Ll Global Inc

METABOLIC RESPONSES TO PHYSIOLOGIC INSULIN RESENSITIZATION IN TYPE 2 DIABETES - PROJECT SUMMARY/ABSTRACT A HALLMARK OF NORMAL GLUCOSE REGULATION IS THE OSCILLATORY (PEAK-AND-TROUGH) SECRETION OF INSULIN BY THE PANCREAS, WHICH IS PROPOSED TO ENHANCE RECEPTOR SENSITIVITY AND HAS BEEN DEFINITIVELY SHOWN TO OPTIMIZE GLUCOSE UPTAKE AND INTRACELLULAR SIGNALING. IN TYPE 2 DIABETES MELLITUS (T2DM), THIS PHYSIOLOGIC RHYTHM IS DISRUPTED. PRECLINICAL RESEARCH AND SMALL CLINICAL STUDIES HAVE DEMONSTRATED THAT OSCILLATORY INSULIN DELIVERY MORE EFFECTIVELY PROMOTES GLUCOSE DISPOSAL AND SUPPRESSES LIPOLYSIS THAN DOES CONTINUOUS INFUSION OF AN EQUAL AMOUNT OF INSULIN. WELL CELL GLOBAL HAS DEVELOPED A PATENTED TREATMENT REGIMEN, PHYSIOLOGIC INSULIN RESENSITIZATION (PIR), THAT MIRRORS THE NATURAL OSCILLATORY PATTERN OF INSULIN DURING OUTPATIENT INFUSION SESSIONS DELIVERED SEVERAL TIMES PER WEEK. SMALL STUDIES HAVE DEMONSTRATED THAT PIR IMPROVES GLYCEMIC CONTROL, REDUCES INFLAMMATION, AND ENHANCES KIDNEY FUNCTION IN T2DM PATIENTS. HOWEVER, ADOPTION BY THE MEDICAL COMMUNITY HAS BEEN LIMITED DUE TO THE ABSENCE OF ADEQUATELY POWERED RANDOMIZED CLINICAL TRIALS (RCTS) AND A LACK OF UNDERSTANDING OF THE MECHANISMS RESPONSIBLE FOR PIR’S EFFECTIVENESS. THIS PROJECT SEEKS TO DEFINE THE PHYSIOLOGICAL BASIS OF PIR’S BENEFICIAL EFFECTS THROUGH A RANDOMIZED CLINICAL STUDY OF 20 T2DM PATIENTS RECEIVING PIR AND 20 MATCHED CONTROLS RECEIVING STANDARD OF CARE OVER A PERIOD OF 12 MONTHS. SPECIFIC AIM 1 WILL EVALUATE THE PHYSIOLOGICAL AND METABOLIC EFFECTS OF PIR USING AN INSULIN-MODIFIED FREQUENTLY SAMPLED INTRAVENOUS GLUCOSE TOLERANCE TEST (IVGTT) WITH LONGITUDINAL ASSESSMENTS OF INSULIN SENSITIVITY, BETA CELL FUNCTION, AND ADIPOCYTE LIPOLYSIS AS A COMPLEMENT TO DATA FROM BLOOD AND URINE SUCH AS HBA1C, INFLAMMATORY BIOMARKERS, AND KIDNEY ASSESSMENTS. SPECIFIC AIM 2 WILL USE DUAL-ENERGY X-RAY ABSORPTIOMETRY (DXA) AND MULTIPARAMETRIC MRI/MRS TO ASSESS CHANGES IN BODY COMPOSITION, ORGAN FAT, AND FIBROINFLAMMATION IN KEY TISSUES INCLUDING PANCREAS, LIVER, AND KIDNEY. TOGETHER, THESE STUDIES WILL ESTABLISH A MECHANISTIC FRAMEWORK FOR PIR’S EFFECTS, A CRITICAL FOUNDATION ON WHICH TO ADVANCE THE RATIONALE FOR PIR’S USE FROM SMALL STUDY CLINICAL OBSERVATIONS TO A RIGOROUSLY VALIDATED TREATMENT STRATEGY. SUCCESSFUL COMPLETION OF THIS PROJECT, ALONG WITH ONGOING RCTS, WILL PROVIDE THE EVIDENCE BASE NEEDED TO SUPPORT WIDER CLINICAL ADOPTION OF PIR, WITH THE POTENTIAL TO TRANSFORM T2DM MANAGEMENT, REDUCE LONG-TERM COMPLICATIONS, AND LOWER HEALTHCARE COSTS.

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