Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention

Type 2 diabetes is a serious and common chronic disease resulting from a complex inheritance-environment interaction along with other risk factors such as obesity and sedentary lifestyle. Type 2 diabetes and its complications constitute a major worldwide public health problem, affecting almost all populations in both developed and developing countries with high rates of diabetes-related morbidity and mortality. The prevalence of type 2 diabetes has been increasing exponentially, and a high prevalence rate has been observed in developing countries and in populations undergoing “westernization” or modernization. Multiple risk factors of diabetes, delayed diagnosis until micro- and macro-vascular complications arise, life-threatening complications, failure of the current therapies, and financial costs for the treatment of this disease, make it necessary to develop new efficient therapy strategies and appropriate prevention measures for the control of type 2 diabetes. Herein, we summarize our current understanding about the epidemiology of type 2 diabetes, the roles of genes, lifestyle and other factors contributing to rapid increase in the incidence of type 2 diabetes. The core aims are to bring forward the new therapy strategies and cost-effective intervention trials of type 2 diabetes.

[1]  J. Iwamoto,et al.  Effects of Vitamin K2 and Risedronate on Bone Formation and Resorption, Osteocyte Lacunar System, and Porosity in the Cortical Bone of Glucocorticoid-Treated Rats , 2008, Calcified Tissue International.

[2]  S. Larsson,et al.  Diabetes mellitus, body size and bladder cancer risk in a prospective study of Swedish men. , 2008, European journal of cancer.

[3]  A. Belkina,et al.  Obesity genes and insulin resistance. , 2010, Current opinion in endocrinology, diabetes, and obesity.

[4]  E. Ntzani,et al.  Genetic risk factors for type 2 diabetes: insights from the emerging genomic evidence. , 2012, Current vascular pharmacology.

[5]  J. Lindström,et al.  Tools for Predicting the Risk of Type 2 Diabetes in Daily Practice , 2008, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[6]  E. Tasali,et al.  Obstructive Sleep Apnea and Type 2 Diabetes: Is There a Link? , 2012, Front. Neur..

[7]  B. Ahrén.  Are Sulfonylureas Less Desirable Than DPP-4 Inhibitors as Add-on to Metformin in the Treatment of Type 2 Diabetes? , 2011, Current diabetes reports.

[8]  A. Ghasemi,et al.  Potential Therapeutic Effects of Nitrate/Nitrite and Type 2 Diabetes Mellitus , 2013, International journal of endocrinology and metabolism.

[9]  F. Takeuchi,et al.  Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population , 2009, Diabetes.

[10]  P. Poulsen,et al.  Increased Risk of Type 2 Diabetes in Elderly Twins , 2009, Diabetes.

[11]  A. Alberti,et al.  Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: potential role of insulin. , 2008, World journal of gastroenterology.

[12]  R. Haynes.  Diabetic complications , 2009, Journal of general internal medicine.

[13]  A. Sinclair,et al.  European Diabetes Working Party for Older People 2011 clinical guidelines for type 2 diabetes mellitus. Executive summary. , 2011, Diabetes & metabolism.

[14]  C. Glass,et al.  Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. , 2007, The Journal of clinical investigation.

[15]  M. Hanefeld,et al.  Dapagliflozin, an SGLT2 inhibitor, for diabetes , 2010, The Lancet.

[16]  J. Sowers,et al.  Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors , 2010, Cardiovascular diabetology.

[17]  G. Musso,et al.  Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. , 2011, Annual review of medicine.

[18]  H. Bays.  Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors: Targeting the Kidney to Improve Glycemic Control in Diabetes Mellitus , 2013, Diabetes Therapy.

[19]  C. Snehalatha,et al.  The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1) , 2006, Diabetologia.

