Introduction to Personalized Medicine in Diabetes Mellitus

The world is facing an epidemic rise in diabetes mellitus (DM) incidence, which is challenging health funders, health systems, clinicians, and patients to understand and respond to a flood of research and knowledge. Evidence-based guidelines provide uniform management recommendations for “average” patients that rarely take into account individual variation in susceptibility to DM, to its complications, and responses to pharmacological and lifestyle interventions. Personalized medicine combines bioinformatics with genomic, proteomic, metabolomic, pharmacogenomic (“omics”) and other new technologies to explore pathophysiology and to characterize more precisely an individual’s risk for disease, as well as response to interventions. In this review we will introduce readers to personalized medicine as applied to DM, in particular the use of clinical, genetic, metabolic, and other markers of risk for DM and its chronic microvascular and macrovascular complications, as well as insights into variations in response to and tolerance of commonly used medications, dietary changes, and exercise. These advances in “omic” information and techniques also provide clues to potential pathophysiological mechanisms underlying DM and its complications.

[1]  R. Vasan,et al.  2-Aminoadipic acid is a biomarker for diabetes risk. , 2013, The Journal of clinical investigation.

[2]  S. Saydah,et al.  The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988–2010 , 2013, Diabetes Care.

[3]  A. El-Osta,et al.  Epigenetic changes in diabetes , 2013, Clinical genetics.

[4]  C. Forsblom,et al.  Urinary Liver-Type Fatty Acid–Binding Protein and Progression of Diabetic Nephropathy in Type 1 Diabetes , 2013, Diabetes Care.

[5]  J. Samet,et al.  Fasting Glucose Level and the Risk of Incident Atherosclerotic Cardiovascular Diseases , 2013, Diabetes Care.

[6]  Jussi Paananen,et al.  Genetic Variants Associated With Glycine Metabolism and Their Role in Insulin Sensitivity and Type 2 Diabetes , 2013, Diabetes.

[7]  B. Astor,et al.  sRAGE and Risk of Diabetes, Cardiovascular Disease, and Death , 2013, Diabetes.

[8]  T. Gardner,et al.  Predicting Development of Proliferative Diabetic Retinopathy , 2013, Diabetes Care.

[9]  Robert J. Goodloe,et al.  The Influence of Obesity-Related Single Nucleotide Polymorphisms on BMI Across the Life Course , 2013, Diabetes.

[10]  J. Danesh,et al.  Genome-Wide Association Study Identifies a Novel Locus Contributing to Type 2 Diabetes Susceptibility in Sikhs of Punjabi Origin From India , 2013, Diabetes.

[11]  M. McKinley,et al.  Sex hormone binding globulin and insulin resistance , 2013, Clinical endocrinology.

[12]  F. Hu,et al.  Diabetes Genetic Predisposition Score and Cardiovascular Complications Among Patients With Type 2 Diabetes , 2013, Diabetes Care.

[13]  Terho Lehtimäki,et al.  Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults , 2013, Diabetes Care.

[14]  Atsushi Araki,et al.  Predicting Macro- and Microvascular Complications in Type 2 Diabetes , 2013, Diabetes Care.

[15]  G. Morahan,et al.  Definition of High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Types Using Only Three Single Nucleotide Polymorphisms , 2013, Diabetes.

[16]  F. Azizi,et al.  Wrist circumference as a novel predictor of diabetes and prediabetes: results of cross-sectional and 8.8-year follow-up studies. , 2013, The Journal of clinical endocrinology and metabolism.

[17]  A. Butte,et al.  Systematic identification of interaction effects between genome- and environment-wide associations in type 2 diabetes mellitus , 2013, Human Genetics.

[18]  A. Peters,et al.  Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach , 2013, Diabetes.

[19]  F. Hu,et al.  FTO Genotype and 2-Year Change in Body Composition and Fat Distribution in Response to Weight-Loss Diets , 2012, Diabetes.

[20]  S. Inzucchi,et al.  Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379 , 2013, Diabetes Care.

[21]  K. Xiang,et al.  Genetic variants of LPIN1 indicate an association with Type 2 diabetes mellitus in a Chinese population , 2013, Diabetic medicine : a journal of the British Diabetic Association.

[22]  D. Holmes Pharmacogenomic Testing and Antithrombotic Therapy: Ready for Prime Time? , 2013, Rambam Maimonides medical journal.

