Obesity Pre-Diabetes to Type 2 Diabetes Gül Bahtiyar, MD, MPH Woodhull Medical Center Clinical Associate Professor NYU School of Medicine.

Obesity Pre-Diabetes to Type 2 Diabetes Gül Bahtiyar, MD, MPH Woodhull Medical Center Clinical Associate Professor NYU School of Medicine

Overview  1/3 of U.S. population is obese  2/3 of U.S. population is overweight or obese  74% Increase over 10 year period  Costs U.S. companies $13 billion/year  Employers have important roles in addressing this epidemic

Obesity on the Map

Obesity Has a Hefty Price Tag  ~$117 billion in 2000 ($61 billion direct and $56 billion indirect)  6-10% of U.S. health care spending  Health costs >30% higher than normal weight individuals

Definitions of Obesity ClassificationBMI (kg/m 2 )Comorbidity Risk Underweight< 18.5Low* Normal range18.5 to 24.9Average Overweight25.0 to 29.9Increased Obese class 130.0 to 34.9Moderate Obese class 235.0 to 39.9Severe Obese class 3 (Morbidly obese) 40.0Very severe *risk of other clinical problems increased Calculate your own BMI: http://www.nhlbisupport.com/bmi/http://www.nhlbisupport.com/bmi/

Apples and Pears Waist circumference is tied to cardiovascular risk Tipping Point: Men: >40 inches Women: >35 inches

 Diabetes  Coronary artery disease  Peripheral artery disease  Stroke  Hypertension  Hyperlipidemia  Arthritis  Obstructive sleep apnea  Pulmonary disease  PCOS/infertility  Dysmenorrhea  Pregnancy complications  Gallbladder disease  GERD  Skin infections  Urinary incontinence  Depression  Eating disorders  Social stigma  Cancers: breast, endometrial, colon, prostate, gallbladder, kidney, esophagus…  Increase in all causes mortality Obesity Major Player in Many Diseases

Natural Selection?

Energy Balance

Helping Shift the Balance of Energy  Lifestyle modification  Mindful eating  Exercise  Healthy self-talk  Diets  Medication  Surgery

An Informed Approach  Recognize as chronic disease  Responsibility exists at many levels  Prevention as individual and society  Can make impact in workplace

Why Workplace Solutions?  Workplace can be part of the problem  Employees willing to pay for it  An ideal opportunity for social reinforcement

Workplace Solutions: A Range of Options  Education  Community resources  Getting involved  Inexpensive approaches

Education Strategies: A Simple Way to Start  Employee newsletter  Informational e-mails  Bulletin boards  Include: –Calories burned from common activities –Mindful eating tips –Local walking/bike trails –Upcoming fitness activities/events

Small Changes Each Day Add Up…  Diet over regular soda, 1 can.......15 pounds/year  1 Candy bar/day...........................26 pounds/year  Skim milk over whole, 1cup..........7 pounds/year  1Tbs mustard instead of mayo.......9 pounds/year  2 Scoops ice cream/day................33 pounds/year  Apple juice, 8oz cup.....................12 pounds/year  Orange juice, 8oz cup...................10 pounds/year  2 Beers/day....................................31 pounds/year

Workplace Involvement Pays Off  Scheduling physical breaks during the day  Onsite wellness centers, exercise/walking trails  Stress management programs  Encourage walking/biking to/from work and during breaks  Memberships or discounts to health clubs  Walking clubs, weight loss competitions

Inexpensive Approaches for Better Nutrition  Offering healthier food choices at reasonable prices  Provide nutritional info in cafeteria  Provide healthier snacks at meetings and other employee events  Provide bottled water and healthier items in vending machines

Create a Healthy Work Environment  Encourage employees to use stairways  Discourage employees from eating at their desks  Support physical activity breaks during the workday  Offer alternative work schedules  Have a weekly casual day  Provide enough time for lunch so employees can walk or use the gym and don’t eat in a rush

Additional Strategies  Wellness programs with onsite or online wellness coaches are effective  Incentives  Ongoing reminders through newsletters, posters, speakers  Weight management support groups

Partner with Community Resources  Local speakers or personal trainers  Walk-a-thons, bike-a- thons  Health fairs  Onsite employee meetings with Overeaters Anonymous or Weight Watchers

Global Projections for the Diabetes Epidemic: 2000-2030 (in millions) NA 19.7 33.9 72% LAC 13.3 33.0 248% EU 17.8 25.1 41% A+NZ 1.2 2.0 65% SSA 7.1 18.6 261% World 2000 = 171 million 2030 = 552 million Increase 213% China 20.8 42.3 204% Wild, S et al.: Global prevalence of diabetes: Estimates for 2000 and projections for 2030 Diabetes Care 2004;40(5):134-141 India 31.7 79.4 251% MEC 20.1 52.8 263%

Geographic Distribution of Diabetes in the US Shrestha S et al. Am J Prev Med 2011;40(4):434-39

Projected Obesity Prevalence from 1960 to 2025 Kopelman P. Nature 2000; 404, 635-643

Back Visceral AT Subcutaneous AT Front Intra-abdominal (Visceral) Fat The dangerous inner fat!

To assess IAA, the simplest anthropometric index is the measurement of waist circumference, which is strongly correlated with direct measurement of IAA by CT scan or MRI, considered to be the gold standard 300 200 100 0 r = 0.80 6080100120 Front Back Subcutaneous AT Visceral AT Waist circumference (cm) IAA (cm 2 ) Pouliot et al. Am J Cardiol. 1994;73:460-8. Després et al. 2001 BMJ. 2001;322:716-20 AT: adipose tissue Waist Circumference Correlates Closely with Intra-abdominal Adiposity (IAA)

Haffner SM et al. Diabetes Care 1999; 22: 562–568 Bloomgarden ZT. Clin Ther 1998; 20: 216–231 > 80% of diabetics are insulin resistant Genetic factors Environmental factors Family history Ethnicity Obesity Age Diet Lack of exercise Insulin Resistance is a Root Cause of Diabetes

Narayan et al. JAMA 2003;290:1884-1890. Diabetes: Lifetime Risk Roger VL et al. Published online in Circulation Dec. 15, 2010

Criteria for Testing for Diabetes in Asymptomatic Adult Individuals ADA. II. Diabetes Care 2013;36(suppl 1):S14 1. Testing should be considered in all adults who are overweight (BMI ≥25 kg/m 2 *) and have additional risk factors: Physical inactivity First-degree relative with diabetes High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Women who delivered a baby weighing >9 lb or were diagnosed with GDM Hypertension (≥140/90 mmHg or on therapy for hypertension) HDL cholesterol level 250 mg/dL (2.82 mmol/L) Women with polycystic ovary syndrome (PCOS) A1C ≥5.7%, IGT, or IFG on previous testing Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) History of CVD

