We also have a committee focused clinical fellows in endocrinology. In fulfilling that role, solely on trainees and early career professionals. The we have developed many useful programs and I am con- Trainee and Career Development Core Committee, jointly fident the Society will continue to expand and imp rove chaired by Joy Wu and Tony Means, proposes and helps on our current trainee focus. In addition, we need to coordinate the Society’s efforts for this segment of our improve our outreach to trainees, including those outside membership. This dedication to the needs of stude nts, the United States, so that the Society can serve as many trainees, and young professionals has resulted in an of our members and young professionals as possible. impressive array of programs and services. On another note, I wanted to remind everyone that I have previously mentioned the Endocrine Trainee online registration for ENDO 08 opens in January—reg- Day conference, a 1-day program that precedes ENDO. ister and make your hotel reservations early for the best This program includes both a clinical fellow and a basic rates and choices. I hope to see you in San Francisco. ■ trainee and student track, in which participants are briefed about recent treatments for selected endocrine Sincerely, disorders, recent developments in endocrine science, career guidance, and tips on navigating ENDO. Additional career guidance is provided by the Career Development Workshops held during the annual meeting. Workshop presentations focus on establishing a research lab, obtaining funding, publishing in peer-reviewed journals, and selecting from among a number of career options. In the fall, the Society hosts the Clinical Investiga- Margaret Shupnik, Ph.D. tors Workshop for Trainees, a 3-day set of presentations President, The Endocrine Society

F ROM  THE E DITOR

Dear Readers, intended to help this segment of the endocrine profession. We also high- In this first issue of Endocrine light Endocrine Trainee Day at ENDO News for the year, we have many 08—an event inaugurated last year items that highlight opportunities for to encourage discussions among peers fellows and trainees as they embark and with endocrinology leaders—at on their careers. These budding endo- which experts in research and in clini- crinologists are the future of the fi eld; cal practice will give their perspec- their discoveries and clinical work will tives and advice. help improve our understanding of Our cover feature this month endocrine function and dysfunction brings you up-to-date informtion for years to come. about promising new hypertesion In her letter to readers (prior treatments in the pipeline and page), Endocrine Society President another feature talks about steroid Margaret Shupnik talks about the misuse—a hot topic in the general many efforts to encourage participa- media these days. Finally, we bring tion of fellows and trainees in Society you an article about a new Society leadership. Doctoral-level trainees now white paper on improving minority can both vote and serve on Society participation in clinical trials. committees. This year’s annual meet- We hope you enjoy this January ing, ENDO 08, has even more events issue. ■ to help trainees discover career and funding opportunities. Sincerely, In the Society Update section, you can read Trainee Corner, which Cathy Kristiansen this month features the Society’s Editor Trainee Awards program. Here, Sum-Endocrine News mer Research Opportunities Awards and Summer Research Fel lowships are explained, as are various other awards

2008 E LECTION   FOR   O FFICERS   AND C OUNCIL The polls are now open for the 2008 Election and you are encouraged to vote. All members with voting privileges were sent an electronic ballot in early January. You can access online voting instructions by visiting http://www.endo-society.org/membership/election.cfm . Vote. D Q o a u c t t e   s 3 o t r i 0 a o 1 l n . - 9 l s e   4 s v 1 h e . o l 0   u 2 t l r 0 d a N 6   i   b n e o e e w r     e   d e s t i   h k r a i a e r s n c   e t y   @ e e n e d a o   r n t w ! d   o       e o l E - i s l g i o i z c b a i l b e e e t   t t h o    v K o a t n e   .   y.org. Ballots will be accepted through March 3, 2008.

Look for the electronic ballots in your e-mail.

EndocrineNews ™ is a trademark owned by The Endocrine Society MargaretA.Shupnik,Ph.D.  President [e-mail] Robert M. Carey, M.D., M.A.C.P.  President-Elect [e-mail] Andrew F. Stewart, M.D. Secretary-Treasurer [e-mail] Leonard Wartofsky, M.D.  Past-President [e-mail] Scott Hunt Executive Director [e-mail] Robert A. Fulcher Senior Director, Marketing & Communications [e-mail] Cathy Kristiansen Editor [e-mail] Jacqueline Ruttimann Staff Writer [e-mail] touch three Magazine Design & Production  www.touch3.com Cadmus Communications Printing & Prepress www.cadmus.com

Endocrine News is published 12 times a year by The Endocrine Society, 8401 Connecticut Ave., Suite 900, Chevy Chase, MD 20815 Phone [phone] Fax [phone] www.endo-society.org. • Send comments and suggestions for Endocrine News to [e-mail].  • Please send letters to the editor to [e-mail]. • For advertising information, contact Steve Hamburger at [e-mail] or 212-643-1750. • For classified advertising information, contact Christine Whorton at placement@ endo-society.org or 800-361-3906. Some photographs in this publication are chosen for design purposes and are not meant to be a representation.

