Abstract

WE PROPOSE TO INNOVATE IN THERAPEUTIC STRATEGIES IN USE FOR THE TREATMENT OF DIABETES THROUGH THE IDENTIFICATION AND VALIDATION OF MOLECULES WITH THE ABILITY TO CONTROL GLUCOSE UPTAKE AT THE INTESTINAL EPITHELIUM, FOR THEIR USE IN THE CONTROL OF THE HYPERGLYCEMIA CHARACTERISTIC OF DIABETES. THE PROBLEM-OPPORTUNITY APPROACH DERIVES FROM THE HIGH MORBIDITY AND MORTALITY OF THE COMORBIDITIES OF DIABETES MELLITUS. THE HEALTH MINISTRY FIGURES INDICATE THAT IN CHILE THE PREVALENCE OF DIABETES MELLITUS TYPE 2 (DM2) INCREASED FROM 6.3% TO 9.4% OF THE POPULATION IN THE PERIOD 2003 TO 2010, AFFECTING A UNIVERSE OF ABOUT 1,200 000 PEOPLE. THE DM2 TODAY AFFECTS 230 MILLION PEOPLE WORLDWIDE AND IS EXPECTED THAT BY THE YEAR 2025 WILL AFFECT ABOUT 324 MILLION. IN 2005, DIABETES WAS THE SEVENTH LEADING CAUSE OF DEATH WITH A RATE OF 2% (1.1 MILLION DEATHS) AND IS EXPECTED TO INCREASE BY OVER 50% IN 10 YEARS. THE OPPORTUNITY OF PROJECT ARISES FROM THE NEED FOR THERAPEUTIC STRATEGIES TO PREVENT THE DEVELOPMENT AND PROGRESSION OF DM2. CURRENT STRATEGIES ARE BASED ON INJECTIONS OF INSULIN, OR THE USE OF DRUGS THAT MODIFY THE PRODUCTION OR THE BODY\\\\\\\\\\\\\\\'S RESPONSE TO INSULIN. HOWEVER, THESE STRATEGIES LOSE THEIR EFFECTIVENESS AS PATIENTS DEVELOP RESISTANCE TO INSULIN, A COMPLEX SITUATION AS 90% OF PATIENTS WITH TYPE 2 DIABETES SUFFER FROM RESISTANCE. MOREOVER, OBESITY-RELATED DIABETES IS USUALLY CHARACTERIZED BY A HIGH RESISTANCE TO INSULIN, WHICH CANNOT BE REVERSED WITH MORE INSULIN. THE RELEVANCE OF THE PROJECT BUILDS ON THE WORK OF 18 YEARS OF BASIC RESEARCH OF THE PROPOSERS ON THE MOLECULAR MECHANISMS OF GLUCOSE TRANSPORT AND ITS REGULATION AT THE CELLULAR AND MOLECULAR LEVEL. WE HAVE PRODUCED INFORMATION THAT REVEALS THE EXISTENCE OF NEW REGULATORY SITES IN THE FAMILY OF GLUT GLUCOSE TRANSPORTERS, INFORMATION HITHERTO UNPUBLISHED. THESE SITES ARE LOCATED EXOFACIALLY AND THEIR PROPERTIES DETERMINE THE FUNCTIONAL CHARACTERISTICS OF THE GLUT TRANSPORTERS AND THEIR EFFICIENCY IN THE TRANSPORT OF GLUCOSE IN A MANNER INDEPENDENT OF THE PRESENCE OR ABSENCE OF INSULIN. INFORMATION REGARDING THE EXISTENCE AND MOLECULAR IDENTITY OF THESE REGULATORY SITES, PRELIMINARY IDENTIFICATION OF SPECIFIC INHIBITORS THAT BIND TO THESE SITES, AND APPLICATIONS DERIVED FROM THESE FINDINGS ARE NOT PUBLICLY AVAILABLE AND ARE THE BASIS FOR THIS PROPOSAL. AN ESSENTIAL ASPECT OF THE PROJECT IS THE INTELLECTUAL PROTECTION OF THESE FINDINGS BY OBTAINING NATIONAL AND INTERNATIONAL PATENTS. WE PROPOSE TO IDENTIFY AND VALIDATE NOVEL MOLECULES THAT INHIBIT THE ACTIVITY OF THE GLUT TRANSPORTERS OF INTESTINAL LOCATION. THESE INHIBITORS MUST MEET THE FOLLOWING CHARACTERISTICS: I) TO SHOW SPECIFICITY FOR GLUT2 OVER THAN GLUT4 AND GLUT1, II) HAVE AN AFFINITY AT THE MICROMOLE LEVEL AND, III) SLOWLY CROSS THE INTESTINAL BARRIER. CONTROL OF GLUCOSE UPTAKE IN THE INTESTINE WOULD PREVENT OR ATTENUATE THE PROGRESSION OF HYPERGLYCEMIA, LEADING TO IMPROVEMENT IN LIFE EXPECTANCY AND QUALITY OF LIFE OF PEOPLE AND TO RELIEVE PRESSURE ON HEALTH SYSTEMS. THE PROPOSED PROJECT IS A WORLDWIDE PRODUCT INNOVATION, BECAUSE CURRENTLY THERE ARE NO SUBSTITUTES AVAILABLE ON THE MARKET OR UNDER DEVELOPMENT OR PATENTING. THE PROJECT\\\\\\\\\\\\\\\'S TARGET MARKET INVOLVES THE PATIENTS WITH DIABETES IN CHILE AND WORLDWIDE. PRODUCER AND DISTRIBUTOR MARKET IS COMPOSED OF THE RESEARCH UNITS OF LARGE PHARMACEUTICAL COMPANIES MARKETING DRUGS FOR DIABETES: GLAXOSMITHKLINE, TAKEDA PHARMACEUTICAL CO. LTD., PFIZER AND / OR BIOTECHNOLOGY COMPANIES THAT ASSUME THE RISK OF MARKETING.