2. In the absence of criteria (risk factors on previous slide), testing for diabetes should begin at age 45 years 3. If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly), and risk status Criteria for Testing for Diabetes in Asymptomatic Adult Individuals ADA. II. Diabetes Care 2013;36(suppl 1):S14

Natural History of Diabetes Disease Progression

* IFG = impaired fasting glucose. Adapted from: International Diabetes Center (IDC), Minneapolis, Minnesota. 0 50 100 150 200 250 -10-5051015202530 Years of Diabetes Glucose (mg/dL) Relative  -cell Function (%) Insulin Resistance Insulin Level  -cell failure 50 100 150 200 250 300 350 Fasting Glucose Post-meal Glucose Obesity IFG * Diabetes Uncontrolled Hyperglycemia Diagnosis of Diabetes Natural History of Diabetes

Genetic susceptibility, obesity, Western lifestyle Type 2 diabetes IR  Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13 Insulin Resistance and  -cell Dysfunction are Core Defects of Diabetes Insulin Resistance β-Cell Dysfucntion Glucagon Incretins Diabetes

To convert mg/dL to mmol/L multiply mg/dl by 0.055 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001;24:S5-S20 American Diabetes Association. Diabetes Care 2010;33:S11-61 Fasting Plasma Glucose 126 mg/dL 100 mg/dL 7.0 mmol/L 5.6 mmol/L Prediabetes Normal Diabetes 2 hour Plasma Glucose on OGTT 200 mg/dL 140 mg/dL 11.1 mmol/L 7.8mmol/L Impaired Glucose Tolerance Normal Diabetes Hemoglobin A1C 6.5 % 5.7% Prediabetes Normal Diabetes Diagnostic Criteria for Glycemic Abnormalities The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001;24:S5-S20 American Diabetes Association. Diabetes Care 2010;33:S11-61 WHO position statement 2011: HbA1c > 6.5 diagnostic for DM, levels below do not exclude diagnosis using glucose tests, no formal recommendation to interprete levels < 6.5 %

Obese Lean -50% -63% Butler et al. Diabetes. Diabetes. 2003;52:102-110 ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus  -cell Mass in Diabetes

What actually is Insulin Resistance?

 Glycogen synthesis  Gluconeogenesis Liver Muscle Adipose tissue Insulin is a Powerful Anabolic Hormone  Glycogen synthesis  Protein synthesis  Triglyceride synthesis  Triglyceride deposition  Glucose oxidation  ATP production Mitochondria DeFronzo et al. Diabtes Metab Res rev 2006;22:423-436  Endothelial NO synthesis  Peripheral vasodilatation  Regional blood flow  Glucose delivery and uptake Capillary Insulin

Insulin Receptor and Signaling

 Glycogen synthesis  Gluconeogenesis Liver Muscle Adipose tissue Reduce Response to Circulating Insulin  Glycogen synthesis  Proteolysis  Glucose uptake  Lipolysis  Circulation FFA  Glucose uptake  FFA oxidation  ATP production  Small dense LDL Mitochondria DeFronzo et al. Diabtes Metab Res rev 2006;22:423-436  Endothelial NO synthesis  Peripheral vasodilatation  Regional blood flow  Glucose delivery and uptake Capillary Insulin Resistance

Acanthosis Nigricans

AGE=Advanced glycation end products, CRP=C-reactive protein, HDL=High-density lipoprotein,, IL-6 =Interleukin-6, LDL=Low-density lipoprotein, PAI-1=Plasminogen activator inhibitor-1, SAA=Serum amyloid A protein, TF=Tissue factor, TG=Triglycerides, tPA=Tissue plasminogen activator Subclinical Atherosclerosis Atherosclerotic Clinical Events Hyperglycemia  AGE  Oxidative stress Inflammation  IL-6  CRP  SAA Infection  Defense mechanisms  Pathogen burden HTN Endothelial dysfunction Dyslipidemia  LDL  TG  HDL Thrombosis  PAI-1  TF  tPA Disease Progression Biondi-Zoccai GGL et al. JACC 2003;41:1071-1077 Mechanisms by which Pre-diabetes leads to Coronary Heart Disease Insulin Resistance

35% 31% 34% 37% 18% 45% 37% 27% 36% GAMI n = 164 EHS n = 1920 CHS n = 2263 GAMI = Glucose Tolerance in Patients with Acute Myocardial Infarction study EHS = Euro Heart Survey CHS = China Heart Survey Prediabetes Normoglycemia Type 2 Diabetes Anselmino M, et al. Rev Cardiovasc Med. 2008;9:29-38 Most Cardiovascular Patients Have Abnormal Glucose Metabolism

0 10 20 30 40 50 No history of MIHistory of MI 7-year incidence of cardiovascular events (%) No history of MIHistory of MI Haffner SM et al. N Engl J Med 1998; 339: 229–234 Non-diabetic (n = 1,373) Diabetes (n = 1,059) Marked Increase in the Risk of Myocardial Infarction in Diabetes 7 years follow-up 4% 20% 19% 45%

WOMEN MEN Sprafka JM et al. Diabetes Care 1991;14:537-543 100 80 60 40 0 Survival (%) Months Post-MI No diabetes n=228 n=1628 Months Post-MI 0204060 Diabetes 80 020406080 Diabetes No diabetes n=156 n=568 Minnesota Heart Survey Survival Following a Myocardial Infarction

50% of patients with diabetes have preexisting coronary artery disease CVD is 2 to 4 fold higher among people with diabetes 35-45% of patients presenting with myocardial infarction have undiagnosed diabetes Atherosclerotic complications responsible for 80% of mortality among patients with diabetes Lewis GF. Can J Cardiol. 1995;11(suppl C):24C-28C Norhammar A, et.al. Lancet 2002;359;2140-2144 Lewis GF. Can J Cardiol. 1995;11(suppl C):24C-28C Diabetes and Cardiovascular Disease

DPP Research Group. Diabetic Medicine 2007; 24 (2); 137-144 8% of people with pre-diabetes have retinopathy DPP Retinopathy Sub-study

79 million U.S. adults ages 20 and older have pre-diabetes IFG, IGT or an A1C of 5.7% - 6.4% Progression to diabetes evitable

