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Posts Tagged ‘Endocrine Disorders’


Reporter: Aviva Lev-Ari, PhD, RN

Diabetes Drug Discovery and Beyond

October 1-3, 2012

Copley Marriott Hotel, Boston, MA

The Diabetes Drug Discovery and Beyond meeting will cover progress on promising pre-clinical and early clinical phase diabetes drug candidates. But this year, we will also highlight emerging therapeutic targets that probe how the underlying defects in metabolic diseases are connected. Some presentations will cover obesity, other metabolic disorders and cardiovascular disease in the context of diabetes and energy homeostasis.

TUESDAY, OCTOBER 2


TARGETS FOR NEW DIABETES THERAPIES

1:30 pm Chairperson’s Remarks

Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer

1:40 FEATURED SPEAKER

Targeting Diabetes via Glucocorticoid Modulation: The Identification of Advanced 11b-HSD-1 Inhibitors

Jeffrey RoblJeffrey A. Robl, Ph.D., Executive Director, Metabolic Diseases R&D, Bristol-Myers Squibb

Preventing excess glucocorticoid tone in metabolically active tissues such as the liver and adipose may be  beneficial in addressing glucose homeostasis and hyperglycemia in patients with type 2 diabetes. We have optimized a series of triazolopyridine based inhibitors resulting in the advancement of BMS-770767 to phase 2 clinical trials. The discovery of BMS-770767 will be presented as well as a description of its development  properties, pharmacokinetics, and pre-clinical pharmacology profile.

2:10 Dyslipidemia Targets and Diabetes

Rebecca Taub, M.D., CEO, Madrigal Pharmaceuticals

This talk will defining diabetic dyslipidemia and discuss how elevated VLDL, triglycerides and fatty liver might contribute to diabetic CV disease. Novel dyslipidemia mechanisms to treat diabetic dyslipidemia including THRbeta agonists will also be covered.

2:40 Effects of PF-04620110, a Novel Diacylglycerol Acyl-Transferase 1 (DGAT1) Inhibitor on Healthy-Obese Volunteers and Type 2 Diabetic Subjects

Claire Steppan, Ph.D., Associate Research Fellow, Diabetes, Pfizer

Inhibition of DGAT1, the terminal enzyme in the synthesis of triglycerides (TG), has been proposed for the treatment of type 2 diabetes (T2DM). We sought to examine the effects of a potent and selective DGAT1 inhibitor, PF-04620110, on vitamin A absorption, TG, glucose, insulin and total amide glucagon like peptide-1 (GLP-1) levels in both healthy-obese volunteers and Type 2 Diabetic subjects. The results of these studies will be presented.

3:10 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Pharmacological Manipulation of Diacyl Glycerol Acyl Transferase 1 Using Pre-Clinical Models

Shirly Pinto, Ph.D., CVD – Atherosclerosis Team Lead, Merck Research Laboratories

4:15 Sponsored Presentations (Opportunities Available)

4:45 Beneficial and Adverse Effects of Glucokinase Activators on Glucose Metabolism in Rat Liver Cells

Gabriel Baverel, Ph.D., CEO and CSO, Metabolomics, Metabolys, Inc.

Using a metabolic flux approach, we show the potential beneficial and adverse effects of three gluco-kinase activator drug candidates for type2 diabetes. We report the gluco-kinase activators’ effects on glucose utilization and production, glycogen synthesis and degradation, lactic acid and triglyceride accumulation and on the citric acid cycle during glucose metabolism in rat liver cells. Our work illustrates the advantage of metabolic flux analysis for predicting early during the drug development process, both the efficacy and safety of very small amounts of antidiabetic drug candidates.

5:15 Connecting Mitochondrial Dysfunction and Diabetes

James Dykens, CEO, Eyecyte Therapeutics

Mitochondrial dysfunction contributes via bioenergetic and oxidative mechanisms to a host of degenerative and metabolic diseases, including diabetes. Mitochondrial Ca2+ dynamics alter insulin release, while production of free radicals yields dysregulation of glycolysis. Importantly, xenobiotic therapies for diabetes, e.g., biguanides and thiazolidinediones, directly undermine mitochondrial function thereby lowering blood glucose, albeit via an untoward mechanism. The latter results from cell culture conditions that model diabetes and anaerobic poise, not normal aerobic physiology.