[23]  M. Atkinson,et al.  Recent Lessons Learned From Prevention and Recent-Onset Type 1 Diabetes Immunotherapy Trials , 2012, Diabetes.

[24]  R. Green,et al.  Personalized Genetic Risk Counseling to Motivate Diabetes Prevention , 2012, Diabetes Care.

[25]  J. Pankow,et al.  Novel Risk Factors and the Prediction of Type 2 Diabetes in the Atherosclerosis Risk in Communities (ARIC) Study , 2012, Diabetes Care.

[26]  E. Huang,et al.  Public Health Implications of Recommendations to Individualize Glycemic Targets in Adults With Diabetes , 2012, Diabetes Care.

[27]  V. Basevi Standards of Medical Care in Diabetes—2013 , 2012, Diabetes Care.

[28]  M. McCarthy,et al.  The Genetic and Epigenetic Basis of Type 2 Diabetes and Obesity , 2012, Clinical pharmacology and therapeutics.

[29]  R. Sherwin,et al.  Year in diabetes 2012: The diabetes tsunami. , 2012, The Journal of clinical endocrinology and metabolism.

[30]  R. Simó,et al.  A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity , 2012, Molecular and Cellular Endocrinology.

[31]  F. Hu,et al.  TCF7L2 genetic variants modulate the effect of dietary fat intake on changes in body composition during a weight-loss intervention. , 2012, The American journal of clinical nutrition.

[32]  Thomas J. Songer,et al.  Improvements in the Life Expectancy of Type 1 Diabetes , 2012, Diabetes.

[33]  M. Vardi,et al.  Haptoglobin genotype and cardiovascular outcomes in diabetes mellitus - natural history of the disease and the effect of vitamin E treatment. Meta-analysis of the medical literature. , 2012, European journal of internal medicine.

[34]  Nele Friedrich,et al.  Metabolomics in diabetes research. , 2012, The Journal of endocrinology.

[35]  Karel G M Moons,et al.  Prediction models for risk of developing type 2 diabetes: systematic literature search and independent external validation study , 2012, BMJ : British Medical Journal.

[36]  C. Kartha,et al.  Proteomic profiling of high glucose primed monocytes identifies cyclophilin A as a potential secretory marker of inflammation in type 2 diabetes , 2012, Proteomics.

[37]  K. Fujihara,et al.  Screening for pre‐diabetes to predict future diabetes using various cut‐off points for HbA1c and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4) , 2012, Diabetic medicine : a journal of the British Diabetic Association.

[38]  L. Nikitina-Zake,et al.  Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients , 2012, Pharmacogenetics and genomics.

[39]  R. MacIsaac,et al.  Urinary Proteomics for Early Diagnosis in Diabetic Nephropathy , 2012, Diabetes.

[40]  J. Hirschhorn,et al.  Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy , 2012, Diabetes.

[41]  W. Niu,et al.  A meta-analysis of receptor for advanced glycation end products gene: Four well-evaluated polymorphisms with diabetes mellitus , 2012, Molecular and Cellular Endocrinology.

[42]  Marco Pahor,et al.  Making preventive medicine more personalized: implications for exercise-related research. , 2012, Preventive medicine.

[43]  Thomas P Cappola,et al.  Transcriptomic biomarkers of cardiovascular disease. , 2012, Progress in cardiovascular diseases.

[44]  Dharambir K Sanghera,et al.  Type 2 Diabetes Genetics: Beyond GWAS. , 2012, Journal of diabetes & metabolism.

[45]  Kuo-Hsuan Chang,et al.  Effect of pre-diabetes on future risk of stroke: meta-analysis , 2012, BMJ : British Medical Journal.

[46]  Y. Chou,et al.  Proteomic analysis and identification of aqueous humor proteins with a pathophysiological role in diabetic retinopathy. , 2012, Journal of proteomics.

[47]  H. Krumholz,et al.  Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. , 2012, Archives of internal medicine.

[48]  M. McCarthy,et al.  Systematic Assessment of Etiology in Adults With a Clinical Diagnosis of Young-Onset Type 2 Diabetes Is a Successful Strategy for Identifying Maturity-Onset Diabetes of the Young , 2012, Diabetes Care.