[20]  A. Stadlmayr,et al.  A European Evidence-Based Guideline for the Prevention of Type 2 Diabetes , 2010, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[21]  K. Negoro,et al.  Chronic Treatment with Novel GPR40 Agonists Improve Whole-Body Glucose Metabolism Based on the Glucose-Dependent Insulin Secretion , 2013, The Journal of Pharmacology and Experimental Therapeutics.

[22]  L. Kuritzky.  Addition of basal insulin to oral antidiabetic agents: a goal-directed approach to type 2 diabetes therapy. , 2006, MedGenMed : Medscape general medicine.

[23]  H. Thaker,et al.  Targeting insulin resistance in type 2 diabetes via immune modulation of cord blood-derived multipotent stem cells (CB-SCs) in stem cell educator therapy: phase I/II clinical trial , 2013, BMC Medicine.

[24]  K. Khunti,et al.  The Leicester Risk Assessment score for detecting undiagnosed Type 2 diabetes and impaired glucose regulation for use in a multiethnic UK setting , 2010, Diabetic medicine : a journal of the British Diabetic Association.

[25]  R. Urban,et al.  Management of blood glucose in type 2 diabetes mellitus. , 2009, American family physician.

[26]  S. Inzucchi,et al.  Metformin: new understandings, new uses. , 2003, Drugs.

[27]  J. Lehmann,et al.  An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ) (*) , 1995, The Journal of Biological Chemistry.

[28]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[29]  D. Einhorn,et al.  Prevalence of sleep apnea in a population of adults with type 2 diabetes mellitus. , 2007, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[30]  M. Jarvelin,et al.  A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2007, Science.

[31]  Walter C Willett,et al.  Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. , 2004, JAMA.

[32]  M. Hezel,et al.  Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice , 2010, Proceedings of the National Academy of Sciences.

[33]  F. Hu,et al.  A prediction model for type 2 diabetes risk among Chinese people , 2009, Diabetologia.

[34]  J. Kouba,et al.  Vitamin D and Diabetes , 2008, The Diabetes educator.

[35]  A. Scheen.  Drug Interactions of Clinical Importance with Antihyperglycaemic Agents : An Update. , 2005, Drug safety.

[36]  J. Chambers,et al.  The Orphan G Protein-coupled Receptor GPR40 Is Activated by Medium and Long Chain Fatty Acids* , 2003, The Journal of Biological Chemistry.

[37]  R. Holman,et al.  Metformin as first choice in oral diabetes treatment: the UKPDS experience. , 2007, Journees annuelles de diabetologie de l'Hotel-Dieu.

[38]  R. Ratner,et al.  Differential effects of oral hypoglycemic agents on glucose control and cardiovascular risk. , 2007, The American journal of cardiology.

[39]  Dang Qing,et al.  Effects of Diet and Exercise in Preventing NIDDM in People With Impaired Glucose Tolerance The , 2022 .

[40]  K. Hara,et al.  Effects of vitamin K2 (menatetrenone) and alendronate on bone mineral density and bone strength in rats fed a low-magnesium diet. , 2004, Bone.

[41]  R. DeFronzo,et al.  One-Hour Plasma Glucose Concentration and the Metabolic Syndrome Identify Subjects at High Risk for Future Type 2 Diabetes , 2008, Diabetes Care.

[42]  J. Manson,et al.  A prospective study of whole-grain intake and risk of type 2 diabetes mellitus in US women. , 2000, American journal of public health.

[43]  J. Manson,et al.  Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. , 2001, The New England journal of medicine.

[44]  K. Shimamoto,et al.  Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance , 2009, The Lancet.

[45]  D. Altshuler,et al.  Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion , 2009, Nature Genetics.

[46]  M. Ezzati,et al.  National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants , 2011, The Lancet.

[47]  Arvind Kumar Srivastava,et al.  Diabetes mellitus: complications and therapeutics. , 2006, Medical science monitor : international medical journal of experimental and clinical research.

[48]  K. Khunti,et al.  Effectiveness of a Pragmatic Education Program Designed to Promote Walking Activity in Individuals With Impaired Glucose Tolerance , 2009, Diabetes Care.