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News,Notes,&Ins ts Ginsenoside Re colleagues investigated the Reduces Insulin insulin signaling pathway Resistance and the JNK and NF-κ B signaling cascade in 3T3-L1 ➤   In China, diabetes has adipocytes and high-fat been attributed for 2,000 diet (HFD) rats to dissect years to Qi deficiency. In Re’s molecular mechanism the past two centuries, it for improving insulin has been treated with gin- resistance. Their results seng and its extracts. Re- are published in Molecular search recently found that Endocrinology.* ginsenoside Re (Re) shows The team cultured significant anti-hypergly- 3T3-L1 cells in Dulbecco’s cemic effects and reduces minimal essential medium serum insulin levels in fed (DMEM) supplemented with or fasting ob/ob mice, sug- penicillin and measured glu- gesting insulin resistance cose uptake with a [ 3 H]2- improvement in peripheral deoxyglucose uptake assay. tissues. Guang Ning, M.D., They measured glucose infu- Ph.D., of the Shanghai sion rate (GIR) by euglyce- Jiao-Tong University School mic clamp in male Wistar of Medicine, China, and his rats fed regular chow,

A Pituitary-Specific M.D., Ph.D., at Ohio State Mouse Model for University, in Columbus, Carney Complex and his colleagues explored the role of PRKAR1A loss ➤   Carney complex (CNC) on pituitary tumorigenesis. is an inherited neoplasia Their results will soon be syndrome characterized by published in Molecular spotty skin pigmentation, Endocrinology.* myxomas, endocrine tumors, The researchers produced and schwannomas. CNC can a pituitary-specific knockout be caused by null muta- of the corresponding gene in tions in the PRKAR1A gene, mice, Prkar1a , by generating which encodes the type 1A a mouse line that expressed regulatory subunit of protein cre recombinase in pitu- kinase A (PKA). Among the itary cells using a rat Ghrhr syndrome’s endocrine tumors, promoter and crossed these growth hormone (GH)- mice with Prkar1a condi- producing pituitary tumors tional null animals. occur in about 10% of pa- The team compared tients, although biochemical pituitary tumor incidence abnormalities of the GH axis in these pituitary-specific are much more common. knockout mice with tumor Lawrence S. Kirschner, incidence in both wild-type

ww.endo-socie .org HFD, or HFD plus Re. After 2 JNK and NF-κ B activation— weeks, the HFD+Re animals both important in the also received 40 mg Re/kg/ inflammatory response and day by peritoneal injection thus associated with insulin for a further 2 weeks. The resistance. Re also altered researchers infused insulin I κ B α abundance similarly to before clamping to calculate aspirin. whole body insulin sensitiv- The researchers con- ity and examined the insu- clude, “It is certain that lin signaling cascade (IR β , Re has an anti-inflamma- IRS-1, PI3K, Akt and AS160, tion effect,” associated and Glut4 translocation) with anti-hyperglycemic and the JNK MAPK and NF- action in a state of insulin κ B signaling cascade. resistance, so Re might be Re increased glucose promising as an anti- uptake in 3T3-L1 cells and diabetic drug. ■ GIR in HFD rats. Re initiated * Zhang Z, Li X, Lv W, et al. insulin signaling at IRS-1, passing through PI3K and Ginsenoside Re Reduces Insulin Resistance through Inhibition of its downstream signaling c-Jun NH2-Terminal Kinase and cascade. Re also impressively Nuclear Factor-B. Mol Endocrinol , suppressed January 2008.