[49]  T. Lehtimäki,et al.  Circulating Metabolite Predictors of Glycemia in Middle-Aged Men and Women , 2012, Diabetes Care.

[50]  D. Matthews,et al.  Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach , 2012, Diabetes Care.

[51]  B. Viollet,et al.  Cellular and molecular mechanisms of metformin: an overview. , 2012, Clinical science.

[52]  K. Ohlendieck Pathobiochemical Changes in Diabetic Skeletal Muscle as Revealed by Mass-Spectrometry-Based Proteomics , 2012, Journal of nutrition and metabolism.

[53]  Manuel Mayr,et al.  MicroRNAs in vascular and metabolic disease. , 2012, Circulation research.

[54]  H. Schunkert,et al.  Strategies Beyond Genome-Wide Association Studies for Atherosclerosis , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[55]  D. Selvarajah,et al.  Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy , 2012, Diabetes/metabolism research and reviews.

[56]  A. Mainous,et al.  Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001–2004 NHANES , 2012, Diabetic medicine : a journal of the British Diabetic Association.

[57]  K G M Moons,et al.  Prediction models for the risk of cardiovascular disease in patients with type 2 diabetes: a systematic review , 2011, Heart.

[58]  P. Flatt,et al.  Emerging Applications of Metabolomic and Genomic Profiling in Diabetic Clinical Medicine , 2011, Diabetes Care.

[59]  G. Luo,et al.  Phospholipidomic identification of potential plasma biomarkers associated with type 2 diabetes mellitus and diabetic nephropathy. , 2011, Talanta.

[60]  V. Manolopoulos,et al.  Pharmacogenomics of oral antidiabetic medications: current data and pharmacoepigenomic perspective. , 2011, Pharmacogenomics.

[61]  A. Astrup Cardiovascular morbidity and mortality in diabetes mellitus: prediction and prognosis. , 2011, Danish medical bulletin.

[62]  N. Rishe,et al.  Metabolic Profiling in Personalized Medicine: Bridging the Gap between Knowledge and Clinical Practice in Type 2 Diabetes Identifying Asymptomatic Subjects at Risk of Developing Dm2 Predictors of Cardiovascular Complications in Dm2 Patients Conclusion & Future Perspective , 2022 .

[63]  Christian Herder,et al.  Genetics of type 2 diabetes: pathophysiologic and clinical relevance , 2011, European journal of clinical investigation.

[64]  Jun-jie Zou,et al.  Serum biomarker of diabetic peripheral neuropathy indentified by differential proteomics. , 2011, Frontiers in bioscience.

[65]  E. Shyong Tai,et al.  Nutrigenetics and Nutrigenomics: Viewpoints on the Current Status and Applications in Nutrition Research and Practice , 2011, Lifestyle Genomics.

[66]  S. Carr,et al.  Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. , 2011, The Journal of clinical investigation.

[67]  V. Mootha,et al.  Metabolite profiles and the risk of developing diabetes , 2011, Nature Medicine.

[68]  Thomas W. Mühleisen,et al.  Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease , 2011, Nature Genetics.

[69]  F. Schick,et al.  Effects of a lifestyle intervention in metabolically benign and malign obesity , 2011, Diabetologia.

[70]  Mark I McCarthy,et al.  Genomics, type 2 diabetes, and obesity. , 2010, The New England journal of medicine.

[71]  Peter Donnelly,et al.  Edinburgh Research Explorer Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes , 2022 .

[72]  E. Hoffman,et al.  CCL2 and CCR2 variants are associated with skeletal muscle strength and change in strength with resistance training. , 2010, Journal of applied physiology.

[73]  Rodica Pop-Busui,et al.  Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial , 2010, The Lancet.

[74]  F. Collins,et al.  Genomic medicine--an updated primer. , 2010, The New England journal of medicine.

[75]  Susan C Connor,et al.  Integration of metabolomics and transcriptomics data to aid biomarker discovery in type 2 diabetes. , 2010, Molecular bioSystems.

[76]  Gil Atzmon,et al.  Gene-Gene Interactions Lead to Higher Risk for Development of Type 2 Diabetes in an Ashkenazi Jewish Population , 2010, PloS one.

[77]  Christian Gieger,et al.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk , 2010, Nature Genetics.

[78]  P. O S I T I O N S T A T E M E N T,et al.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[79]  M. Jarvelin,et al.  Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes , 2009, Human molecular genetics.

