SBIR-STTR Award

To date, the use of marketed continuous glucose monitoring systems (CGMs) are limited to glucose trend analysis by patients with insulin-dependent type 1 and type 2 diabetes. Accuracy limitations, particularly in the hypoglycemic range, and low signal-to-noise ratio have precluded expansion of this promising technology into screening applications to identify early signs of diabetes, prior to clinical onset of disease, so preventive measures may be taken. The proposed research is focused on developing an in vitro model of glycemic oscillations in yeast using a combined yeast-biosensor hybrid. The information derived from this model will be used to determine if manifestations of glycemic oscillations can be measured and characterized within the interstitial fluid (ISF) of humans. So far, the phenomenon of in vivo interstitial fluid glycemic oscillations has not been reported. Preliminary in vivo interstitial fluid glucose data, measured in the dermis of swine, revealed an oscillatory phenomenon that may be indicative of intracellular glycolysis. Included in the Specific Aims is the development of an in vitro yeast-biosensor hybrid system that models the in vivo ISF environment. This unique hybrid, continuous glucose monitoring system will be used to develop a model of glycemic oscillations in yeast. Data from the in vitro model will be used to develop pattern recognition algorithms to characterize in vivo ISF oscillations specific to type 1 and type 2 diabetes. Successful completion of the proposed research will provide advances in continuous glucose monitoring technology that have the potential to resolve inaccuracy issues encountered by patients using CGMs. It is our belief the proposed research will break-down technical barriers that preclude the use of this technology as a stand-alone system with expanded utility for screening and preventative applications that may bring the artificial pancreas on step closer to reality. , ,

Public Health Relevance:
The potential for continuous glucose monitoring systems (CGMs) to detect glycemic oscillations in interstitial fluid will advance the use of this technology into the realm of preventative medicine by providing an inexpensive screening tool, capable of identifying people with abnormal glucose metabolism long before overt clinical symptoms are apparent. The outcomes of the proposed research will allow physicians to intervene early in the progression of diabetes symptoms with low cost diet and lifestyle changes as opposed to high cost therapeutic intervention. Early stage intervention will have a significant impact on reducing the over $200 billion annual cost to the US healthcare system to treat the chronic complications of diabetes.

Thesaurus Terms:
Algorithms;Artificial Pancreas;Belief;Beta Cell;Biological Models;Biosensor;Blood;Cardiovascular;Cardiovascular Body System;Cardiovascular System;Cardiovascular System (All Sites);Cell Communication And Signaling;Cell Signaling;Cell Surface Receptors;Cell Membrane;Cells;Characteristics;Chronic;Clinical;Clinical Research;Clinical Study;Complications Of Diabetes Mellitus;Corium;Coupled;Cutis;Cyclicity;Cytoplasmic Membrane;D-Glucose;Data;Defect;Dermis;Development;Dextrose;Diabetes Complications;Diabetes Mellitus;Diabetes Mellitus, Adult-Onset;Diabetes Mellitus, Brittle;Diabetes Mellitus, Insulin-Dependent;Diabetes Mellitus, Juvenile-Onset;Diabetes Mellitus, Ketosis-Prone;Diabetes Mellitus, Ketosis-Resistant;Diabetes Mellitus, Non-Insulin-Dependent;Diabetes Mellitus, Noninsulin Dependent;Diabetes Mellitus, Slow-Onset;Diabetes Mellitus, Stable;Diabetes Mellitus, Sudden-Onset;Diabetes Mellitus, Type 1;Diabetes Mellitus, Type 2;Diabetes Mellitus, Type I;Diabetes Mellitus, Type Ii;Diabetes-Related Complications;Diabetic Complications;Diagnosis;Diagnostic;Diet;Environment;Evaluation;Exhibits;Family Suidae;Frequencies (Time Pattern);Frequency;Glut;Glut1;Gtr1;Gastrointestinal Tract, Pancreas;Gene Expression;Genetic Alteration;Genetic Change;Genetic Defect;Glucose;Glucose Transporter Type 1 Gene;Glycolysis;Government;Healthcare Systems;Human;Human, General;Humulin R;Hybrids;Hypoglycemia;Idd;Iddm;In Vitro;Individual;Insulin;Insulin (Ox), 8a-L-Threonine-10a-L-Isoleucine-30b-L-Threonine-;Insulin Cell;Insulin Resistance;Insulin Secreting Cell;Insulin, Regular;Insulin-Dependent Diabetes Mellitus;Intercellular Fluid;Interstitial Fluids;Intervention;Intervention Strategies;Intracellular Communication And Signaling;Kinetic;Kinetics;Lead;Life;Life Style;Lifestyle;Link;Mody;Man (Taxonomy);Man, Modern;Marketing;Math Models;Maturity-Onset Diabetes Mellitus;Measures;Medical;Methods;Model System;Modeling;Models, Biologic;Monitor;Mutation;Niddm;Needles;Noise;Non-Insulin Dependent Diabetes;Non-Insulin-Dependent Diabetes Mellitus;Novolin R;Onset Of Illness;Organ System, Cardiovascular;Outcome;Pancreas;Pancreatic;Patients;Pattern;Pattern Recognition;Pattern Recognition/Display/Analysis;Pb Element;Periodicity;Persons;Physicians;Pigs;Plasma Membrane;Population;Preventive;Preventive Medicine;Protocol;Protocols Documentation;Publishing;Receptor Protein;Reporting;Research;Reticuloendothelial System, Blood;Rhythmicity;Slc2a1;Slc2a1 Gene;Screening Procedure;Series;Signal Transduction;Signal Transduction Systems;Signaling;Staging;Suidae;Surface;Suspension Substance;Suspensions;Swine;Symptoms;System;System, Loinc Axis 4;Systems, Health Care;T1 Diabetes;T1d;T1dm;T2d;T2dm;Technology;Therapeutic Intervention;Time;Time Series Analysis;Type 1 Diabetes;Type 2 Diabetes;Type Ii Diabetes;Universities;Vascular, Heart;Yeasts;Adult Onset Diabetes;Base;Biological Signal Transduction;Circulatory System;Cost;Diabetes;Disease Onset;Disorder Onset;Extracellular;Genome Mutation;Glucose Metabolism;Glucose Meter;Glucose Monitor;Glucose Transport;Heavy Metal Pb;Heavy Metal Lead;Human Subject Protection;Hypoglycemic;Hypoglycemic Episodes;In Vitro Model;In Vivo;In Vivo Model;Insulin Dependent Diabetes;Insulin Resistant;Intervention Therapy;Interventional Strategy;Juvenile Diabetes;Juvenile Diabetes Mellitus;Ketosis Prone Diabetes;Ketosis Resistant Diabetes;Mathematical Model;Mathematical Modeling;Maturity Onset Diabetes;Patient Population;Plasmalemma;Porcine;Preventative Medicine;Public Health Relevance;Receptor;Screening;Screenings;Sensor (Biological);Suid;Suspension;Tool;Trend;Type I And Type Ii Diabetes;Type I Diabetes