and conventional Prkar1a an- axis abnormalities analo- imals. Tumors existed in both gous to those in human groups at 18 months, but the CNC patients, so this model pituitary-specific knockout might be useful to study the mice exhibited a significant- pituitary tumorigenesis in ly higher tumor frequency humans and, more gener- (10/21, 48%) vs. controls ally, for studying pituitary (5/28, 18%). This differ- signaling pathway– ence was even more striking specific phenomena. They when prolactinomas—tumors conclude that complete loss observed at background of Prkar1a is necessary “for levels in both groups (N=4 CNC-associated pituitary per group)—were removed tumorigenesis, and that from the analysis. Impor- the secretory effects … (of tantly, serum GH levels were Prkar1a loss) are limited to significantly elevated in the GH-secreting cells.” ■ pituitary-specific knock- out animals compared to * P Y a i r n l  o Z w ,  W AF i , l  li A a s m a s S -Si K m ir o s n c s h  n L, e  rAS controls, regardless of the Pituit-ifi  c ,   knockoutofth . e presence of frank tumor, as Carne a y r  y C s o p m ec plexGenePrkar1a seen in CNC patients. leads to pituitary tumorigenesis. The researchers observe that Molecular Endocrinology , in press. the mouse tumors reveal GH

CM o-thLi YK

Not an actual SYMLIN patient.

SYMLIN is indicated as an adjunct treatment for patients with type 2 or type 1 diabetes who use mealtime insulin and have not a chieved desired glucose control despite optimal insulin therapy (with or without a concurrent sulfonylurea agent and/or metformin in type 2 dia betes). WARNING SYMLIN is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with SYMLIN use occurs, it is seen within 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk. Most adverse events were gastrointestinal in nature (nausea). The incidence of nausea was higher at the beginning of treatment with SYMLIN and decreased with time in most patients. SYMLIN and insulin should always be administered as separate injections and should ne ver be mixed. Proper patient selection is critical to safe and effective use of SYMLIN. * In a 6-month, open-label clinical trial, insulin-using patients with type 2 (n = 166) or type 1 (n = 265) diabetes lost, on ave rage, 6 lbs. Please see Brief Summary of SYMLIN Prescribing Information on reverse side. www.SYMLIN.com

In my fight with diabetes, I bring SYMLIN ® to the table

SYMLIN offers me: • Improved A1C • Postprandial glucose control • Enhanced satiety with proven weight loss*

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NOW AVAILABLE New SymlinPen ™ offers your patients simple, fixed dosing.

01-07-5929-A ©2007 Amylin Pharmaceuticals, Inc. All rights reserved. The SYMLIN mark, SYMLIN design mark, and SymlinPen are trademarks of Amylin Pharmaceuticals, Inc.

ageMP25P5:70/11/21dxq.a41812 2 7 1Q 3 Q 13 071. 81a4 211. C 0 m 2 7 y 21 242-765  212  t , Ar c.In

