DM and role of genomics July 2015 2 (1)

Diabetes

Diabetes Mellitus and role of GenomicsByMaria Armie Pacheco RN, BSN,CPA NRutgers State University

DM and genomics

Case Presentation 28 Year old AA male presents to the E.R .with C/O of abdominal pain associated with nausea/vomiting, generalized weakness, increased frequency in urination, extreme thirst (as per the patient I cant seem to drink enough water, I am also extremely hungry although I am too tired to eat), the patients complaint also included mild blurring of vision.

DM and Genomics

Medical History : No past medical history reported Familial history: Grandmother, Father, Uncle and aunt with DM.Social History: denies smoking, (+)ETOH and elicit drug useImmunization: Flu Vaccine updatedMedications: No current medication Allergies: NKDA

DM and GenomicsPhysical Exam:

V/S : BP 100/61 Temp. 36.2 HR 118 Spo2 94% RR- 28General Constitutional: AAO3, in mild distress, speech is clear, appropriate affectSkin: Dry, cool, intactHEENT: Normocephalic, atraumatic, no ear discharges, anicteric sclerae, pupils reactive and size 3mm bil., no thyromegaly, no lymphadenopathyCardiopulmonary: ST, S1S2, no murmurs, no rubs, no gallops, clear lungs bilaterallyGI: soft abdomen, mild tenderness on palpation, no bruisingGU: (+) frequency, non-distended bladder, no dysuria, no hematuriaMusculoskeletal: overall muscle strength 4/5, no ROM limitation, no fallsPsychological: anxious about current status, no suicidal tendencies

DM and GenomicsChest X-ray: no cardiomegaly, no PTX, no signs of pleural effusionEKG: Sinus tachycardia at 118CT: Normal findingsLabs : WBC 11,000, HGB 11.4, HCT 34.3, Na 136, K 4.1, Cl 108, CO2 14,Glucose: 514, osmolality 310BUN 21, Creatinine 1.5, U/A : (+) ketones, (+) glucoseAlb 3.5, Bili 0.7, AST 32, ALT 53, ALK P 89ABG: PH 7.32, CO2 29.1, PO2 95, Hco3 17 SpO2 97

DM and GenomicsDifferential Diagnosis:

DMDKA PancreatitisCholecystitisAppendicitis

DM and Genomics

This patient presented with early manifestations of Diabetic Ketoacidosis (DKA)

DM and Genomics Diabetes mellitus is a group of metabolic disorders characterized by: hyperglycemia abnormalities in carbohydrate, fat, and protein metabolism. It is resultant of insulin secretion, insulin sensitivity or both

Incidence Rates in U.S. (Nat. Diabetes Statistics Report/2014).

2.9 million people or 9.3% of the U.S. population has DMDiagnosed : 21.0 millionUndiagnosed: 8.1 million (27.8% of people with diabetes are undiagnosed)

Diabetes mellitus

Forms of DM:

Type I absence of insulinType 2 Insulin deficiency Insulin resistanceMODYGestational DM

DM and GenomicsType 1 Epidemiology:Hallmark - autoimmune destruction of beta cellsRepresents approximately 10% of all casesLifelong insulin Incidence of T1D is increasing at a rate of 3% per annumPuberty - peak age at onset Risk factors:GeneticsEnvironmental risk factors- initiators of beta cell autoimmunityEnteroviruses (CVB)Cows milk vs breast milk

DM and genomicsType 2

accounts for up to 90% of all DM cases and is usually characterized by the presence of both insulin resistance and relative insulin deficiency. increase lipolysis and free fatty acid production,increased gluconeogenesisdecreased skeletal muscle uptake of glucose B-cell dysfunction is progressive and contribute to worsening blood glucose control over time. Type II DM occurs when a diabetogenic lifestyle (excessive calories, inadequate exercise and obesity) is superimposed upon a susceptible genotype

DM and GenomicsType 2

Epidemiology:Most common form (90% of all cases)High in Native A., predominant in Hispanics and AA than in CaucasiansPrevalence increases with age of populationPrevalence increased by 6-fold in adolescents (Bloomgard/2004)

Risk factors:ObesitySedentary lifestyleWaist-to-hip ratio (WHR)

DM and Genomics

hypothalamus

PolyphagiaPolydipsiaPolyuria

Liver(glycogenolysis) adipocytes

VLDL/Triglyc.

receptor siteIntra-cellular

Energyfor cellular activities

Intra-vascularOsmotic pressure

Glucose+Insulin

Absence/ deffic. /Insensitivity.