StudySubjectsInterventionRelative Risk Reduction Da Quing 1 IGTDiet or Exercise or Both42% / 49% / 34% Finnish DPS 2 IGTLifestyle58% DPP 3 IGTLifestyle58% DPP 3 IGT /“IFG”Metformin31% STOP-NIDDM 4 IGTAcarbose25% EDIP 5 IFGAcarboseNS XENDOS 6 IGTOrlistat45% TRIPOD 7 Prior GDMTroglitazone55% DREAM 8,9 IFGRosiglitazone / Ramipril62% / NS ACT NOW 10 IGTPioglitazone72% ORIGIN 11 IGT / “IFG”Insulin Glargine / Omega-3  1 Li G et al. Lancet. 2008;371:1783-1789 | 2 Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350 | 3 Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403 | 4 Chiasson JL et al. Lancet. 2002;359:2072- 2077| 5 Kirkman MS et al. Diabetes Care. 2006;29:2095-2101 | 6 Torgerson JS et al. Diabetes Care. 2004;27:155-161 | 8 DREAM Trial Investigators. Lancet. 2006;368;1096-1105 | 9 DREAM Trial Investigators. N Engl J Med. 2006;355:1551- 1562 | 10 DeFronzo RA et al. N Engl J Med. 2011;364:1104-1115 | 11 ORIGIN Trial Investigators. Am Heart J. 2008;155:26-32. IFG: impaired fasting glucose IGT: impaired glucose tolerance GDM: gestational diabetes mellitus NS: not significant Medication Behavior Prevention of Diabetes is Possible

Tuomilehto J et al. NEJM 2001;344:1343-1350 Intervention Control 11% 23% % with Diabetes Mellitus † Defined as a glucose >140 mg/dl 2 hours after an oral glucose challenge 522 patients with a mean BMI=31 kg/m 2 patients and IGT † were randomized to intervention ‡ or usual care for 3 years Lifestyle modification reduces the risk of developing DM ‡ Aimed at reducing weight (>5%), total intake of fat ( 15 g/1000 cal); and physical activity (moderate at least 30 min/day ) Finnish Diabetes Prevention Study

51 Gerstein HC et al. Lancet 2006;368:1096-1105 0.6 0.4 0.2 0.0 01234 Placebo Rosiglitazone Incident DM or Death Years 60% RRR, P<0.0001 5,269 patients with IFG and/or IGT, but without known CVD randomized to rosiglitazone (8 mg) or placebo for a median of 3 years Thiazolidinediones reduce the risk of developing DM Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) Trial Benefit observed regardless of ethnicity, sex, age, weight, and fat distribution

.......................... Diabetes Prevention Program and Outcome Study (DPP and DPPOS)

Diabetes Prevention Program (DPP) To determine whether diet and exercise or metformin could prevent or delay the onset of type 2 diabetes in persons with impaired glucose tolerance Adults at high risk for type 2 diabetes / Presence of IGT Mean age 51 years Mean BMI 34 68% women 45% minority groups African Americans Hispanics/Latinos American Indians Asian Americans and Pacific Islanders Average follow-up 2.8 years DPP Research Group. N Engl J Med 2002; 346:6

Diabetes Prevention Program (DPP) Lifestyle intervention 5% to 7% weight reduction Healthy low-calorie, low-fat diet 30 minutes of physical activity, 5 days a week Diet Exercise Behavior change modification Metformin 850 mg po q12h + Standard Lifestyle Oral diabetes drug Placebo + Standard Lifestyle DPP Research Group. N Engl J Med 2002; 346:6 Taught one-on-one by case managers

Placebo (n=1082) Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Metformin, p<0.001 vs. Placebo) Risk reduction 31% by metformin 58% by lifestyle DPP Incidence of Diabetes DPP Research Group. N Engl J Med 2002; 346:6

DPP Research Group. Lancet. 2009; 374:1677-1686 DPP Outcome Study Weight Change Over Time – Overall

DPP Research Group. Lancet. 2009; 374:1677-1686 DPPOS Incidence of Diabetes – Overall Risk reduction 19% by metformin 34% by lifestyle

Lifestyle Intervention; reduced the rate of developing diabetes by 34% reduced the rate of developing diabetes by 49% in those age 60 and older delayed diabetes by about 4 years reduced cardiovascular risk factors reduced A1C and FPG Metformin; reduced the rate of developing diabetes by 18% compared with placebo. delayed diabetes by 2 years compared with placebo. reduced A1C and fasting glucose compared with placebo. After 10 years follow-up DPP Research Group. The Lancet 2009: Vol.374, No. 9702.

How to Treat Diabetes?

AA1c Target Aspirin Daily BBlood Pressure Control CCholesterol Management Cigarette Smoking Cessation DDiabetes and Pre-Diabetes Management EExercise FFood Choices ABC for Diabetes Care

Blood Glucose ParameterADA 1 AACE 2 A1C<7%≤6.5% Preprandial Glucose/FPG 70-130 mg/dL<110 mg/dL Peak PPG*/2-h PPG<180 mg/dL<140 mg/dL 1-American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. 2 2- Rodbard HW, et al. Endocr Pract. 2007;13(suppl 1):3-68 What is the HbA1c Goal?

A1c (%) Average Blood Sugar (mg/dL) 6126 7154 8183 9212 10240 11269 12298 *ADA target fasting sugar level: 70-130 mg/dL American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. How Does A1C Compare with Blood Sugar Readings?

% relative risk reduction P=0.03 P<0.01 P=0.05 P=0.02 UKPDS Group. Lancet 1998;352:837-853 Intensive glycemic control in DM reduces the risk of microvascular complications United Kingdom Prospective Diabetes Study (UKPDS) 3,867 patients with diabetes randomized to intensive therapy with a sulphonylurea or insulin (mean HbA 1C 7.0%) or conventional therapy (mean HbA 1C 7.9%) for 10 years Effect of Intensive Glycemic Control

HbA 1c Micro complications Heart attack * Deaths related to diabetes* 21% Stratton IM et al. UKPDS 35. BMJ 2000; 321: 405–412 Amputation or fatal PVD 37% 14% 12% 43% Stroke ** 1% * p<0.0001 ** p=0.035 Tight Glycemic Control Reduces Complications United Kingdom Prospective Diabetes Study (UKPDS)

MEDICATIONS

Primary sites of action of oral antidiabetic agents  Glucose output  Insulin resistance Biguanides  Insulin secretion Sulfonylureas/ meglitinides  Carbohydrate breakdown/ absorption  -glucosidase inhibitors  Insulin resistance Thiazolidinediones Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

Selection Oral Hypoglycemic Therapy Consider Metformin; Obesity Normal liver/renal function Contraindicated: Creatinin > 1.4 ( women), > 1.5 (men) IV contrast CHF Dehydration Alcohol excess > 80 years old unless CrCl is normal

Selection Oral Hypoglycemic Therapy Consider Thiazolidinedione (TZD); Obesity, insulin resistance Normal liver function Do not start if initial ALT is 2.5 times > N After Rx; If ALT is 2.5 times > N, check weekly If ALT is 3 times > N, discontinue Rx Contraindicated: Class III and IV CHF LFTs > 2.5 times higher than normal

The dual action of thiazolidinediones reduces HbA 1c + HbA 1c Insulin resistance IR  -cell function  Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.