5:45 End of Day

WEDNESDAY, OCTOBER 3

8:00 am Interactive Breakfast Breakout Discussion Groups

Targeting GPCRs

Moderator: Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.

  • Screening strategies for discovery of novel GPCR agonists
  • GPCRs linked to incretin release
  • Targeting GPCRs in the periphery versus CNS

Cardiovascular Challenges

Moderator: Rebecca Taub, CEO, Madrigal Pharmaceuticals

  • Cardiovascular disease in diabetics—why the high incidence
  • History of anti-diabetic therapies effects on diabetic CV disease
  • Update on regulatory requirements to show CV safety with new diabetic therapies

Better Diabetes Models and Markers

Moderator: Jerome J. Schentag, PharmD, Professor of Pharmaceutical Sciences, University at Buffalo

  • Are there diabetes biomarkers coming forward that offer sufficient advantages to replace our current reliance on glucose and HBA1c?
  • What models and biomarkers are best suited to re-cast our perspective on diabetes as a cardiovascular event with MACE consequences?
  • Should we consider biomarkers of Type 1 diabetes to be different than for Type 2 diabetes from the perspective of CV events and metabolic syndrome?


TARGETING MEMBRANE PROTEINS FOR TYPE2 DIABETES

9:05 Chairperson’s Remarks

Peter Cornelius, Ph.D., Director of Metabolic Diseases, SystaMedic Inc.

9:10 FEATURED PRESENTATION

Discovery of Ertugliflozin: An Anti-Diabetic Agent from a New Class of SGLT2 Inhibitors

Vincent MascittiVincent Mascitti, Ph.D., Senior Director, Pfizer Global R&D

Inhibition of sodium-dependent glucose co-transporter 2 (SGLT2), located in the kidney, promotes reduction of plasma glucose concentration. The medicinal and synthetic organic chemistry rationale that led to the rapid identification of Ertugliflozin (PF-04971729), an anti-diabetic agent currently in development and belonging to a new class of SGLT2 inhibitors bearing a dioxa-bicyclo[3.2.1]octane bridged ketal motif, will be presented.

9:40 Targeting FGF21 for Type 2 Diabetes

Andrew C. Adams, Ph.D., Post-Doctoral Research Fellow, Diabetes Research, Lilly Research Laboratories

10:10 Coffee Break in the Exhibit Hall with Poster Viewing

10:55 Update on the Clinical Candidate ARRY-981: A GPR119 Agonist

Brad Fell, Senior Research Investigator, Medicinal Chemistry, Array BioPharma

GPR119 is a promising new target for the treatment of type 2 diabetes. Agonists of this GPCR, which promote insulin secretion from pancreatic ß-cells and GLP-1 release from enteroendocrine L-cells, provide a unique opportunity for a single drug to elicit insulin secretion via two distinct pathways. However, several GPR119 agonists have recently demonstrated poor clinical efficacy. We will discuss our novel GPR119 clinical candidate, ARRY-981, that has shown meaningful and durable glucose control in preclinical models of diabetes.

11:25 Inflammation, Obesity and Diabetes: Pre-Clinical Investigations of a CCR2 Antagonist

Dana Johnson, Ph.D., Senior Scientific Director, Drug Discovery, Janssen Pharmaceuticals, Johnson & Johnson

With the growing idea of insulin resistance due, in part, to low grade systemic inflammation, mechanistic investigations aimed at altering inflammatory tone have been undertaken by us as well as others. Recruitment of the macrophage and continued activity in the adipose tissue appears to drive insulin resistance, in part, via the secretion of Moncocyte Chemoattractant Protein 1 (MCP-1) and its cognate receptor C-C Chemokine Receptor-2 (CCR2). Our efforts in disrupting the macrophage recruitment via the use of CCR2 antagonists will be presented.

11:55 Monoclonal Antibody Antagonists of the Glucagon Receptor as Therapeutic Agents

Bernard B. Allan, Ph.D., Scientist, Department of Molecular Biology, Genentech, Inc.