[49]  Deborah R Erlich,et al.  Diabetes update: new drugs to manage type 2 diabetes. , 2013, FP essentials.

[50]  M. McCarthy,et al.  Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes , 2008, Nature Genetics.

[51]  S. Kalra,et al.  The novel use of GLP-1 analogue and insulin combination in type 2 diabetes mellitus. , 2012, Recent patents on endocrine, metabolic & immune drug discovery.

[52]  S. Malozowski,et al.  Interleukin-1-receptor antagonist in type 2 diabetes mellitus. , 2007, The New England journal of medicine.

[53]  F. Hu,et al.  Diet and risk of Type II diabetes: the role of types of fat and carbohydrate , 2001, Diabetologia.

[54]  Zygimantas Cepaitis,et al.  Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. , 2005, Diabetes.

[55]  F. Ashcroft,et al.  Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. , 2006, The New England journal of medicine.

[56]  L. Aiello,et al.  Retinopathy in diabetes. , 2004, Diabetes care.

[57]  J. Iwamoto,et al.  Vitamin K2 Promotes Bone Healing in a Rat Femoral Osteotomy Model with or without Glucocorticoid Treatment , 2010, Calcified Tissue International.

[58]  C. Mathieu,et al.  Vitamin D and diabetes: Its importance for beta cell and immune function , 2011, Molecular and Cellular Endocrinology.

[59]  F. Ashcroft,et al.  KATP channels and islet hormone secretion: new insights and controversies , 2013, Nature Reviews Endocrinology.

[60]  N. Thornberry,et al.  Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). , 2009, Best practice & research. Clinical endocrinology & metabolism.

[61]  P. Norwood,et al.  A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers , 2009, Diabetes Care.

[62]  S. Salekzamani,et al.  Daily consumption of vitamin D- or vitamin D + calcium-fortified yogurt drink improved glycemic control in patients with type 2 diabetes: a randomized clinical trial. , 2011, The American journal of clinical nutrition.

[63]  B. Prabhakar,et al.  Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells , 2012, BMC Medicine.

[64]  M. Christensen,et al.  Clinical potential of lixisenatide once daily treatment for type 2 diabetes mellitus , 2013, Diabetes, metabolic syndrome and obesity : targets and therapy.

[65]  L. Groop,et al.  Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus , 2008, Nature Genetics.

[66]  Kevin Haynes,et al.  Association between longer therapy with thiazolidinediones and risk of bladder cancer: a cohort study. , 2012, Journal of the National Cancer Institute.

[67]  JoAnn E Manson,et al.  Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. , 2005, Journal of applied physiology.

[68]  S. Bornstein,et al.  Screening for type 2 diabetes in primary care , 2009, BMJ : British Medical Journal.

[69]  S. Chua,et al.  Molecular mapping of SSRs for Pgm1 and C8b in the vicinity of the rat fatty locus. , 1995, Genomics.

[70]  T. Valle,et al.  Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. , 2001, The New England journal of medicine.

[71]  R. Pratley,et al.  Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes , 2007, Current medical research and opinion.

[72]  Simona Ioja,et al.  Relationship between Sleep Disorders and the Risk for Developing Type 2 Diabetes Mellitus , 2012, Postgraduate medicine.

[73]  Yong Zhao,et al.  New hope for type 2 diabetics: targeting insulin resistance through the immune modulation of stem cells. , 2011, Autoimmunity reviews.

[74]  In-kyu Lee,et al.  Metformin Inhibits Hepatic Gluconeogenesis Through AMP-Activated Protein Kinase–Dependent Regulation of the Orphan Nuclear Receptor SHP , 2008, Diabetes.

[75]  Heiner Boeing,et al.  Use of Multiple Metabolic and Genetic Markers to Improve the Prediction of Type 2 Diabetes: the EPIC-Potsdam Study , 2009, Diabetes Care.