Selection Oral Hypoglycemic Therapy Consider Insulin Secretagogue (Sulfonylurea); Non-obesity or mild obese Repaglinide (Prandin) or Nateglinide (Starlix) are useful for post-prandial hyperglycemia (non-sulfonylurea insulin secretagogues) Contraindicated: Severe liver or renal disease

Consider α-Glucosidase Inhibitor; Milder presentation Useful for post-prandial hyperglycemia Contraindicated: Chronic intestinal disorders, Liver and renal failure Selection Oral Hypoglycemic Therapy

Does decreasing insulin resistance decrease macrovascular complications? Myocardial infarction Not significant All-cause mortality Not significant Sulfonylureas/insulin Myocardial infarction Significant All-cause mortality Significant Metformin 21%8%39%36% UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.

INCRETINS

Nauck et al. Diabetologia. 1986 Incretin Effect on Insulin Secretion Oral glucose load Intravenous glucose infusion Time (min) Insulin (mU/l) 80 60 40 20 0 180601200 Time (min) Insulin (mU/l) 80 60 40 20 0 180601200 Incretin effect Control subjects (n=8)People with Type 2 diabetes (n=14)

GLP-1: Effects in Humans GLP-1 is secreted from L-cells of the jejunum and ileum That in turn… Stimulates glucose- dependent insulin secretion Suppresses glucagon secretion Slows gastric emptying Long-term effects in animal models: Increase of β-cell mass and improved β-cell function Improves insulin sensitivity Leads to a reduction of food intake After food ingestion… Drucker. Curr Pharm Des. 2001 Drucker. Mol Endocrinol. 2003

β-Cell massβ-Cell proliferationβ-Cell apoptosis Farilla et al. Endocrinology. 2002 0 4 8 12 16 ControlGLP-1 treated 0 0.5 1.0 1.5 2.0 2.5 Control 0 10 20 30 Control P<0.001 P<0.05 P<0.01 Effect of GLP-1 on β-cell mass in Zucker diabetic fatty rats GLP-1 treated GLP-1 treated β -Cell mass (mg) Proliferating β-cells (%) Apoptotic β-cells (%)

GLP-1 Enhancement Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003 GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: exenatide liraglutide Injectables Block DPP-4, the enzyme that degrades GLP-1: sitagliptin vildagliptin Oral agents

Incretin mimetics and DPP-4 inhibitors: major differences Properties/effectIncretin mimeticsDPP-4 inhibitors Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect YesUnknown Restitution of insulin secretion (2 phases)Yes (exenatide)Yes HypoglycaemiaNo Maintained counter-regulation by glucagon in hypoglycaemia YesNot tested Inhibition of gastric emptyingYesMarginal Effect on body weightWeight lossWeight neutral Side effectsNauseaNone observed AdministrationSubcutaneousOral Gallwitz. Eur Endocr Dis. 2006

Selection Hypoglycemic Therapy Glucagon Like Peptide-1 (Exenatide) Produced by the L-cells of the small bowel Increases endogenous insulin secretion in a glucose-dependent fashion, Controls gastric emptying Inhibits appetite Restore functioning beta cell mass Modulates secretion of glucagon, somatostatin Start 5 mcg SC BID, then 10 mcg SC BID

Selection Hypoglycemic Therapy Sitagliptine (Januvia) DPP-4 inhibitor Allows elevated and prolonged plasma levels of GLP-1 Approved in 2006 Long acting Promote beta-cell preservation in animal models

DM Management with Oral Hypoglycemics Titrate the dose over 2 months Reinforce Medical Nutrition Therapy and exercise Add drug of another class If FPG > 130 mg/dl or 2 h PP PG > 180 mg/dl A1c > 7% If goal PG is not achieved and DM > 5 yrs Add third oral medication or INSULIN

INSULIN

Insulin Secretion

Insulin Insulin Type Product Onset Peak Duration Aspart Analog NovoLog 10-30 min 0.5-3 hrs 3-5 hrs Lispro Anolog Humalog “ “ “ Regular Humulin, Novolin R 30 min 1-5 hrs 8 hrs NPH Humulin, Novolin N 1-4 hrs 4-15 hrs 16-26 hrs Glargine Lantus,Levemir 1-2 hrs ------ 24 hrs Premixed 70/30, 75/25, 50/50

Insulin Injections

Overcoming Barriers to Insulin Therapy Delays in initiating insulin therapy; Clinician concerns; Hypoglycemia Weight gain Increasing CVD risk Patients concerns; Sign of personal failure, Misconceptions Labor intensive and complicated Many concerns may be addressed through education and setting appropriate expectations

Basal Insulin with Oral Hypoglycemics A1c 8.5% to 10% Initial dose of Lantus or NPH 10-20 units/day (0.2 to 0.3 units/kg) Monitor FBG and adjust the dose Increase the dose by 2 Units if FBG >140 for 3 d Rate of hypoglycemia is lower with Lantus AM dosing of Lantus are comparable with PM dose

Basal-Prandial Insulin with Oral Hypoglycemics A1c > 10% High postprandial glucose despite normalization of FBG Initial dose of Lantus 0.3 units/kg Give approximately same dose as prandial insulin divided into 3 2hpp BG Goal: 80-150 mg/dl Correction dose: 1500/daily total insulin Carb to insulin ratio: Usually 1 Unit /15 g of Carb

NOT EVERYONE NEEDS 1800 CAL/D ADA DIET IBW for woman; 5’= 100 lb + every 1’ x 5 IBW for man;5’= 110 lb + every 1’ x 5 If weight 10 lb more than IBW, daily requirement will be: 10 x IBW Nutrition

IBW Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet.

