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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


Core Defects Of Type 2 Diabetes: Filling The Knowledge Gaps, Improving Practice


GOAL
To provide endocrinologists, diabetologists, and primary care physicians with up-to-date information on the treatment and management of type 2 diabetes.

TARGET AUDIENCE
This activity is designed for endocrinologists, diabetologists, and primary care physicians. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this activity. At the conclusion of this activity, the participant should be able to:

  • Outline the physiologic effects of incretin hormones, including the mechanism of action, the role of GLP-1, and GLP-1 impairment in type 2 diabetes.
  • Evaluate the therapeutic strategies based on GLP-1 pathways, in addition to the methods to enhance GLP-1 receptor stimulation and action.
  • Discuss the challenges with current therapies for type 2 diabetes and explain the new clinical approaches to the disease.
  • Assess the early evidence from the clinical trial results of the GLP-1Ðrelated agents, including glucagon-like peptide-1 analogs, DPP-IV inhibitors, and exenatide.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from Eli Lilly and Company.

Full Disclosure Policy Affecting CME Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:

PROGRAM DIRECTOR

Annabelle Rodriguez, MD
Director, Diabetes Management Service
Johns Hopkins Bayview Medical Center
Assistant Professor of Medicine
Division of Endocrinology
The Johns Hopkins University School of Medicine
The Johns Hopkins Hospital
Baltimore, Maryland, USA
Dr Rodriguez reports having no significant financial or advisory relationships with corporate organizations related to this activity.

PARTICIPATING FACULTY

A. Enrique Caballero, MD
Associate Medical Director of Professional Education
Director of the Latino Diabetes Initiative
Endocrinologist/Clinical Investigator
Joslin Diabetes Center
Harvard Medical School
Boston, Massachusetts, USA
Dr Caballero reports receiving grants/ research support from Aventis; and serving as a consultant for Amylin, Aventis, Eli Lilly and Company, Pfizer Inc, and Takeda.

Antonio R. Chacra, MD
Professor de Endocrinologia
Departamento de Medicina Interna
Universidade Federal de São Paulo
Escola Paulista de Medicina
São Paulo, Brasil
Dr Chacra reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Adriana Costa e Forti, MD, PhD
Professora Adjunta da Faculdade de Medicina
Universidade Federal do Ceará
Diretora do Centro Integrado de Diabetes e Hipertensão
Fortaleza, Ceara, Brasil
Dr Forti reports having no significant financial or advisory relationships with corporate organizations related to this activity.

Notice: Faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Core Defects Of Type 2 Diabetes: Filling The Knowledge Gaps, Improving Practice
Annabelle Rodriguez, MD

According to the World Health Organization's prevalence estimates, approximately 4.6 million people in Brazil had type 2 diabetes in 2000, and that number is expected to more than double by 2030.1 Although the prevalence of diabetes in Brazil has been reported at rates varying from 6.2% to 12.1%, the trend for increasing prevalence with age has been repeatedly confirmed.2-4 In the Ribeir‹o Preto study, prevalence rates for diabetes increased from 3.3% in those patients aged 30 to 39 to 21.7% in those aged 60 to 69.3 In a study in Bambui, the prevalence of diabetes and impaired fasting glycemia was reported at 2.3% and 5.6%, respectively, for the adult population (18—59 years of age), but was reported at 14.6% and 13.3%, respectively, in the elderly population (³60 years of age).4 The finding that less than 50% of patients in the study were receiving medications for diabetes underscores one of the complicated issues of effectively managing this disease. Results also emphasized the importance of reducing physical inactivity, obesity, dyslipidemia, and alcohol consumption to stem the increasing prevalence of diabetes.

Long-term management of type 2 diabetes is challenging because of the abnormal metabolism of carbohydrates, lipids, and proteins, in addition to the presence of insulin resistance and impaired insulin secretion. Cardiovascular problems, retinopathy, neuropathy, and other complications are commonly present by the time a diagnosis of diabetes has been made. These complications magnify the need for earlier diagnosis and intervention to prevent serious diabetes-related conditions.

In a community screening program conducted in 2001, 95% of Brazilian municipalities participated and 73% of the targeted population was screened.5 Of those screened, 15.7% were identified as having type 2 diabetes. Results from this program highlighted the effectiveness of a screening program to identify patients with type 2 diabetes and increase awareness at the primary-care level.

Studies indicate that improved glycemic control may slow the progression of disease severity. As an indicator of glycemic control, an A1c level of 6.5% and below is commonly used as a target goal associated with reduced complications. Although diet, exercise, and pharmacologic agents are frequently used to improve glycemic control, it remains an elusive goal for many patients with type 2 diabetes. Oral agents used in the treatment of type 2 diabetes frequently do not adequately control glycemia, prompting continued research into identifying alternative approaches for pharmacologic intervention.