Excess glucagon signaling plays a key role in the development of hyperglycemia in type 1 and type 2 diabetic patients. We have generated potent anti-glucagon receptor antagonist antibodies and will present the mechanisms underlying their anti-diabetic activities in pre-clinical models, including their direct effects on hepatic glucose metabolism and indirect effects on beta-cell mass.

12:25 pm Sponsored Presentation (Opportunity Available)

12:40 Luncheon Workshop (Sponsorship Opportunity Available) or Lunch on Your Own


NEW THERAPEUTIC APPROACHES

1:55 Chairperson’s Remarks

Jesper Gromada, Ph.D., Executive Director, Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research

2:00 XMetA, an Allosteric Agonist Antibody to the Insulin Receptor that Selectively Activates Insulin Receptor Metabolic Signaling and Restores Glycemic Control in Mouse Models of Diabetes

John Corbin, Ph.D., Associate Director, Molecular Interactions and Biophysics, Preclinical Research, XOMA

The XMetA antibody represents novel drug class for the treatment of diabetes. XMetA has unique properties including selective partial agonism of insulin receptor metabolic signaling resulting in improvements in the disease state of both hyperinsulinemic insulin resistant and insulinopenic diabetic animals. The in vitro and in vivo data to be presented for XMetA will provide a clear demonstration of how allosteric modulation of the insulin receptor with a monoclonal antibody can translate to improvements in disease.

2:30 Phenotype-Driven Approaches towards Novel Beta-Cell Proliferative and Protective Therapies

Bryan Laffitte, Ph.D., Associate Director, Genomics Institute of the Novartis Research Foundation

Type 1 and type 2 diabetes are characterized by a loss of beta cell mass. However, therapeutic options aimed at preservation or restoration of endogenous beta cell mass, are not currently available. We used phenotypic screening approaches for both small molecule and biologic agents to identify regulators of beta cell survival and beta cell proliferation. We report on several series of small molecules that induce beta cell proliferation and/or protect beta cells from various forms of stress and have potential as therapeutic options for both type 1 and type 2 diabetes.

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing

3:40 Gastric Bypass in Mice as a Model for Target Identification

Vincent Aguirre, M.D., Ph.D., Assistant Professor, Internal Medicine, University of Texas Southwestern Medical Center

We will discuss a mouse model of gastric bypass, which recapitulates effects of this procedure on body weight, body composition, glucose homeostasis, and stool energy observed in humans. The reproducibility of this model allows high-resolution comparison of effects of gastric bypass across genetic models using advanced methodologies, such as MRS metabolic flux, proteo metabolomics, and deep sequencing. As such, it enables targeted investigation of bypass-induced biological pathways and refined identification of novel pharmaceutical targets capable of mimicking beneficial effects of bariatric surgery.

4:10 Cell-Based Therapies to Treat Diabetes

Norma Kenyon, Ph.D., Professor of Surgery, Microbiology and Immunology and Biomedical Engineering; Executive Director of the Wallace H. Coulter Center for Translational Research; School of Medicine, University of Miami

This presentation will focus on the role of stem cell-based therapies to treat diabetes, highlighting the therapeutic potential of mesenchymal stem cells in diabetes. Our research group’s focus is on ways to transplant islet cells without the need for anti-rejection drugs, including the incorporation of stem cells into transplant protocols.

4:40 Discovery of Lorcaserin: A Selective 5-HT2C Agonist for Weight Management

Graeme Semple, Ph.D., Vice President, Discovery Chemistry, Arena Pharmaceuticals, Inc.

Compelling evidence suggests that drugs which activate the 5-HT2C receptor cause weight loss and thus have potential for use as weight management agents. Because serotonin elicits a number of biological responses through modulation of other 5HTrelated proteins, selectivity was a critical challenge particularly with respect to the closely related 5-HT2A and 5-HT2B receptors. This presentation outlines some of events, challenges and achievements that led to the discovery and development of lorcaserin.

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Pathophysiology of GLP-1 in Type 2 Diabetes

Reporter: Aviva Lev-Ari, PhD, RN

By Mark Abrahams, MD

Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY

Published: 05/23/2012

 

 

 

For many years, it has been well known that causes of type 2 diabetes include: decreased ability of pancreatic beta cells to produce insulin, insulin resistance, and increased production of glucose by the liver.1,2 More recently, the role of the incretin hormones, GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide) has been elucidated. This article reviews the pathophysiology of GLP-1 and the impaired incretin effect observed in type 2 diabetes.