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SYMLIN Brief Summary: For complete details, please see Prescribing Information. WARNING  SYMLIN is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with SYMLIN use occurs, it is seen within 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk. INDICATIONS AND USAGE SYMLIN is given at mealtimes and is indicated for: • Type 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin. • Type 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy. CONTRAINDICATIONS SYMLIN is contraindicated in patients with any of the following: • a known hypersensitivity to SYMLIN or any of its components, including metacresol; • a confirmed diagnosis of gastroparesis; • hypoglycemia unawareness. WARNINGS Patient Selection Proper patient selection is critical to safe and effective use of SYMLIN. Before initiation of therapy, the patient’s HbA1c, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weight should be revi ewed. SYMLIN therapy should only be considered in patients with insulin-using type 2 or type 1 diabetes who fulfill the following crit eria: • have failed to achieve adequate glycemic control despite individualized insulin management; • are receiving ongoing care under the guidance of a healthcare professional skilled in the use of insulin and supported by the s ervices of diabetes educator(s). Patients meeting any of the following criteria should NOT be considered for SYMLIN therapy: • poor compliance with current insulin regimen; • poor compliance with prescribed self-blood glucose monitoring; • have an HbA1c >9%; • recurrent severe hypoglycemia requiring assistance during the past 6 months; • presence of hypoglycemia unawareness; • confirmed diagnosis of gastroparesis; • require the use of drugs that stimulate gastrointestinal motility; • pediatric patients. Hypoglycemia. SYMLIN alone does not cause hypoglycemia. However, SYMLIN is indicated to be co-administered with insulin therapy and in this setting SYMLIN increases the risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diab etes. Severe hypoglycemia associated with SYMLIN occurs within the first 3 hours following a SYMLIN injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Therefore, when introducing SYMLIN therapy, appropriate precautions need to be taken to avoid increasing the risk for insulin-induced seve re hypoglycemia. These precautions include frequent pre- and post-meal glucose monitoring combined with an initial 50% reduction in pre-meal doses of short-acting insulin (see DOSAGE and ADMINISTRATION). Symptoms of hypoglycemia may include hunger, headache, sweating, tremor, irritability, or difficulty concentrating. Rapid reduct ions in blood glucose concentrations may induce such symptoms regardless of glucose values. More severe symptoms of hypoglycemia includ e loss of consciousness, coma, or seizure. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of di abetes; diabetic nerve disease; use of medications such as beta-blockers, clonidine, guanethidine, or reserpine; or intensified diabetes control. The addition of any antihyperglycemic agent such as SYMLIN to an existing regimen of one or more anti- hyperglycemic agents (e.g., insulin, sulfonylurea), or other agents that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments and particularly close monitoring of blood glucose. The following are examples of substances that may increase the blood glucose-lowering effect and susceptibility to hypoglycemia: oral anti-diabetic products, ACE inhibitors, diisopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicy lates, and sulfonamide antibiotics. Clinical studies employing a controlled hypoglycemic challenge have demonstrated that SYMLIN does not alter the counter-regulat ory hormonal response to insulin-induced hypoglycemia. Likewise, in SYMLIN-treated patients, the perception of hypoglycemic symptom s was not altered with plasma glucose concentrations as low as 45 mg/dL. PRECAUTIONS General: Hypoglycemia (See WARNINGS). SYMLIN should be prescribed with caution to persons with visual or dexterity impairment. Information for Patients: Healthcare providers should inform patients of the potential risks and advantages of SYMLIN therapy. Healthcare providers should also inform patients about self-management practices including glucose monitoring, proper injection technique, timing of dosing, and proper storage of SYMLIN. In addition, reinforce the importance of adherence to meal planning, physical activity, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. Refer patient s to the SYMLIN Medication Guide and Patient Instructions for Use for additional information. Instruct patients on handling of special situations such as intercurrent conditions (illness or stress), an inadequate or omitt ed insulin dose, inadvertent administration of increased insulin or SYMLIN dose, inadequate food intake or missed meals. SYMLIN and insulin should always be administered as separate injections and never be mixed. Women with diabetes should be advised to inform their healthcare professional if they are pregnant or contemplating pregnancy. Renal Impairment: The dosing requirements for SYMLIN are not altered in patients with moderate or severe renal impairment (Cl Cr >20 to ≤50 mL/min). No studies have been done in dialysis patients. Hepatic Impairment: Studies have not been performed in patients with hepatic impairment. However, hepatic dysfunction is not expected to affect blood concentrations of SYMLIN. Allergy: Local allergy. Patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than SYMLIN, such as irritants in a skin cleansing agent or improper injection technique. Systemic Allergy. In controlled clinical trials up to 12 months, potential systemic allergic reactions were reported in 65 (5%) of type 2 patients and 59 (5%) of type 1 SYMLIN-treated patients. Similar reactions were reported by 18 (4%) and 28 (5%) of placebo-treated type 2 and type 1 patients, respectively. No patient receiving SYMLIN was withdrawn from a trial due to a potential systemic allergic reaction. Drug Interactions Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointes tinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., α-g lucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a conc omitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at l east 1 hour prior to or 2 hours after SYMLIN injection.