In Phase 1, measuring and characterizing glucose oscillations in yeast cells immobilized on the surface of a glucose sensor was completed. Using this as a model, it was postulated that within the subcutaneous environment, cells (e.g., fibroblasts, adipocytes) would be in close proximity to the surface of the glucose sensor thereby mimicking the in vitro environment of the yeast cells on the surface of the glucose sensor. A 12- hour clinical study was completed wherein glucose measurements within interstitial fluid were highly correlated with reference glucose measurements. Moreover, measurements of glucose oscillations within subcutaneous tissue showed clear differences between normal subjects and those with type 1 and type 2 diabetes. Further studies in Phase 2 are aimed at building a data base of measurements, over longer time periods, to provide the means for characterizing different states of glycemia along the continuum from normal to impaired glucose tolerance to type 2 diabetes. Information gained from human studies in Phase 2, could provide the means of controlling an insulin pump based on periodic changes in cellular glucose metabolism, rather than relying solely on peripheral fingerstick blood glucose measurements for calibration purposes. Continuous glucose monitoring is an evolving, revolutionary technology that promises to improve the quality of life for millions of people with diabetes. In order to realize its full potential, more accurate devices that can be used for diagnosis and control, by providing physiological feedback to an insulin pump, are required. Measuring subcutaneous metabolic oscillations of glucose could provide a missing link for insulin pump feedback control, more accurate glucose measurements and novel methods for diagnosing stages of impaired glucose tolerance and insulin resistance. Measuring and characterizing aberrations in glucose metabolism within interstitial fluid and correlating them to known defects in glucose metabolism could be a major leap forward in diabetes management and provide an inexpensive tool for discovering new insights into the genetic and molecular origins of insulin resistance. The proposed Phase 2 research may result in a CGM system that reduces the need for frequent fingerstick blood glucose re-calibration eventually leading to a user calibration-free CGM that can be interfaced with an insulin pump to form an artificial pancreas.

Public Health Relevance Statement:


Public Health Relevance:
The potential for continuous glucose monitoring systems (CGMs) to detect cellular glycemic oscillations in interstitial fluid will advance the use of CGM technology into the realm of preventative medicine by providing an inexpensive screening tool, capable of identifying people with abnormal glucose metabolism long before overt clinical symptoms are apparent. In addition, our proposed research seeks to advance the state-of-the-art in continuous glucose monitoring by developing a convenient and useful method for evaluating glycemic control over shorter periods of time (days or weeks) that could potentially supplement quarterly assessments of glycemic control using hemoglobin A1C measurements. The measurement of subcutaneous glucose oscillations could lead to better control of an insulin pump based on cellular feedback as opposed to current CGM technologies that require frequent re-calibration using fingerstick glucose monitoring.

NIH Spending Category:
Bioengineering; Biotechnology; Clinical Research; Diabetes; Prevention

Project Terms:
Adipocytes; Algorithms; American; Artificial Pancreas; base; biomaterial compatibility; Blood Glucose; Caliber; Calibration; Cells; Clinic; Clinical; Clinical Research; Clothing; Communication; Computer software; Data; Databases; Defect; design; Devices; diabetes management; Diabetes Mellitus; Diagnosis; Diagnostic; Electrodes; Electronics; Environment; Evaluation; Event; Feedback; Fibroblasts; Financial compensation; Glucose; glucose metabolism; glucose monitor; glucose sensor; glycemic control; Government; Grant; graphical user interface; Hand; Hemoglobin; Home environment; Hour; Human; Hyperglycemia; Hypoglycemia; Immobilized Cells; impaired glucose tolerance; improved; In Vitro; in vitro testing; insight; Insulin Infusion Systems; Insulin Resistance; Intercellular Fluid; laptop; Lead; Link; Manuscripts; Measurement; Measures; Medical; Metabolic; Methods; Modeling; Molecular Genetics; Monitor; Morphologic artifacts; Movement; Non-Insulin-Dependent Diabetes Mellitus; novel; Patients; Performance; Peripheral; Persons; Phase; Physiological; Pilot Projects; Preventive Medicine; Protocols documentation; public health relevance; Publications; Quality of life; Reporting; Research; research study; Science; screening; sensor; Skin; software development; Software Validation; Staging; Sterilization; subcutaneous; Subcutaneous Tissue; Surface; Symptoms; System; Technology; Testing; Time; tool; Toxicology; type I and type II diabetes; Universities; user-friendly; validation studies; Visit; Wireless Technology; Writing; Yeasts