Recommended calorie intake Calories needed to maintain weight depends upon your age, sex, height, weight, and activity level. Men, active women - 15 cal/lb Most women, sedentary men, and adults over 55 years - 13 cal/lb Sedentary women, obese adults - 10 cal/lb Pregnant, lactating women - 15 to 17 cal/lb

To lose 1 to 2 pounds per week (a safe rate of weight loss), subtract 500 to 1000 calories from the total number of calories needed to maintain weight. Example, an overweight man who weighs 250 lbs would need to eat 2500 calories per day to maintain his weight. To lose 1 to 2 pounds per week, he should eat 1500 to 2000 calories per day. As weight is lost, the recommended calorie intake should be recalculated. Recommended calorie intake

Carb. intake:45-65 % of total calories Protein intake:15-20 % of total calories Diabetics with any degree of CKD should be have 0.8 g/kg, around 10 % of total calories Fat intake:25-35 % of total calories Saturated fat intake should be < 7% of total calories Intake of trans fat should be minimized Nutrition

ADA Guidelines 1.Diabetic focused visit : Every 3-6 months Review physical activities, diet, BMI Review Meds and frequency of low blood sugars 2.HbA1c should be checked every 3 –6 month (Goal<7%) 3.Urine for microalbumin should be checked every year If >30 mcg/mg creatinine or >30 mg/24 hr, start on ACE inhibitor unless contraindicated 4. Yearly lipid profile with a goal of : Triglyceride < 150 mg/dl HDL > 40 mg/dl (men), > 50 mg/dl (women) LDL < 100 mg/dl

6.Blood pressure should be <130/85 and < 125/75 if diabetic nephropathy 7.Aspirin prophylaxis for every one unless contraindicated 8.Yearly dilated eye examination by ophthalmologist or referrals if needed 9.Yearly comprehensive lower extremities examination including monofilament test 10. Dental examination every 6 month for dentate person and every 1 year for edentate 11. Nutrition therapy by dietitian every 6-12 months ADA Guidelines

ACCORD Study Group. N Engl J Med. 2008;358:2545-2559 ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572 10,251 participants Mean age: 62 y Median duration of diabetes: 10 y Mean A1C at entry: 8.3% Known heart disease or at least 2 risk factors 10,251 participants Mean age: 62 y Median duration of diabetes: 10 y Mean A1C at entry: 8.3% Known heart disease or at least 2 risk factors Standard A1C 7.0%–7.9% Standard A1C 7.0%–7.9% ACCORDADVANCE Intensive A1C < 6.0% Intensive A1C < 6.0% CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) may cause harm in high- risk patients with type 2 diabetes ( 20% increased in mortality). 11,140 participants Mean age: 66 y Mean duration of diabetes: 8 y Mean A1C at entry: 7.48% History of major CV event or at least 1 risk factor 11,140 participants Mean age: 66 y Mean duration of diabetes: 8 y Mean A1C at entry: 7.48% History of major CV event or at least 1 risk factor Standard A1C usual care Standard A1C usual care Intensive A1C ≤ 6.5% Intensive A1C ≤ 6.5% CONCLUSION: Intensive glucose-lowering did not significantly reduce CVD events (primary outcome) reduces renal complications in high-risk patients by 21% (95% CI, 7–34%) and did not increase mortality Recent Trials Show No Reduction in CV Events with More Intensive Glycemic Control

HbA1C value of <7.0% is appropriate and well supported by clinical trial results: There are no data to support an A1C goal of <7.0% for reducing cardiovascular risk For individual patients, intensifying the regimen should be weighed by the potential risks and benefits: History of severe hypoglycemia Limited life expectancy Children Comorbid conditions Longstanding diabetes and minimal or stable microvascular complications Inzucchi SE et al. Diabetes Care 2012;35:1364-1379. American Diabetes Association. Diabetes Care. 2008;31:S12-S54 What is the HbA1c Goal?

Most IntensiveLess Intensive Least Intensive Patient Age Disease Duration 40 45 50 55 6065 7075 5 10 15 20 Other Comorbidities None Few/MildMultiple/Severe Hypoglycemia Risk Low HighModerate 8.0% 6.0%7.0% Established Vascular Complications NoneEarly MicrovascularAdvanced Microvascular Psychosocioeconomic Considerations Highly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, Comprehensive Support Systems Less Motivated, Nonadherent, Limited Insight, Poor Self-Care Capacities, Weak Support Systems Cardiovascular Ismail-Beigi F et al. Ann Intern Med 2011;154: 554-559 Individualizing HbA1c Targets in Diabetes

AgentExamples MechanismAction SUsglyburide, glipizide, glimepiride Closes K ATP channels  Pancreatic insulin secretion ‘Glinides repaglinide, nateglinide Closes K ATP channels  Pancreatic insulin secretion BiguanidesmetforminActivates AMP-kinase  Hepatic glucose production TZDsrosiglitazone, pioglitazone Activates PPAR-  Peripheral insulin sensitivity  -GIs acarbose, miglitolBlocks small bowel  -glucosidase  Intestinal carbohydrate absorption GLP-1 R agonists exenatide, liraglutideActivates GLP-1 receptors  Pancreatic insulin secretion;  glucagon secretion; delays gastric emptying;  satiety Amylino- mimetics pramlintideActivates amylin receptors  Pancreatic glucagon secretion; delays gastric emptying;  satiety DPP-4 inhibitors sitagliptin, saxagliptinInhibits DPP-4,  endogenous incretins  Pancreatic insulin secretion;  pancreatic glucagon secretion Bile acid sequestrants colesevelamBinds bile acid cholesterol ? SGLT inhibitors dapagliflozin, canagliflozin Selectively inhibits SGLT2  Renal glucose elimination Inzucchi SE et al. Diabetes Care 2012;35:1364-1379 Therapeutic Landscape of Diabetes

Agent  A1c AdvantagesDisadvantagesCost SUs1–2%  Microvasc risk Hypo, wt gain,  -cell exhaust $ ‘Glinides 1–1.5%  PPGHypo, wt gain,  -cell exhaust, dose frequency $ $ $ Biguanides1–2%Wt loss, no hypo,  CVD, ?  malignancy GI, lactic acidosis B12-deficiency $ TZDs1–1.5% No hypo;  -cell preserv  TG  HDL  BP ?  CVD (pio) Wt gain, edema / HF Bone fxs, ?  CVD (rosi) $ $ $  -GIs 0.5–1%  PPG, ?  CVD; GI, dose frequency$ GLP-1 R agonists 1% Wt loss,?  -cell preserv, ? CV benefits GI; ? pancreatitis, injections $ $ $ Amylino- mimetics 0.5% Wt loss,  PPG GI, dose frequency, injections $ $ $ DPP-4 inhibitors 0.6–0.8%No hypoUrticaria / Angioedema; ? pancreatitis $ $ $ Bile acid sequestrants 0.5% No hypo;  LDL-CGI;  TGs $ $ $ SGLT inhibitors 1%No hypoUTI$ $ $ Therapeutic Landscape of Diabetes Inzucchi SE et al. Diabetes Care 2012;35:1364-1379