The significant reduction in the “incretin effect” observed in patients with type 2 diabetes offers strong evidence as to the importance of GLP-1. The incretin effect refers to the observation that, when challenged by glucose delivered via an oral route (as would occur with ingestion of a meal), the resulting increase in insulin levels is higher than that seen when glucose is delivered intravenously.3 The impaired ability of patients with type 2 diabetes to mount such a postprandial incretin effect appears to be due primarily to decreased circulating levels of GLP-1. This may be secondary to either decreased secretion by the gut or increased elimination of GLP-1 (elimination occurs most notably via enzymatic degradation by DPP-4 [dipeptidyl peptidase-4]).4

Despite the impaired incretin effect seen in patients with type 2 diabetes, the ability of GLP-1, when present, to elicit the secretion of insulin by pancreatic beta cells appears to be preserved.4Furthermore, it has also been shown that the ability of GLP-1 to slow gastric emptying and decrease glucagon secretion remains intact in these patients.4 This implies that the impaired incretin effect appears to be largely a function of decreased circulating levels of incretin hormones, rather than a decreased ability of target tissues to respond appropriately.

At present, it is not known if the decreased incretin effect seen in patients with type 2 diabetes is a cause or effect of the disease. While it may be intuitive to think about pathophysiology as preceding clinical disease, at least two studies suggest otherwise. In one study in patients with chronic pancreatitis, the investigators leveraged the assumption that these patients eventually develop diabetes.5 This study compared patients with chronic pancreatitis and secondary diabetes to patients with chronic pancreatitis and normal glucose tolerance. In the patients with secondary diabetes, the incretin effect was significantly impaired—but not so in patients with normal glucose tolerance. The authors concluded that clinical diabetes is more likely a cause of an impaired incretin effect rather than a consequence. In another study comparing identical twins, one with type 2 diabetes and one without, impaired secretion of GLP-1 was seen only in the siblings with diabetes—also suggesting that clinical disease may precede deficits in GLP-1 secretion.6Regardless, this subject remains controversial.

The relationship between obesity and the incretin effect is an area of active exploration as well. In one study investigating the impact of obesity on the incretin effect, a proportional relationship was observed between severity of obesity and degree of impairment of incretin effect. The authors concluded that obesity was an independent cause of diminished incretin effect.7

In summary, decreased levels of circulating GLP-1 and GIP appear to be primarily responsible for the impaired ability of the type 2 diabetes patient to mount an effective postprandial insulin response—while tissue sensitivity to hormone, when present, remains intact. Obesity is believed to contribute to the development of such an impaired incretin effect, and the question of incretin effect as either causing, or resulting from, clinical disease remains controversial.

 

References:

  1. Boyle PJ, et al. Application of Incretin Mimetics and Dipeptidyl Peptidase IV Inhibitors in Managing Type 2 Diabetes Mellitus. J Am Osteopath Assoc. 2007;107(suppl):S10-S16.
  2. Freeman JS. The Pathophysiologic Role of IncretinsJ Am Osteopath Assoc. 2007;107(suppl):S6-S9.
  3. Phillips WT, et al. Rapid Gastric Emptying of an Oral Glucose Solution in Type 2 Diabetic Patients. J Nucl Med. 1992;33:1496-1500.
  4. Freeman JS. Role of the Incretin Pathway in the Pathogenesis of Type 2 Diabetes Mellitus. Cleve Clin J Med. 2009;76(suppl 5):S12-S19.
  5. Knop FK, et al. Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State?Diabetes. 2007;56:1951-1959.
  6. Vaag AA, et al. Gut Incretin Hormones in Identical Twins Discordant for Non-Insulin-Dependent Diabetes Mellitus (NIDDM)-Evidence for Decreased Glucagon-Like Peptide 1 Secretion During Oral Glucose Ingestion in NIDDM Twins. Eur J Endocrinol. 1996;135:425-432.
  7. Muscelli E, et al. Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients. Diabetes. 2008;57:1340-1348.

 

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