CHOO/CHONUtilization = Ketosis

RetinopathyNeuropathyNephropathy

CHD PAD CVA

Gastro paresisInfectionsSkin Changes

16

T1D and genomicsHLA region on chromosome 6MHC multiple histocompatibility complexinvolved in presenting antigen to immune system MHC

MHC1 MHC 2 MHC 3 Humoral Cell-mediated

T-killer cell (CD8) T-helper cell (CD4) Several T1D susceptibility genes: .. .

HLA-DQB1, DQB1*0201, DQB1*0302, HLA DR3, HLADQ1*0301 ..INS - chromosome 1 CTLA-4 chromosome 2

Common susceptibility genes in DM:

DM and GenomicsCriteria for the Diagnosis of DM:

Symptoms of DM + Random blood glucose conc. >200mgs/dlOr FPG = 126 mg/dl orOr AIC > 6.5 % orOr 2-hr plasma glucose>200mg/dl during OGTT

Criteria for DKA Diagnosis:

Plasma glucose > 250ph 10

Impaired fasting glucose Impaired glucose tolerance

Interventions:

DKA Management:

Replace fluids (2-3L 0.9% NSS over 1-3h), then 15-20ml/kg/h; 0.45% NS 250-500ml/h; D5.45(150-250ml/h) when plasma glucose level is 200mgs/dlShort acting Insulin(0.1u/kg) then 0.1/kg/h cont. infusion. Increase 2-3 fold if negative response by 2-4h.If K+ is 150meq/L, use .45%When hemodynamically stable, IVF administration directed at reversing the free H2O deficit.Potassium repletion is necessary, depending on serum K measurements.Hypophosphatemia may occur during treatment give KPO4Insulin bolus 0.1u/kg followed by IV insulin @ constant infusion rate of 0.1 u/kg/hr.When plasma glucose falls to 250-300mg/dl, glucose should be added to IVF and insulin rate decreased to 0.05u/kg/hr.Once patient resumes eating SC insulin regimenPatient should be discharged from hospital on insulin.

Insulin TherapyBrandsTime givenPeakDurationRapid actingNovolog, AspartLisproGiven before or with meals 15 mins prior.1-3 hours 3-5 hoursShort actingNovolin RGiven 30-1 hr. before meals2-4 hours6-8 hoursIntermediateNPH (Novolin)Begins to work 1-2 hrs.4-12 hours22-24 hoursLong actingLantus4-6 hrs.None24-36 hrs.Long actingLevemir2-8 hrs.Flat peak24 hrs.CombinationsNovolog Mix 70/30Begins to work 10-20 mins.1-12 hrs.22-24 hrs.

DM Pharmacologic agents

Biguanides : MetforminSulfonylureas: glyburide, glipizide, glimepirideMeglitinide derivatives: repaglinide, nateglinideAlpha- glucosidase inhibitorsThiazolidinediones (TZDs): pioglitazone (Actos), rosiglitazone (Avandia)Glucagonlike peptide1 (GLP-1) agonists: exenatide, liraglutideDipeptidyl peptidase IV (DPP-4) inhibitors: sitagliptin, saxagliptin, linagliptinAmylinomimetics: Pramlintide acetate Bile acid sequestrantsDopamine agonists: bromocriptine mesylate (Cycloset)

Outcome and Follow up Care for this patient:Goal of therapy in DM are:

ameliorate symptoms reduce micro vascular and macro vascular complicationsreduce mortality and improve quality of life.