[76]  P. Zimmet,et al.  The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives , 2012, Nature Reviews Endocrinology.

[77]  Harsinen Sanusi,et al.  The role of antioxidants in the pathophysiology, complications, and management of diabetes mellitus. , 2013, Acta medica Indonesiana.

[78]  R. Vigersky,et al.  An Overview of Management Issues in Adult Patients with Type 2 Diabetes Mellitus , 2011, Journal of diabetes science and technology.

[79]  Ewout W Steyerberg,et al.  The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases , 2007, Genetics in Medicine.

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

[81]  G. Ursin,et al.  Meat consumption and the risk of type 2 diabetes: a systematic review and meta-analysis of cohort studies , 2009, Diabetologia.

[82]  A. Gastaldelli.  Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus. , 2011, Diabetes research and clinical practice.

[83]  B. Popkin,et al.  Adults with healthier dietary patterns have healthier beverage patterns. , 2006, The Journal of nutrition.

[84]  Markolf Hanefeld,et al.  Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. , 2003, JAMA.

[85]  Walter C Willett,et al.  Dietary Patterns and Risk for Type 2 Diabetes Mellitus in U.S. Men , 2002, Annals of Internal Medicine.

[86]  W. Rathmann,et al.  Prevalence of undiagnosed diabetes and impaired glucose regulation in 35–59‐year‐old individuals in Southern Germany: the KORA F4 Study , 2010, Diabetic medicine : a journal of the British Diabetic Association.

[87]  Jaakko Tuomilehto,et al.  The diabetes risk score: a practical tool to predict type 2 diabetes risk. , 2003, Diabetes care.

[88]  S. Park,et al.  Management of Type 2 Diabetes Mellitus in Older Adults , 2012, Diabetes & metabolism journal.

[89]  P. Vermunt,et al.  Behavior change in a lifestyle intervention for type 2 diabetes prevention in Dutch primary care: opportunities for intervention content , 2013, BMC Family Practice.

[90]  M. Rogero,et al.  Focus on Vitamin D, Inflammation and Type 2 Diabetes , 2012, Nutrients.

[91]  T. Valle,et al.  Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial. , 2003, Journal of the American Society of Nephrology : JASN.

[92]  R. Eckel,et al.  Insulin sensitivity determines the effectiveness of dietary macronutrient composition on weight loss in obese women. , 2005, Obesity research.

[93]  P. Schwarz,et al.  Prevention of Diabetes Self-Management Program (PREDIAS): Effects on Weight, Metabolic Risk Factors, and Behavioral Outcomes , 2009, Diabetes Care.

[94]  D. S. Bell.  Combine and conquer: advantages and disadvantages of fixed‐dose combination therapy , 2013, Diabetes, obesity & metabolism.

[95]  J. Manson,et al.  A prospective study of cigarette smoking and the incidence of diabetes mellitus among US male physicians. , 2000, The American journal of medicine.

[96]  S. Engel,et al.  Sulphonylureas and risk of cardiovascular disease: systematic review and meta‐analysis , 2013, Diabetic medicine : a journal of the British Diabetic Association.

[97]  D. Dicker,et al.  Dipeptidyl Peptidase-4 Inhibitors and Their Effects on the Cardiovascular System , 2013, Current Cardiology Reports.

[98]  H. Hassan,et al.  Hypothyroidism in Male Rats of Different Ages Exposed to Nitrate Polluted Drinking Water , 2008 .

[99]  N. Chaturvedi.  The burden of diabetes and its complications: trends and implications for intervention. , 2007, Diabetes research and clinical practice.

[100]  J. Kenardy,et al.  Psychological interventions for overweight or obesity. , 2014, The Cochrane database of systematic reviews.

[101]  A. D. de Craen,et al.  Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes : the Leiden 85-Plus Study. , 2002, Diabetes.

[102]  K. Kosaka,et al.  Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. , 2005, Diabetes research and clinical practice.