Insulin Secretion

Insulin Type Product Onset Peak Duration Aspart Analog NovoLog 10-30 min 0.5-3 hrs 3-5 hrs Lispro Anolog Humalog “ “ “ Regular Humulin, Novolin R 30 min 1-5 hrs 8 hrs NPH Humulin, Novolin N 1-4 hrs 4-15 hrs 16-26 hrs Glargine, Detemir Lantus,Levemir 1-2 hrs ------ 24 hrs Premixed 70/30, 75/25, 50/50 Insulin Coverage

Delays in initiating insulin therapy; Clinician concerns; Hypoglycemia Weight gain Increasing CVD risk Patients concerns; Sign of personal failure, Misconceptions Labor intensive and com plicated Many concerns may be addressed through education and setting appropriate expectations Overcoming Barriers to Insulin Therapy

A1c 8.5% or more Initial dose of basal insulin 0.2 to 0.3 units/kg Monitor FBG and adjust the dose Increase the dose by 2 Units if FBG >110 for 3 days Rate of hypoglycemia is lower with long acting insulin than NPH AM dosing of basal insulin are comparable with PM dose Basal Insulin with Oral Hypoglycemics

Cardiovascular events 3 Microvascular complications 1 Macrovascular complications 2 Tight blood glucose control 1. UKPDS Group. Lancet 1998; 352: 837–53 2. UKPDS. BMJ 1998; 317: 703–13 3. Colhoun HM et al. Lancet 2004; 364: 685–96 Treatment Targets in Diabetes Provide a Basis for Improved Outcomes Tight blood pressure control Tight cholesterol control

AA1c Target Aspirin Daily BBlood Pressure Control CCholesterol Management Cigarette Smoking Cessation DDiabetes and Pre-Diabetes Management EExercise FFood Choices ABC for Diabetes Care

National Health and Nutrition Examination Survey (NHANES) from 2007 to 2010 52% of patients reached HbA1C goal of < 7% 18% of adults with diabetes have the combination of HbA1C < 7%, BP < 130/80 mm Hg, Total Cholesterol < 200 mg/dl 78% of our patients with diabetes have not met the basic treatment goals Are We Achieving our the Goal? Casagrande S. Diabetes Care 2013;doi: 10.2337/dc12-2258

Inpatient Diabetes Care

A- Patient who is on oral anti-diabetic medication (OAD): Assess if there are contra-indications for OAD use (CHF, renal or hepatic dysfunction, etc.) If no contraindication and glucose is in the “target” range (~110-180 mg/dl), continue with OAD’s and monitor blood glucose (BG) If there are contra-indications to OAD’s or the patient is hyperglycemic (above “target” range), start insulin using basal and prandial standard orders. Patients with Known Diabetes Who are Able to Eat Not Critically Ill

B- Patient who is on insulin before admission should (minimally) receive their usual insulin program Patients should receive their usual insulin program REMEMBER; that the patients’ usual insulin may be inadequate in the face of inter-current illness No matter what the prior insulin program was, be sure that your orders provide for the basal and prandial insulin replacement Patients’ prior insulin dose gives an index of insulin sensitivity. Use it to derive the “correction doses”. Patients with Known Diabetes Who are Able to Eat Not Critically Ill

C- Patients made NPO for a procedure in the AM Give usual dose of basal insulin the evening before and start D5W at 100 cc/min in the morning If the patient is on NPH BID, can give ½ the usual AM dose and start D5W at 100 cc/min in the morning Continue with the sliding scale coverage Patients with Known Diabetes Who are Able to Eat Not Critically Ill

“Target” BG Fasting: ~110 mg/dl Throughout the day: ~140 (110-180) If the patient is persistently above the “target” start insulin therapy Principles: 1- NO SLIDING SCALE ALONE! The usual “sliding scale” order (only short-acting insulin given when the patient is above target) is non-physiologic and does not work to control glucose! May be used to supplement basal and prandial insulin. Patients with Known Diabetes Who are Unable to Eat Not in the ICU or CCU,

2- Physiologic replacement requires both “basal and prandial” insulin 3- Analog short acting insulin is designed to be used with each meal. Regular insulin should be used only when IV insulin is needed If the patient was not previously on insulin, do this (finger sticks a.c. and h.s) Daily insulin requirement is 0.5 units/kg Start basal insulin (as Glargine) at doses of 0.2 to 0.3 units/kg body weight/day Patients with Known Diabetes Who are Unable to Eat Not in the ICU or CCU,

e.g.: a 70 kg individual should start with 14 units of basal insulin SQ qhs] Give approximately the same total daily dose of prandial insulin as the basal insulin dose- use 1/3 of daily dose with each meal [e.g.: if the basal dose is 14 units, give 4 units of short acting with each meal if the pre-meal glucose is within the “desirable range of 110-160mg/dl Patients with Known Diabetes Who are Unable to Eat Not in the ICU or CCU,

REMEMBER; short acting insulin works fast. The order should advise the nurse to give the pre-prandial insulin when the meal is in the patients’ room and ready to be eaten. If the pre-meal glucose is above 160 mg/dl, add “correction dose” of short acting insulin In general, the “correction dose” is calculated by dividing the patients’ daily requirement dose into 1500. The result is the predicted glucose lowering effect of 1 unit of insulin. Patients with Known Diabetes Who are Unable to Eat Not in the ICU or CCU,

e.g.: if the patient’s total insulin is 30 units/day, 1 unit of insulin should lower the glucose by 50 mg/dl (1500/30=50). Therefore, add 1 unit of insulin per 50 mg/dl glucose above 160. If the pre-meal glucose were 250 mg/dl, the preprandial insulin dose should be 2 units + usual dose- in the above example, 4+2 =6 units. Patients with Known Diabetes Who are Unable to Eat Not in the ICU or CCU,

Adjust the basal insulin dose every 24-48 hours based on the fasting (pre-breakfast) glucose value- make the appropriate changes in the prandial doses as well For patients coming of insulin drip, begin basal insulin 2 hours before the drip is stopped and start short acting insulin as soon as the patient is able to eat. Patients with Known Diabetes Who are Unable to Eat Not in the ICU or CCU,

THANK YOU

Newsweek, September 4, 2000 2000 Newsweek, September 4, 2000 2000 Time, September 4, 2000