In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No for mal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. Pregnancy Teratogenic Effects: Pregnancy Category C. No adequate and well-controlled studies have been conducted in pregnant women. Studies in perfused human placenta indicate that SYMLIN has low potential to cross the maternal/fetal placental barrier. Embryo fetal toxicity studies with SYMLIN have been performed in rats and rabbits. Increases in congenital abnormalities (neural tube defect , cleft palate, exencephaly) were observed in fetuses of rats treated during organogenesis with 0.3 and 1.0 mg/kg/day (10 and 47 times the exposure resulting from the maximum recommended human dose based on AUC, respectively). Administration of doses up to 0.3 mg/kg/day SYMLIN (9 times maximum recommended dose based on AUC) to pregnant rabbits had no adverse effects in embryofetal development; however, animal reproduction studies are not always predictive of human response. SYMLIN should be used during pregnancy only if it is determined by the healthcare professional that the potential benefit justifies the potential risk to the fetus. Nursing Mothers It is unknown whether SYMLIN is excreted in human milk. Many drugs, including peptide drugs, are excreted in human milk. Theref ore, SYMLIN should be administered to nursing women only if it is determined by the healthcare professional that the potential benefi t outweighs the potential risk to the infant. Pediatric Use Safety and effectiveness of SYMLIN in pediatric patients have not been established. Geriatric Use SYMLIN has been studied in patients ranging in age from 15 to 84 years of age, including 539 patients 65 years of age or older. The change in HbA1c values and hypoglycemia frequencies did not differ by age, but greater sensitivity in some older individuals cannot be ruled out. Thus, both SYMLIN and insulin regimens should be carefully managed to obviate an increased risk of severe hypoglycemia. ADVERSE REACTIONS Adverse events (excluding hypoglycemia, discussed below) commonly associated with SYMLIN when co-administered with a fixed dose of insulin in the long-term, placebo-controlled trials in insulin-using type 2 patients and type 1 patients, respectively, are pre sented in the following paragraphs. The same adverse events were also shown in the open-label clinical practice study, which employed flexible insulin dosing. These are also presented below. Adverse events in patients with insulin-using type 2 diabetes —Treatment-emergent adverse events occurring with ≥5% incidence and greater incidence with SYMLIN (120 mcg) compared with placebo in long-term, placebo-controlled trials are shown f or placebo + insulin (N=284), SYMLIN + insulin (N=292), and for the open-label clinical practice study of SYMLIN + insulin (N=166) , respectively (n [%]): nausea 34 (12), 81 (28), 53 (30); headache 19 (7), 39 (13), 8 (5); anorexia 5 (2), 27 (9), 1 (<1); vomiti ng 12 (4), 24 (8), 13 (7); abdominal pain 19 (7), 23 (8), 3 (2); fatigue 11 (4), 20 (7), 5 (3); dizziness 11 (4), 17 (6), 3 (2); coughing 12 (4), 18 (6), 4 (2); pharyngitis 7 (2), 15 (5), 6 (3). Adverse events in patients with type 1 diabetes —Treatment-emergent adverse events occurring with ≥5% incidence and greater incidence with SYMLIN (30 or 60 mcg) compared to placebo in long-term, placebo-controlled studies are shown for placebo + insul in (N=538), SYMLIN + insulin (N=716), and for the open-label clinical practice study of SYMLIN + insulin (N=265), respectively (n [%]): nausea 92 (17), 342 (48), 98 (37); anorexia 12 (2), 122 (17), 0 (0); inflicted injury 55 (10), 97 (14), 20 (8); vomiting 36 (7), 82 (11), 18 (7); arthralgia 27 (5), 51 (7), 6 (2); fatigue 22 (4), 51 (7), 12 (4.5); allergic reaction 28 (5), 41 (6), 1 (<1); dizziness 21 (4), 34 (5), 5 (2). Most adverse events were gastrointestinal in nature. In patients with type 2 or type 1 diabetes, the incidence of nausea was hi gher at the beginning of SYMLIN treatment and decreased with time in most patients. The incidence and severity of nausea are reduced when S YMLIN is gradually titrated to the recommended doses (see DOSAGE and ADMINISTRATION). Severe Hypoglycemia SYMLIN alone (without the concomitant administration of insulin) does not cause hypoglycemia. However, SYMLIN is indicated as a n adjunct treatment in patients who use mealtime insulin therapy and co-administration of SYMLIN with insulin can increase the ri sk of insulin-induced hypoglycemia, particularly in patients with type 1 diabetes (see Boxed Warning). The incidence of severe hypogl ycemia during the SYMLIN clinical development program is summarized in the following paragraphs. Severe hypoglycemia in patients with insulin-using type 2 diabetes —Incidence and event rate of severe hypoglycemia in long-term, placebo-controlled studies (no insulin dose-reduction during initiation) and in the open-label, clinical practice st udy (insulin dose-reduction during initiation) are as follows. In the long-term, placebo-controlled studies, the patient-ascertaine d* event rate (event rate/patient year) for placebo + insulin was 0.24 and 0.13, at 0-3 months (n=284) and at >3-6 months (n=251), respective ly, and the patient-ascertained incidence was 2.1% and 2.4%, respectively; medically assisted** event rate (event rate/patient year ) was 0.06 and 0.07, at 0-3 months and at >3-6 months, respectively, and the medically assisted incidence was 0.7% and 1.2%, respecti vely. Also in these studies, the patient-ascertained event rate (event rate/patient year) for SYMLIN + insulin was 0.45 and 0.39, at 0-3 months (n=292) and at >3-6 months (n=255), respectively, and the patient-ascertained incidence was 8.2% and 4.7%, respectively; medica lly assisted event rate (event rate/patient year) was 0.09 and 0.02, at 0-3 months and at >3-6 months, respectively, and the medica lly assisted incidence was 1.7% and 0.4%, respectively. In the open-label, clinical practice study of SYMLIN + insulin, the patient -ascertained event rate (event rate/patient year) was 0.05 and 0.03, at 0-3 months (n=166) and at >3-6 months (n=150), respectively, and the patient-ascertained incidence was 0.6% and 0.7%, respectively; medically assisted event rate (event rate/ patient year) was 0.0 5 and 0.03, at 0-3 months and at >3-6 months, respectively, and the medically assisted incidence was 0.6% and 0.7%, respectively. Severe hypoglycemia in patients with type 1 diabetes —Incidence and event rate of severe hypoglycemia in long-term, placebo- controlled studies (no insulin dose-reduction during initiation) and in the open-label, clinical practice study (insulin dose-r eduction during initiation) are as follows. In the long-term, placebo-controlled studies, the patient-ascertained* event rate (event rat e/patient year) for placebo + insulin was 1.33 and 1.06, at 0-3 months (n=538) and at >3-6 months (n=470), respectively, and the patient- ascertained incidence was 10.8% and 8.7%, respectively; medically assisted** event rate (event rate/ patient year) was 0.19 and 0.24, at 0-3 months and at >3-6 months, respectively, and the medically assisted incidence was 3.3% and 4.3%, respectively. Also in t hese studies, the patient-ascertained event rate (event rate/patient year) for SYMLIN + insulin was 1.55 and 0.82, at 0-3 months (n= 716) and at >3-6 months (n=576), respectively, and the patient-ascertained incidence was 16.8% and 11.1%, respectively; medically assist ed event rate (event rate/patient year) was 0.50 and 0.27, at 0-3 months and at >3-6 months, respectively, and the medically assis ted incidence was 7.3% and 5.2%, respectively. In the open-label, clinical practice study of SYMLIN + insulin, the patient-ascertai ned event rate (event rate/ patient year) was 0.29 and 0.16, at 0-3 months (n=265) and at >3-6 months (n=213), respectively, and the pati ent- ascertained incidence was 5.7% and 3.8%, respectively; medically assisted event rate (event rate/ patient year) was 0.10 and 0. 04, at 0-3 months and at >3-6 months, respectively, and the medically assisted incidence was 2.3% and 0.9%, respectively. * Patient-ascertained severe hypoglycemia: Requiring the assistance of another individual (including aid in ingestion of oral carbohydrate); and/or requiring the administration of glucagon injection, intravenous glucose, or other medical intervention. ** Medically assisted severe hypoglycemia: Requiring glucagon, IV glucose, hospitalization, paramedic assistance, emergency room visit, and/or assessed as an SAE by the investigator. OVERDOSAGE Single 10 mg doses of SYMLIN (83 times the maximum dose of 120 mcg) were administered to three healthy volunteers. Severe nause a was reported in all three individuals and was associated with vomiting, diarrhea, vasodilatation, and dizziness. No hypoglycemi a was reported. SYMLIN has a short half-life and in the case of overdose, supportive measures are indicated. DOSAGE AND ADMINISTRATION SYMLIN dosage differs depending on whether the patient has type 2 or type 1 diabetes (consult Prescribing Information for dosing instructions). When initiating therapy with SYMLIN, initial insulin dose reduction is required in all patients (both type 2 and type 1) to reduce the risk of insulin-induced hypoglycemia. As this reduction in insulin can lead to glucose elevations, patien ts should be monitored at regular intervals to assess SYMLIN tolerability and the effect on blood glucose, so that individualized insulin adjustments can be initiated. If SYMLIN therapy is discontinued for any reason (e.g., surgery or illnesses), the same initiation protocol s hould be followed when SYMLIN therapy is re-instituted. The SymlinPen TM pen-injectors and SYMLIN vials are manufactured for: Amylin Pharmaceuticals, Inc., San Diego, CA 92121 USA 1-800-349-8919 http://www.symlin.com Rx only Literature revised September 2007. 01-06-3081-B ©2007 Amylin Pharmaceuticals, Inc. All rights reserved. The SYMLIN mark, SYMLIN design mark, and SymlinPen are trademarks of Amylin Pharmaceuticals, Inc.