Therapeutic alliance between patient/family/health care team

Recognize:Self-management educationOngoing diabetes support

DM and GenomicsArticle:

Continuous Subcutaneous Insulin Infusion at 25 yearsEvidence base for the expanding use of insulin pump therapy in type 1 DM

Purpose:

To review the evidence base for the expanding use of CSII, in the light of its efficacy and possible side effects, and to initiate a debate about the need for clinical guidelines on the most suitable patients for pump therapy

DM and Genomics

Findings:

Evidence suggests that hypoglycemia is less common on CSII than injection therapyFrequency of ketoacidosis is decreased with use of CSII, the likelihood of DKA are attributed to remediable factors: doctor inexperience, use of unbuffered insulin, breakdown of less reliable pumps, cannula dislodgement and unsuitable patients.Dawn phenomena is decreased with CSII.Evidence from RCTs indicate large proportion Type 1 subjects, the glycemic control on CSII is comparable with or only slightly better than that achievable by intensive insulin injection regimen.CSII work efficacious on suitable patients: willingness/able to learn about undertake pump therapy and its associated procedures such regular monitoring of blood sugar

Diabetes mellitus

Conclusion:

The evidence base suggests that the expanding use of CSSI is justified. The unwillingness to fund pump therapy arises in part from the erroneous belief that it is indicated for a large proportion of type 1 diabetics, which would open a floodgate of cost implication. Clinical guidelines for CSII, those who stand to benefit could be greatly helped at an affordable cost. A continued audit of the clinical reasons for starting pump therapy, its metabolic effectiveness, possible side effects, impact on long-term tissue complications, quality of life, and patient choice of treatment methods in type 1 DM must still be sought after.

DM and PharmacogenomicsArticle: Pharmacogenetics of Anti-diabetes Drugs

Purpose: To explore the role of causal gene or polymorphism, and its impact on response to anti-hyperglycemic medications. To provide a comprehensive review of pharmacogenetics investigations of specific anti-diabetes medications namely, sulfonylureas, biguanides, and thiazolidinedione's.

Pharmacogenetic studies of Anti-Diabetes Drugs Sulfonylureas

Agents: Tolbutamide, gliclazide, glibenclamide, and glimepirideMODY- arises from mutations in hepatocyte nuclear factor 1 homeobox A gene (HNF1A)Sulfonylureas causes dramatic changes in HbA1clevelsMutations in potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) successful with sulfonylureas treatment rather than insulinMutations in ATP-binding cassette, sub family C (CFTR/MRP), member 8 gene (ABCC8) can be successfully treated with sulfonylureasCYP2C19 genotype results to poor metabolism of sulfonylureas Other markers:Genotype GLy972Arg has high incidence of sulfonylureas therapy failureTCF7L2 (alleles at rs12255372 and rs7903146 carriers) sub-optimal response to sulfonylureas

Pharmacogenetic studies of Anti-Diabetes Drugs(Biguanides) Metformin

- Ameliorates hyperglycemia by decreasing hepatic glucose output and GI glucose absorption and improving insulin sensitivity Not metabolized, undergoes renal elimination via glomerular filtration Hydrophilic OCT1 and OCT2 (solvent carriers)Genetic variants reducing Metformin activity:

SLC22A1SLCA22A2SLC47A1

Pharmacogenetic studies of Anti-Diabetes DrugsThiazolidinediones (TZD)

Pioglitazone (Actos) and Rosiglitazone (Avandia)

Insulin-sensitizing drugs that are agonists for the nuclear receptor proliferator-activated receptor-y (PPARG).Increases insulin sensitivity on adipose tissue and muscle3 known variants of PPARG : PPARG-a, PPARG-y, PPARG2PPARG2 is predominant in adipose tissueTZD found to be associated with weight gain and edemaMonotherapy is not recommended in patients at-risk for CHFVariation in CYP2C8 gene is associated with pharmacokinetic characteristics of Avandia- lesser drug clearance rate requiring lower dosage

Findings:

Genetic associations do provide information regarding specific genetic markers that may be predictive of drug efficacy. To date, association studies have not formally assessed specificity or sensitivity but they do provide some information on the utility of a given marker as a predictive tool. Furthermore, there has not been a study to jointly examine all variants for a given therapy to assess whether the joint information accounts for a greater proportion of the variability in drug response compared to the individual markers alone. Prospective studies testing the power of genetic markers to predict drug response are requisite to fully endorse their introduction into the clinical care setting.Rapid advances in genomic technologies have revolutionized studies of human genetics. As of this study, 38 loci underlying susceptibility to T2D have been identified, mostly in populations of northern European ancestry

DM and Role of Genomics

Conclusion:

Pharmacogenetics research provides a means to better understand and improve on pharmacotherapy. Studies have identified several gene variants that are potentially associated with differential response to anti-diabetes medications; these preliminary results are promising and warrant investigations in larger, well-designed cohorts to assess their potential roles in optimal drug selection and individualized pharmacotherapy in patients with T2D. At this time, larger, well-powered studies with clearly defined outcomes and utilizing a global approach are needed, as they will not only be more informative than extant candidate gene investigations, but will also be necessary to define the array of genetic variants that may underlie drug response. Such results will likely enable achievement of optimal glucose control, improvement of therapeutic efficacy, and reduction in risk of adverse drug events in at-risk patients, which together will lead to personalized treatment strategies for all individuals with T2D.

Implications for APN

Understanding the pharmacogenetics of anti-diabetes medications can provide critical baseline information for the management of patients with DM.Knowledge on the variations of a patients genetic make up can help the APN provide individualized treatment goals for better outcomes.Keeping abreast with current genome-wide studies will help enhance the APN and other disciplines involved in the care of a diabetic patient provide them with the most effective treatment strategy given their individual background

Continue to provide the following:

Life style changes counselingReferral to education programsStrategies to assist with problem solvingContinual patient educationContinuing support and encouragement,Relapse prevention, Ongoing follow-up.

DM and GenomicsReferences:Ahlqvist, E. (2015). The genetics of diabetic complications. Nat Rev Nephrol (6) 121-125.Albright, A., Khoury, M., Valdez, R. (2008). Public health genomics approach to diabetes. Diabetes 57:11:2911-2914.American Diabetic Association. (2013). Retrieved from .diabetes.org: http://www.diabetes.org/diabetes-basics/symptoms/Bak, P., Grey, M., Melkus, G., & Whittemore, R. (2003, August 15). Promoting lifestyle change in the prevention and management of type 2 diabetes. Retrieved from US National Library of Medicine: National Institutes of Health: http://www.ncbi.nlm.nih.gov/pubmed/14509099Dipiro, C. V., Dipiro, J. F., Schwinghammer, T. L., & Wells, B. G. (2012). Pharmacotherapy Handbook (Vol. 8 Edition). USA: Mc Graw Hill.DiStefano, J., Watanabe, R. (2010). Pharmacogenetics of Anti-Diabetes Drugs. Pharmaceuticals Aug 13. doi 10.3390/ph3082610Fryhoper, S. (2014). The fight against type 2 DM: the promise of genomics. Retrieved from www.medscape.comGriffing, G. T., & Khardori, R. (2012, March 13). Type 2 Diabetes Mellitus Differential Diagnoses. Retrieved from emedicine.medscape.com: http://emedicine.medscape.com/article/117853-differentialHanson, M. (2015). Genetics: Epigenetic mechanisms underlying type 2 diabetes mellitus. Nat Rev Endocrinol (5)261-263McCarthy, M. (2010). Genomics, type 2 diabetes, and obesity. N Engl J Med 2010; 363:2339-2350.Narayan, N., Weber, K. (2015). Screening for hyperglycemia: the gateway to diabetes prevention and management for all americans. Annal Intern Med. 162 (11):795-796.Sas, K. (2015). Metabolomics and diabetes: analytical and computational approaches. Diabetes 2015 Mar (3) 718-32Standards of Medical Care in Diabetes (2013). American Diabetes Association. Retrieved from www.care.diabetesjournals.orgWild, R., Roglic, G., Green, A. (2004). Global prevalence of diabetes. Diabetes Care 27:1047-1053