50% of ß-cell function is already lost at diagnosis Elevated PPG occurs before diagnosis Impaired glucose tolerance 100 75 50 25 Years from Diagnosis Beta Cell Function (%) -12 -10 -6 -2 0 2 6 10 14 Postprandial hyperglycemia Type 2 diabetes phase I Type 2 diabetes phase II Type 2 diabetes phase III Lebovitz HE. Diabetes Review 1999;7(3):139 153 Stages of Type 2 Diabetes in Relationship to ß-cell Function Type 2 Diabetes is Characterized by Insulin Resistance and Progressive ß-cell Failure

Insulin resistant; low insulin secretion (54%) Insulin resistant; good insulin secretion (29%) Insulin sensitive; good insulin secretion (1%) Insulin sensitive; low insulin secretion (16%) 83% Haffner SM, et al. Circulation 2000; 101:975–980 More than 80% of Patients Progressing to Diabetes are Insulin Resistant San Antonio Heart Study N = 1,734 11% (n=105) progressed to Diabetes in 7 years

How does Insulin Work?

Reactive Oxygen Species

NutrientRecommended Intake Saturated fatLess than 7% of total calories Polyunsaturated fatUp to 10% of total calories Monounsaturated fat Up to 20% of total calories Total fat25–35% of total calories Carbohydrate50–60% of total calories Fiber20–30 grams per day ProteinApproximately 15% of total calories CholesterolLess than 200 mg/day Total calories (energy)Balance energy intake and expenditure to maintain desirable body weight/ prevent weight gain Sodium intake should be <1500 mg/day (AHA 2011) Nutrient Composition of Therapeutic Lifestyle Changes Diet

DeFronzo R et al. Diabetes. 2009;58:773-795. Decreased Incretin Effect Decreased Insulin Secretion Increased Hepatic Glucose Production Islet–  cell Increased Glucagon Secretion Decreased Glucose Uptake Increased Lipolysis IncreasedGlucoseReabsorption HYPERGLYCEMIA Neurotransmitter Dysfunction Pathophysiology of Diabetes

Chronic hyperglycemia Oversecretion of insulin to compensate for insulin resistance 1,2 High circulating free fatty acids Glucotoxicity Pancreas Lipotoxicity  -cell dysfunction Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23  -cell Failure

Atherosclerosis Hyperglycemia Dyslipidemia Hypertension Damage to blood vessels Clotting abnormalities Inflammation IR Zimmet P. Trends Cardiovasc Med 2002; 12:354–362. Insulin Resistance is Linked to Cardiovascular Risk Factors

Screening and Diagnosis of Disorders of Glucose Metabolism IFG: fasting (8 hours) plasma glucose 100–125 mg/dL IGT: 2-hour value in 75-g OGTT 140–199 mg/dL Diabetes: FPG ≥ 126 mg/dL or 2-hour OGTT ≥ 200 mg/dL; should be confirmed on a separate day IFG or IGT IFG and IGT + Other Features* DiabetesDiabetes Screen for Diabetes: Fasting plasma glucose or 2-hour, 75-g oral glucose tolerance test Screen for Diabetes: Fasting plasma glucose or 2-hour, 75-g oral glucose tolerance test Lifestyle Intervention Lifestyle Intervention and / or Metformin Lifestyle Intervention + Metformin *<60 years of age, reduced HDL-C, BMI ≥35 kg/m 2, hypertension, elevated triglycerides, A1C >6.0%, family history of diabetes in first-degree relative IFG=impaired fasting glucose; IGT=impaired glucose tolerance

Age-adjusted CVD death rate per 10,000 person years No. of risk factors (total cholesterol, HTN, smoking) Stamler J et al. Diabetes Care. 1993;16:434-444 Age-Adjusted CVD Death Rates Multiple Risk Factor Intervention Trial (MRFIT)

Types of Diabetes Type 1 Diabetes Mellitus Type 2 Diabetes Mellitus Gestational Diabetes Other types: LADA (latent autoimmune diabetes of adults) MODY (maturity-onset diabetes of youth) Secondary Diabetes Mellitus

Patient Characteristics at Time of Diagnosis Type 1 Type 2 Age 40 Body habitus ThinCentral obesity Insulin secretion NoneVariable Insulin resistance NoneExcessive Concomitant NoneHTN Conditiondyslipidemia atherosclerosis Ethnicity WhiteHispanic, AA

Diagnosed in some women during pregnancy Occurs more frequently among African Americans, Hispanic/Latino Americans, and American Indians. Also more common among obese women and women with a family history of diabetes. Requires treatment to normalize maternal blood glucose levels to avoid complications in the infant. After pregnancy, 5% to 10% of women with gestational diabetes are found to have type 2 diabetes. Women who have had gestational diabetes have a 20% to 50% chance of developing diabetes in the next 5-10 years. Gestational Diabetes

Latent Autoimmune Diabetes in Adults A form of autoimmune diabetes which is diagnosed in individuals who are older than the usual age of onset of type 1 DMautoimmune diabetes Alternate terms for "LADA" include –Late-onset Autoimmune Diabetes of Adulthood –Slow Onset Type 1 diabetes –Type 1.5 Often, patients with LADA are mistakenly thought to have type 2 diabetes, based on their age at the time of diagnosis.type 2 diabetes

LADA About 80% of adults with recently diagnosed type 2 diabetes but with GAD auto-antibodies (i.e. LADA) progress to insulin requirement within 6 years. The potential value of identifying this group at high risk of progression to insulin dependence includes: –the avoidance of using metformin treatment –the early introduction of insulin therapy

Maturity Onset Diabetes of the Young MODY is a monogenic form of diabetes with an autosomal dominant mode of inheritance: –Mutations in any one of several transcription factors or in the enzyme glucokinase lead to insufficient insulin release from pancreatic ß-cells –Different subtypes of MODY are identified based on the mutated gene. Diagnosis of MODY was based on presence of non-ketotic hyperglycemia in adolescents or young adults in conjunction with a family history of diabetes. However, genetic testing has shown that MODY can occur at any age and that a family history of diabetes is not always obvious.