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Diabetes Risk in Post- The researchers say that m o ausal Women hormone therapy might en p reduce diabetes risk in ➤ Depending on the some patients. They suggest hormones used, postmeno- further studies to determine pausal women who opt for whether “1) reductions hormone therapy might in endogenous estrogen have decreased risk for production at menopause bone fractures and certain (i.e., ovarian aging) trig- types of cancers. Another ger changes in peripheral benefit recently seen in insulin action independent mice but not quantified in of chronological aging and humans might be a reduc- changes in adiposity; 2) tion in diabetes. physiologic changes in glu- Rachael E. Van Pelt, cose and insulin metabolism Ph.D., and her team at the following estrogen with- University of Colorado Den- drawal translate to increased ver, studied 11 postmeno- an estrogen-treated day and after estrogen treatment, risk of diabetes; and 3) the pausal women treated with a control (no estrogen) day.  the mean glucose disposal  potential consequences of an estrogen-based trans- The results of this study will  rate was not different on  estrogen deficiency can be dermal patch (Estraderm), appear soon in The Journal the estrogen-treated day  mitigated only when treated one day before receiving a of Clinical Endocrinology & compared to the control day.  early in menopause.” ■ hyperglycemic clamp that Metabolism.* However, estrogen increased infused glucose and L- The team found no alter-  glucose disposal in women * Van Pelt RE, Schwartz RS, Kohrt arginine to test their insulin ation in insulin secretion or  who were only a few years c W lea M r . a   n In c s e u   l a i f n t   e s r e  s c u re b t a i c o u n t   e a   n e d st   radiol  secretion and clearance. clearance on the estrogen-  past menopause, but de- administration in postmenopaus - The researchers measured treated day compared to  creased glucose disposal in al women. J Clin Endocrinol Metab , serum insulin, glucose, the control day. Although  women who were more years in press. C-peptide, and estrogen on fasting glucose was lower  past menopause. Neonatal Leptin that supplementing neonate showed more resistance Reduces Obesity and and lower sensitivity to Metabolic Risks r o a f  t o s  ra w l i   t le h  p p ti h n y   s d i u ol ri o n gi g c  l a a l  c d ta o t s i e o s n    insulin. Leptin-treated ani- ➤ The worldwide increase protected against adult obe- mals also had lower plasma in obesity has spurred sity. In their current study, leptin concentrations investigation into the envi- the team investigated how regardless of feeding regime ronmental factors in early neonate leptin supplementa- and exogenous leptin life affecting adult body tion influences glucose and suppressed feeding more weight regulation. Several leptin homeostasis and food strongly in those animals studies have shown that preferences in rats. A report when mature. breastfeeding, compared will soon be published in “Taking into account with formula feeding, lowers Endocrinology.* that leptin is not present the risk of later obesity. The researchers found in infant formula and that Levels of leptin—an ap- that leptin-treated animals leptin in human breast milk petite-suppressing hor- weighed less in adulthood varies widely, … these find- mone not present in infant and ate fewer calories than ings may have important formula—in maternal milk controls, which had a stron- implications for the preven- are negatively correlated ger preference for fat-rich tion of obesity and the with infant body mass index  food. Under various feeding  metabolic syndrome,” the (BMI), suggesting that  conditions (ad libitum,  researchers concluded. ■ leptin might lower the risk  fasting, and after fasting), le t -treated animals had * Sánchez J, Priego T, Palou M, for childhood obesity.  p in Tobaruela A, Palou A, Picó C. And I r n e  e u  a P rl a i l e o r  u r ,  e P s h e . a D rc ., h   , a   t the  l a o n w d e   r a     p s l m as al m l a    i i n n s c u r l e i a n s  l e e  i v n e   ls  Oral supplementation with er physiological doses of leptin Universidad de las Islas Ba-  these levels after eating. during lactation in rats improves insulin sensitivity and affects leares in Palma de Mallorca,  Control animals not treated food preferences later in life. Spain, and his team showed  with leptin during lactation Endocrinology , in press.