[103]  B. Blumberg,et al.  Vitamin K2 Regulation of Bone Homeostasis Is Mediated by the Steroid and Xenobiotic Receptor SXR* , 2003, Journal of Biological Chemistry.

[104]  Aziz Sheikh,et al.  Predicting risk of type 2 diabetes in England and Wales: prospective derivation and validation of QDScore , 2009, BMJ : British Medical Journal.

[105]  Y. Terauchi,et al.  Long-term efficacy and safety of sitagliptin in the treatment of Japanese Type 2 diabetes (ASSET-K1) to a target of HbA1c<7% , 2013, Journal of Endocrinological Investigation.

[106]  R. Telford.  Low physical activity and obesity: causes of chronic disease or simply predictors? , 2007, Medicine and science in sports and exercise.

[107]  K. Dou,et al.  Prevalence of diabetes among men and women in China. , 2010, The New England journal of medicine.

[108]  C. Abraham,et al.  Systematic review of reviews of intervention components associated with increased effectiveness in dietary and physical activity interventions , 2011, BMC public health.

[109]  S. Shoelson,et al.  Type 2 diabetes as an inflammatory disease , 2011, Nature Reviews Immunology.

[110]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[111]  M. Bullano,et al.  Differences in hypoglycemia event rates and associated cost-consequence in patients initiated on long-acting and intermediate-acting insulin products. , 2004, Current medical research and opinion.

[112]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[113]  Ho-Young Son,et al.  Epidemic obesity and type 2 diabetes in Asia , 2006, The Lancet.

[114]  R. Hayes,et al.  Insulin-like growth factor-I and insulin are associated with the presence and advancement of adenomatous polyps. , 2005, Gastroenterology.

[115]  Wolfgang Rathmann,et al.  Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. , 2004, Diabetes care.

[116]  A. Ghasemi,et al.  Is nitric oxide a hormone? , 2011, Iranian biomedical journal.

[117]  S. Blair.  Physical inactivity: the biggest public health problem of the 21st century. , 2009, British journal of sports medicine.

[118]  S. Dejager,et al.  Incretin Therapies in the Management of Elderly Patients with Type 2 Diabetes Mellitus , 2011, Hospital practice.

[119]  J. Lindström,et al.  Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study , 2006, The Lancet.

[120]  P. Woo,et al.  Bacteremia Due to Clostridium hathewayi in a Patient with Acute Appendicitis , 2004, Journal of Clinical Microbiology.

[121]  Jean Tichet,et al.  Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia , 2009, Nature Genetics.

[122]  C. Östenson,et al.  Alcohol consumption and risk of pre‐diabetes and type 2 diabetes development in a Swedish population , 2012, Diabetic medicine : a journal of the British Diabetic Association.

[123]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[124]  E. Ferrannini,et al.  Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise , 2010, Diabetes Care.

[125]  M. Spitz,et al.  Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. , 1999, Journal of the National Cancer Institute.

[126]  X. Wang,et al.  Profile of vildagliptin in type 2 diabetes: efficacy, safety, and patient acceptability , 2013, Therapeutics and clinical risk management.

[127]  E. Rimm,et al.  Dietary fat and meat intake in relation to risk of type 2 diabetes in men. , 2002, Diabetes care.

[128]  D. English,et al.  Alcohol intake, consumption pattern and beverage type, and the risk of Type 2 diabetes , 2006, Diabetic medicine : a journal of the British Diabetic Association.

[129]  J. Diamond.  Medicine: Diabetes in India , 2011, Nature.

[130]  K. Timper,et al.  Diabetes mellitus Type 2--the new face of an old lady. , 2012, Swiss medical weekly.

[131]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[132]  M. Neurath,et al.  Prevalence of sleep apnoea in diabetic patients , 2011, The clinical respiratory journal.

[133]  A. Olokoba,et al.  Type 2 diabetes mellitus: a review of current trends. , 2012, Oman medical journal.