Incretins, by virtue of their ability to stimulate insulin secretion, have been studied intensely for use in managing patients with type 2 diabetes who can produce insulin endogenously. One such incretin, glucagon-like peptide-1 (GLP-1), is secreted by L cells in the gastrointestinal tract. Patients with type 2 diabetes have reduced GLP-1 levels but a preserved insulin secretory response. These factors combined provide the rationale for GLP-1 therapy in type 2 diabetes. Studies have demonstrated that GLP-1 enhances insulin secretion and stimulates b-cell proliferation. The utility of GLP-1 as a therapy is tempered by the peptide's rapid hydrolysis by dipeptidyl peptidase-IV (DPP-IV). To circumvent this issue, therapeutic approaches focus on enhancing GLP-1 receptor stimulation and action through the use of oral DPP-IV inhibitors and slowly hydrolyzed or nonhydrolyzable analogs of GLP-1 (incretin mimetics). In 2005, the US Food and Drug Administration approved the first of these compounds—a natural GLP-1—like peptide, exendin-4 (exenatide)—as adjunctive therapy for patients with type 2 diabetes who had not achieved adequate glycemic control with metformin, a sulfonylurea, or a combination of these agents.

In this issue of Johns Hopkins Advanced Studies in Medicine, Antonio R. Chacra, MD, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, presents the current understanding of the biologic action of incretin hormones. Dr Chacra explains the studies that alluded to the presence of incretin hormones, in addition to the studies that suggested the utility of incretin-based therapies for type 2 diabetes. The biologic action of incretin hormones is presented, with focus on the role of GLP-1 in the central regulation of feeding, effects on b cells, and impairment in type 2 diabetes. In particular, he describes the acute effects of GLP-1 as enhancing glucose-dependent insulin secretion, subacute effects as stimulating transcription of proinsulin and biosynthesis of insulin, and chronic effects on stimulating proliferation and neogenesis of b cells. Dr Chacra also explains the observed impairment of the incretin effect in type 2 diabetes that has led to incretin-based approaches to this disease state.

Adriana Costa e Forti, MD, PhD, Federal University of Ceará, Fortaleza, Brazil, continues the discussion by exploring the therapeutic strategies for type 2 diabetes that are based on GLP-1 pathways and clinical trial results of GLP-1—based therapies. Dr Forti describes the molecular action of GLP-1 in activating a signal transduction pathway that ultimately increases insulin biosynthesis and secretion. She describes the importance of the Zander study that demonstrated the dual action of GLP-1 in stimulating insulin secretion from b cells and reprogramming defective b cells to become more sensitive to glucose.

Treatment approaches, such as exenatide, liraglutide, CJC-1131, and Albugon (albumin/GLP-1, GlaxoSmithKline, Triangle Park, NC), are currently under study and are based on enhancing incretin action. Dr Forti reviews results from recent clinical trials of the oral DPP-IV inhibitor vildagliptin (NVP-LAF237), in addition to the GLP-1 analogs liraglutide (NN2211), CJC-1131, and the naturally occurring peptide exendin-4 (exenatide), including results from a 52-week open-label extension of the AMIGO trials.

A. Enrique Caballero, MD, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, concludes the issue with a clinician interview. Dr Caballero discusses the impact of type 2 diabetes on societies and offers approaches to improved care. He presents a view explaining how exenatide is expected to impact current treatment approaches to type 2 diabetes and the implications of incretin-based therapies for the long-term management of the disease. Lastly, Dr Caballero explores the possible impact of incretin-based therapies on comorbid conditions and their potential role in prediabetic states.

As with many challenging chronic conditions, research continues for therapeutic compounds with greater efficacy and improved safety profiles. The increased understanding of incretin biology has provided a fertile area of research for exploiting incretin-based therapies for the treatment of type 2 diabetes. The next decade is expected to usher in a diverse array of therapeutic options for type 2 diabetes, enabling physicians and their patients to more adequately control blood glucose levels. We hope this issue of Johns Hopkins Advanced Studies in Medicine provides you with pertinent information that you can utilize in your own clinical practice.

REFERENCES

1. World Health Organization. Prevalence of diabetes in the WHO Region of the Americas. Available at: http://www.who.int/diabetes/facts/world_figures/en/index3.html. Accessed March 23, 2006.
2. Theme-Filha MM, Szwarcwald CL, Souza-Junior PR. Socio-demographic characteristics, treatment coverage, and self-rated health of individuals who reported six chronic diseases in Brazil, 2003. Cad Saude Publica. 2005;21 (suppl):43-53. Epub 2006 Jan 31.
3. Torquato MT, Montenegro Junior RM, Viana LA, et al. Prevalence of diabetes mellitus and impaired glucose tolerance in the urban population aged 30-69 years in Ribeirão Preto (Sao Paulo), Brazil. Sao Paulo Med J. 2003;121:224-230.
4. Passos VM, Barreto SM, Diniz LM, Lima-Costa MF. T2DM: prevalence and associated factors in a Brazilian community—the Bambui health and aging study. Sao Paulo Med J. 2005;123:66-71. Epub 2005 Jun 8.
5. Nucci LB, Toscano CM, Maia AL, et al. A nationwide population screening program for diabetes in Brazil. Rev Panam Salud Publica. 2004;16:320-327.

*Director, Diabetes Management Service, Johns Hopkins Bayview Medical Center, Assistant Professor of Medicine, Division of Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Address correspondence to: Annabelle Rodriguez, MD, Director, Diabetes Management Service, Johns Hopkins Bayview Medical Center, Assistant Professor of Medicine, Division of Endocrinology, The Johns Hopkins University School of Medicine, The Johns Hopkins Hospital, A Building, Room 114, 4940 Eastern Avenue, Baltimore, MD 21224 USA.
E-mail: arodrig5@jhmi.edu.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his/her article and all its contents.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.