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Atrial Nariuretic results, the researchers Peptide Against then tested a group of 13 Peripheral Arterial p co at n i v e e n n ts t   io w n it a h l    t P h A e D ra  f p o i r e   s w  h h a o d m     Diseases not accomplished preciabl ap e ➤ Peripheral arterial improvement. They adminis- diseases (PAD) are caused tered intravenous carperitide by arterial sclerosis and continuously for 2 weeks impaired collateral vessel to Fontaine’s class I–III PAD formation. Diabetes exac- patients and for 4 weeks to erbates these conditions, class IV patients. Carperitide contributing to numerous administration improved complications, including recently reported that ANP published soon in Endocri-the patients’ ankle-brachial diabetic gangrene—a at physiological concentra-nology.* pressure index, intermittent condition that can lead to tions induces endothelial  They used C57BL/6 male  claudication, rest pain, and amputations. regeneration in the human  mice in which diabetes  ulcers. The researchers con- Carperitide is a re- coronary artery and umbili -  was induced by repetitive  clude that carperitide may combinant human atrial cal vein. Those findings led  intraperitoneal injections of  provide a new therapeutic nariuretic peptide (ANP) them to further explore  streptozotocin. Carperitide  strategy for treating PAD in approved for use in Japan ANP’s benefits. They exam-  significantly accelerated  patients whose disease does and widely used there to ined the effect of carper-  blood flow recovery in this  not respond to convention- treat congestive heart fail- itide on vascular regenera-  mouse model of ischemia-  al therapies. ■ ure. Its safety is clinically tion in mouse models of  induced angiogenesis. The proven. Hiroshi Itoh, M.D., diabetes and investigated  positive effect occurred in * Park K, Itoh H, Yamahara K, et Ph.D., and colleagues at possible therapeutic effects  both diabetic and non- a n l. a   ri T u h r e e r ti a c p   e p u e t p i t c i   d p e o  a te d n m ti i a n l i   s o t f r   a a t t i r o ia n l    Kyoto University Graduate of carperitide in PAD pa-  diabetic mice. on peripheral arterial diseases. School of Medicine, Japan,  tients. Their study will be Encouraged by these Endocrinology, in press.