[80]  G. Ginsburg,et al.  The SLCO1B1*5 genetic variant is associated with statin-induced side effects. , 2009, Journal of the American College of Cardiology.

[81]  Tianxi Cai,et al.  Joint Effects of Common Genetic Variants on the Risk for Type 2 Diabetes in U.S. Men and Women of European Ancestry , 2009, Annals of Internal Medicine.

[82]  Ralph A. DeFronzo,et al.  From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus , 2009, Diabetes.

[83]  F. Hu,et al.  TCF7L2, dietary carbohydrate, and risk of type 2 diabetes in US women. , 2009, The American journal of clinical nutrition.

[84]  E. Hoffman,et al.  INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men , 2008, BMC Medical Genetics.

[85]  R. D'Agostino,et al.  Genotype score in addition to common risk factors for prediction of type 2 diabetes. , 2008, The New England journal of medicine.

[86]  R. Holman,et al.  10-year follow-up of intensive glucose control in type 2 diabetes. , 2008, The New England journal of medicine.

[87]  E. Rampersaud,et al.  Physical activity and the association of common FTO gene variants with body mass index and obesity. , 2008, Archives of internal medicine.

[88]  Diederick Grobbee,et al.  Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. , 2008, The New England journal of medicine.

[89]  O. Pedersen,et al.  Effect of a multifactorial intervention on mortality in type 2 diabetes. , 2008, The New England journal of medicine.

[90]  Nicola J Cooper,et al.  Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis , 2007, BMJ : British Medical Journal.

[91]  M. Palta,et al.  Lower-than-expected prevalence and severity of retinopathy in an incident cohort followed during the first 4-14 years of type 1 diabetes: the Wisconsin Diabetes Registry Study. , 2006, American journal of epidemiology.

[92]  B. Zinman,et al.  Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. , 2005, The New England journal of medicine.

[93]  B. Fagerberg,et al.  A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500161-JLR200 , 2005, Journal of Lipid Research.

[94]  H. Parving,et al.  Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study , 2004, BMJ : British Medical Journal.

[95]  Oluf Pedersen,et al.  Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. , 2003, The New England journal of medicine.

[96]  E. Araki,et al.  Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. , 1995, Diabetes research and clinical practice.

[97]  H. Glauber,et al.  Impact of cardiovascular disease on health care utilization in a defined diabetic population. , 1994, Journal of clinical epidemiology.

[98]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[99]  D L DeMets,et al.  The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. , 1984, Archives of ophthalmology.

[100]  H. A. S. van den Brenk,et al.  Immunotherapy trials. , 1977, British medical journal.

[101]  Eddy Karnieli,et al.  Preventing type 2 diabetes mellitus: a call for personalized intervention. , 2013, The Permanente journal.

[102]  M. L. Alvarez,et al.  The role of non-coding RNAs in diabetic nephropathy: potential applications as biomarkers for disease development and progression. , 2013, Diabetes research and clinical practice.

[103]  A. Krolewski,et al.  The genetic risk of kidney disease in type 2 diabetes. , 2013, The Medical clinics of North America.

[104]  A. Spiegel,et al.  'Personalized medicine' to identify genetic risks for type 2 diabetes and focus prevention: can it fulfill its promise? , 2012, Health affairs.

[105]  W. Niu,et al.  An updated meta-analysis of methylenetetrahydrofolate reductase gene 677C/T polymorphism with diabetic nephropathy and diabetic retinopathy. , 2012, Diabetes research and clinical practice.

[106]  J. Shaw,et al.  IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. , 2011, Diabetes research and clinical practice.

[107]  S. Schinner Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes , 2009 .

[108]  K. Narayan,et al.  Clinical risk factors, DNA variants, and the development of type 2 diabetes. , 2009, The New England journal of medicine.

[109]  Ross C Brownson,et al.  Declining rates of physical activity in the United States: what are the contributors? , 2005, Annual review of public health.

[110]  E. Feskens,et al.  Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. , 2001, Archives of internal medicine.

[111]  T. Sano,et al.  [Diabetic retinopathy]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[112]  Teven,et al.  MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION , 2000 .

[113]  S. Colagiuri,et al.  The Diabetes Control and Complications Trial , 1983, Henry Ford Hospital medical journal.