[134]  G. Lopaschuk,et al.  Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. , 2006, American journal of physiology. Endocrinology and metabolism.

[135]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[136]  Masataka Harada,et al.  Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 , 2003, Nature.

[137]  E. Weitzberg,et al.  Dietary nitrate – a slow train coming , 2011, The Journal of physiology.

[138]  B. Larijani,et al.  A review on the role of antioxidants in the management of diabetes and its complications. , 2005, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[139]  D. Mozaffarian,et al.  Changes in diet and lifestyle and long-term weight gain in women and men. , 2011, The New England journal of medicine.

[140]  Fuu-Jen Tsai,et al.  A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese , 2010, PLoS genetics.

[141]  J. Shaw,et al.  Global and societal implications of the diabetes epidemic , 2001, Nature.

[142]  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.

[143]  Alicja Wolk,et al.  Diabetes mellitus and risk of breast cancer: A meta‐analysis , 2007, International journal of cancer.

[144]  T. Gislason,et al.  Sleep apnea and glucose metabolism: a long-term follow-up in a community-based sample. , 2012, Chest.

[145]  Ralph B. D'Agostino,et al.  Soft Drink Consumption and Risk of Developing Cardiometabolic Risk Factors and the Metabolic Syndrome in Middle-Aged Adults in the Community , 2007, Circulation.

[146]  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.

[147]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[148]  V. Basevi,et al.  Standards of Medical Care in Diabetes—2012 , 2011, Diabetes Care.

[149]  L. Groop,et al.  Fasting Versus Postload Plasma Glucose Concentration and the Risk for Future Type 2 Diabetes , 2009, Diabetes Care.

[150]  A. Ahluwalia,et al.  Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite , 2008, Hypertension.

[151]  S. Fowler,et al.  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. , 2002 .

[152]  D. Early,et al.  Type 2 Diabetes Mellitus: The Impact on Colorectal Adenoma Risk in Women , 2006, The American Journal of Gastroenterology.

[153]  F. Ismail-Beigi.  Pathogenesis and glycemic management of type 2 diabetes mellitus: a physiological approach. , 2012, Archives of Iranian medicine.

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

[155]  Xu-hui Zhang,et al.  Increased risk of cancer in patients with type 2 diabetes mellitus: A retrospective cohort study in China , 2012, BMC Public Health.

[156]  A. Cecile J.W. Janssens,et al.  Predicting Type 2 Diabetes Based on Polymorphisms From Genome-Wide Association Studies , 2008, Diabetes.

[157]  Ewout W Steyerberg,et al.  Predictive testing for complex diseases using multiple genes: Fact or fiction? , 2006, Genetics in Medicine.

[158]  C. Burant,et al.  TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial , 2012, The Lancet.

[159]  Nicola J Cooper,et al.  Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis , 2008, BMJ : British Medical Journal.

[160]  J. Iwamoto,et al.  Menatetrenone (vitamin K2) and bone quality in the treatment of postmenopausal osteoporosis. , 2006, Nutrition reviews.

[161]  D. Dunger,et al.  Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. , 2002, Journal of the National Cancer Institute.

[162]  J. Iwamoto,et al.  Menatetrenone (vitamin K2) and bone quality in the treatment of postmenopausal osteoporosis. , 2006, Nutrition reviews.

[163]  The Diabetes Prevention Program (DPP): description of lifestyle intervention. , 2002, Diabetes care.

[164]  W. R. Bruce,et al.  Hyperinsulinemia, but not other factors associated with insulin resistance, acutely enhances colorectal epithelial proliferation in vivo. , 2006, Endocrinology.

[165]  S. Del Prato,et al.  [Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin]. , 2013, Deutsche medizinische Wochenschrift.

[166]  Jie Shen,et al.  Interleukin-10 −592C/A, −819C/T and −1082A/G Polymorphisms with Risk of Type 2 Diabetes Mellitus: A HuGE Review and Meta-analysis , 2013, PloS one.