Dexamethasone Alters exposure to elevated glu- with the synthetic gluco- with a conversion into Lipid Metabolism cocorticoid levels produces corticoid dexamethasone. diabetogenic lipids. The re- in Mice insulin resistance. The un- Dexamethasone has a searchers analyzed the low derlying molecular mecha- 50-fold greater affinity for molecular weight metabo- ➤ Glucocorticoids help nisms by which this hap- the glucocorticoid receptor lites from muscle extracts regulate glucose homeosta- pens might reflect potential than cortisol. It can gener- and found no dysregulation sis and lipid metabolism, targets for pharmacological  ate the insulin-resistant  of muscle amino acids, as but prolonged interventions.  state in a relatively short  has been associated with With this in mind, Didier  time, through molecular  dexamethasone-induced Laurent, Ph.D., and his col-  mechanisms that are not  muscle proteolysis. leagues at Novartis Institutes  fully understood.  In a paper to be pub- for Biomedical Research  As expected, the  lished soon in Endocrinol- Inc., in Cambridge, Mass.,  mice showed higher food ogy,* the researchers say characterized muscle  consumption and weight  that given the widespread lipid metabolism in  gain relative to age- and  clinical use of glucocor- a dexamethasone-  diet-matched animals dosed  ticoids, the experimental aggravated with saline only. The re-  model they characterized diet-induced searchers’ detailed study of  might prove useful in obesity (DIO)  many metabolic parameters  finding interventions to murine mod-  found that the dexametha-  prevent and treat steroid el of insulin  sone-induced resistance in  diabetes. ■ resistance. DIO mice is associated with They fed male  a profound perturbation * Gounarides JS, Korach-André C57BL/6 mice  of lipid metabolism. The T M, Killa O ry K, Argentieri G,  a high-fat diet  changes were particularly of u   r d n e e x r a   me ,  t L h a a u s r o e n n e t     o D n .     g E l f u fe c c o t s   e  for 2 months,  evident in muscle, where an tolerance and fat metabolism in and then chal-  increased uptake of circu- a diet-induced obesity mouse lenged them  lating lipids occurred along model. Endocrinology , in press.