Diseases of the exocrine pancreas Extensive damage to pancreas, Includes: Trauma, Infection Chronic necrotizing pancreatitis Pancreatic carcinoma Cystic fibrosis and Hemochromatosis Endocrinopathies Acromegaly Cushing's syndrome Glucagonoma Secondary Causes of Diabetes

Drug/chemical induced diabetes Synthetic glucocorticoids Cyclosporin A Nicotinic acid Interferon Pentamidine Thiazide diuretics (occasionally) Infections Congenital rubella (the most common virus implicated in the development of diabetes) Coxsackievirus B Adenovirus Mumps Cytomegalovirus

Secondary Causes of Diabetes Acromegaly Cushing syndrome Thyrotoxicosis Pheochromocytoma Chronic pancreatitis Cancer Drug induced hyperglycemia: –Atypical Antipsychotics - Alter receptor binding characteristics, leading to IR –Beta-blockers - Inhibit insulin secretion. –Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium release. –Corticosteroids - Cause peripheral insulin resistance and gluconeogensis. –Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels. –Naicin - Increases insulin resistance due to increased free fatty acid mobilization. –Phenothiazines - Inhibit insulin secretion. –Protease Inhibitors - Inhibit the conversion of proinsulin to insulin. –Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased insulin resistance due to increased free fatty acid mobilization.

Insulin resistance and  -cell dysfunction are core defects of type 2 diabetes Insulin resistance Genetic susceptibility, obesity, Western lifestyle Type 2 diabetes IR  -cell dysfunction  Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.

Insulin resistance – reduced response to circulating insulin Insulin resistance  Glucose output  Glucose uptake Hyperglycemia LiverMuscle Adipose tissue IR

Insulin resistance is linked to a range of cardiovascular risk factors Atherosclerosis Hyperglycemia Dyslipidemia Hypertension Damage to blood vessels Clotting abnormalities Inflammation Insulin resistance IR Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.

Why does the  -cell fail? Chronic hyperglycemia Oversecretion of insulin to compensate for insulin resistance 1,2 High circulating free fatty acids Glucotoxicity 2 Pancreas Lipotoxicity 3  -cell dysfunction 1 Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23. 2 Kaiser N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22. 3 Finegood DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.

Excessive hepatic glucose production in Type 2 diabetes Plasma glucose concentration Fasting & postprandial hyperglycaemia Insulin; IR Glucagon Hepatic glucose output IR=insulin resistance

Action of Glucagon Low blood glucose promotes glucagon release from  - cells of pancreas GlycogenGlucose Glucagon stimulates breakdown of glycogen Raises blood glucose

β-Cell function and glucagon in Type 2 diabetes Loss of β-cell function and glucagon oversecretion both play key roles in development Progressive β-cell decline is coupled with inadequate insulin secretion Glucagon is not suppressed during the postprandial period Hepatic glucose production is increased during the fasting period and is not suppressed during the postprandial period

Long-term Complications of Type 2 Diabetes Hyperglycemia Damage to medium and large blood vessels Damage to small blood vessels Macrovascular DiseaseMicrovascular Disease Coronary Artery Disease Cerebrovascular Disease Peripheral vascular disease RetinopathyNephropathyNeuropathy

Feet Diabetic foot Complications are the most common cause of nontraumatic lower extremity amputations in the industrialized world

<-140-200 mg/dl 100 mg/dl 100-126 mg/dl > 126 mg/dl Age > 35 Family Hx of DM Hyperlipidemia HTN Gestational DM Risk Factors of DM Sx of DM Weight loss Polyuira, polydypsia Polyphagia Lethargy Pruritis vulvae, balanitis < 140 mg/dl 140-200 mg/dl > 200 mg/dl 75 mg oral glucose test 2 hour blood glucose > 126 mg/dl< 126 mg/dl

Diagnosis of Diabetes ADA & AACEADA Fasting Plasma Glucose (mg/dL) Postprandial Plasma Glucose (mg/dL) HbA1c No Diabetes <100<140<5.7% Prediabetes100-125140-1995.7%-6.4% Diabetes≥126≥200≥6.5% 1.American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. 2. 2.Rodbard HW, et al. Endocr Pract. 2007;13(suppl 1):3-68.

What are the Goals? Blood Glucose ParameterADA 1 AACE 2 A1C<7%≤6.5% Preprandial Glucose/FPG 70-130 mg/dL<110 mg/dL Peak PPG*/2-h PPG<180 mg/dL<140 mg/dL 1.American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. 2. 2.Rodbard HW, et al. Endocr Pract. 2007;13(suppl 1):3-68.

A1C (%) Average Blood Sugar* (mg/dL) 6126 7154 8183 9212 10240 11269 12298 How Does A1C Compare with Blood Sugar Readings? *ADA target fasting sugar level: 70-130 mg/dL American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61.

Use the Guidelines to Improve Patient Care Primary care providers and their office staff are at the forefront of the diabetes epidemic Help patients understand and control their “ABCs” –A − A1C –B − Blood pressure –C − Cholesterol Always remember the basics –Eye exam, foot exam, urine test –Review nutrition, exercise, and smoking

Neuropathy Visual foot inspection and monofilament testing each year Retinopathy Dilated and complete eye exam — document each year Cardiovascular Disease Check blood pressure at each visit and lipids (cholesterol) each year Nephropathy Check urine albumin and serum creatinine level each year Peripheral Vascular Disease Foot exam that includes checking pedal pulses each year American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. Recommendations for Screening of DM Complications in Stable Patients

National Health and Nutrition Examination Survey (NHANES) from 1999 to 2000; 37% of patients reached HbA1C goal of < 7% 7% of adults with DM have the combination of HbA1C < 7%, BP < 130/80 mm Hg, total cholesterol < 200 mg/dl 93% of our patients with DM have not met the basic treatment goals Goals for Patients With Diabetes

The patient is given an overwhelming or vague goal: “Follow a meal and exercise plan, take medications, and check blood sugars” The patient may feel like a failure if his or her disease is not controlled The health care provider is frustrated and may blame the patient How Do We Break the Cycle? Support patient with education and coaching Need time, knowledge, good communication, and caring Cycle of Frustration Seley JJ. Am J Nurs. 2007;107(suppl 6):4-5. Achieving Control in Diabetes Can Be a Challenge: A Cycle of Frustration

Glucose Monitoring Self-monitoring is an important component of treatment - Helps to gauge treatment efficacy - Help in treatment plan - Provide feedback - Provide patterns that assist in medication selection - Assist in daily insulin dose adjustments 2 - 4 times daily is recommended SMBG should be reviewed during each visit

Goal of Glycemic Control for People with DM Plasma Glucose NormalGoalAction Sugg. ( mg/dl ) ---------------------------------------------------------------------------------- Fasting or 140 Preprandial PG 2 h PP PG 180 Bed time PG 160 A1c (%) 7 ---------------------------------------------------------------------------------- * Plasma glucose values are 10-15 % higher than whole blood glucose values