[167]  H. Rodbard,et al.  American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. , 2007, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[168]  Kunyan Zhang,et al.  Bacteremia Caused by Clostridium symbiosum , 2004, Journal of Clinical Microbiology.

[169]  A. Scheen.  Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation , 2013, Expert opinion on drug metabolism & toxicology.

[170]  J. Iwamoto,et al.  Effects of Vitamin K2 on Cortical and Cancellous Bone Mass, Cortical Osteocyte and Lacunar System, and Porosity in Sciatic Neurectomized Rats , 2010, Calcified Tissue International.

[171]  P. Poulsen,et al.  Heritability of Type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance – a population-based twin study , 1999, Diabetologia.

[172]  J. Iwamoto,et al.  Effects of vitamin K2 on osteoporosis. , 2004, Current pharmaceutical design.

[173]  Philippe Froguel,et al.  Genetics of obesity and the prediction of risk for health. , 2006, Human molecular genetics.

[174]  Qiang Feng,et al.  A metagenome-wide association study of gut microbiota in type 2 diabetes , 2012, Nature.

[175]  N. Wareham,et al.  Diabetes risk score: towards earlier detection of Type 2 diabetes in general practice , 2000, Diabetes/metabolism research and reviews.

[176]  Griffin,et al.  The performance of a risk score in predicting undiagnosed hyperglycemia. , 2002, Diabetes care.

[177]  Yong Zhao.  Stem Cell Educator Therapy and Induction of Immune Balance , 2012, Current Diabetes Reports.

[178]  J. Lehmann,et al.  An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). , 1995, The Journal of biological chemistry.

[179]  J. Manson,et al.  Plasma 25-Hydroxyvitamin D Concentration and Risk of Incident Type 2 Diabetes in Women , 2010, Diabetes Care.

[180]  N. Tajima,et al.  Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double‐blind trial , 2010, Diabetes, obesity & metabolism.

[181]  Shizhong Han,et al.  Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk , 2008, BMC Medical Genetics.

[182]  Edward Giovannucci,et al.  Diabetes and Cancer , 2010, Diabetes Care.

[183]  B. Howard,et al.  Effects of Diet and Exercise in Preventing NIDDM in People With Impaired Glucose Tolerance: The Da Qing IGT and Diabetes Study , 1997, Diabetes Care.

[184]  C. Glass,et al.  Macrophages, inflammation, and insulin resistance. , 2010, Annual review of physiology.

[185]  Kurt Hoffmann,et al.  An Accurate Risk Score Based on Anthropometric, Dietary, and Lifestyle Factors to Predict the Development of Type 2 Diabetes , 2007, Diabetes Care.

[186]  S. Booth,et al.  Phylloquinone intake, insulin sensitivity, and glycemic status in men and women. , 2008, The American journal of clinical nutrition.

[187]  C. Clar,et al.  Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes , 2012, BMJ Open.

[188]  F. Hu,et al.  Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. , 2011, The American journal of clinical nutrition.

[189]  Amine Dahaoui,et al.  Exploring insulin analogue safety and effectiveness in a Maghrebian cohort with type 2 diabetes: results from the A₁chieve study. , 2013, Diabetes research and clinical practice.

[190]  T. Hansen,et al.  SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations , 2008, Nature Genetics.

[191]  Dolores Corella,et al.  Reduction in the Incidence of Type 2 Diabetes With the Mediterranean Diet , 2010, Diabetes Care.

[192]  M. Spitz,et al.  Serum Levels of Insulin Growth Factor (IGF-I) and IGF-Binding Protein Predict Risk of Second Primary Tumors in Patients with Head and Neck Cancer , 2004, Clinical Cancer Research.

[193]  S. Larsson,et al.  Diabetes mellitus and incidence of kidney cancer: a meta-analysis of cohort studies , 2011, Diabetologia.