Type 1 Diabetes Update Robin Goland, MD

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1 Naomi Berrie Diabetes Center Type 1 Diabetes Update 2008 Robin Goland, MD Type 1 diabetes is: A manageable condition A chronic condition Often challenging Entirely compatible with a happy and healthy childhood and family lif 1

2 Type 1 Diabetes Overview Definitions Epidemiology Pathophysiology Diagnosis Prevention of Complications Clinical Management Experimental Treatment Type 1 Diabetes: Historical Description 2

3 Two Main Types of Diabetes What is type 1 diabetes? Auto-immune destruction of insulin-producing cells of pancreas. People with type 1 diabetes are healthy and we expect them to remain healthy throughout their lives. Chronic diabetes complications- microvascular and macrovascular damage. Complications only occur after many years of uncontrolled high blood sugars. 3

4 Type 1 Diabetes Epidemiology 24 million people in US (7% population) have diabetes 5-10% of total is type 1 diabetes Staggering healthcare cost Incidence increasing, particularly in young children Type 1 Diabetes Epidemiology 1.9 per 1000 US school children cases per 100,000 Male:female 1:1 Peak ages 5-7 and at puberty Mostly Caucasians; African Americans at 20-30% less risk Seasonal variation: peak in fall and winter 4

5 Why do people develop type 1 diabetes? Combination of genetic and environmental causes Children inherit diabetes-related genes from both their mother and father, even if no one in either family has diabetes. There is also an environmental factor, not yet identified, such as a virus that tips over a genetically predisposed person into developing diabetes. Trigger often occurs years before diagnosis. Type 1 Diabetes Incidence per 100,000 in Children < 14 years old China Venezuela Israel Kuwait Denmark Lazio Canda USA Sardinia Finland 5

6 Type 1 Diabetes Epidemiology Prevalence in school-age children in US: 1.9 per 1000 Annual incidence: 12 to 15 cases per 100,000 Male: Female ratio: 1:1 Peak ages: 5 to 7 years puberty Mostly Caucasians affected, African-Americans are at 20-30% less risk Seasonal variation: peak in fall and winter Genetic Risk in Type 1 Diabetes: Common HLA Haplotypes 6p DQB1 DRB1 DQA1 DRA High Risk DR3: DQB1*0201, DQA1*0501, DRB1*0301 DR4: DQA1*0301, DQB1*0302, DRB1*0401 Protective DR2: DQB1*0602, DQA1*0102,, DRB1*1501 BDC 6

7 Evidence that Type 1 Diabetes is Autoimmune Autopsy studies documenting immune infiltration of islets Preservation of beta cell function with immune intervention Association with other autoimmune disease: thyroid disease, celiac, others 7

8 Progression of Type 1 Diabetes Progression to Type 1 Diabetes with Positive Antibodies 8

9 Clinical Presentation Can occur at any age Patients often lean and Caucasian although not always Presentation often abrupt, can present in DKA; positive urine ketones Not accompanied by metabolic syndrome Positive antibodies against GAD, insulin, islet cells Low or undetectable c-peptide and insulin level Prevention of T1DM Complications Acute: Hypoglycemia, DKA Chronic: Microvascular Chronic: Macrovascular and Neuropathic Chronic: Psychosocial 9

10 Type 1 Diabetes: DCCT Intensive therapy reduced Retinopathy by 76% Nephopathy by 57% Neuropathy by 60% Adverse effects included hypoglycemia and weight gain EDIC study progression of retinopathy after the DCCT 10

11 Goals of treatment in type 1 diabetes Normal growth and development and a well-adjusted patient and family Promotion of blood sugars near-normal most of the time - perfection not required to stay healthy Reduction of high blood sugars Reduction of low blood sugars Optimal self-management to match insulin with food and activity What we Measure in Type 1 Diabetes BLOOD SUGAR (glucose) by fingerstick. Affected by food, particularly carbohydrate, and use by muscles in exercise. Eating raises blood sugar. Stress and illness also raise blood sugar. Skipping or delaying meals lower blood sugar. Exercise lowers blood sugar. Hemoglobin A1C. 11

12 Normal insulin and glucose levels Blood sugar problems can be fixed and prevented How to recognize low blood sugar (hypoglycemia) How to treat low blood sugar How to prevent low blood sugar How to recognize high blood sugar (hyperglycemia) How to treat high blood sugar How to prevent high blood sugar 12

13 Recognizing low blood sugar Shakiness Palpitations Sweating Anxiety Dizziness Hunger Headache Fatigue Irritability Severe untreated hypoglycemia can cause seizure or loss of consciousness Treatment of low blood sugar 1 Check blood sugar If <70-80 mg/dl, treat with 15 grams of carbohydrate 2 If using pump, suspend or disconnect Check glucose again after 15 minutes If glucose remains under 70 mg/dl, repeat treatment with 15 grams of carbohydrate In unlikely case of low blood sugar emergency (unconsciousness or seizure), use glucagon emergency kit

14 Prevention of low blood sugar Lows often occur because of mismatch between insulin and either food or exercise After taking rapid-acting insulin, the meal should not be delayed Exercise acts to lower blood sugar so reduce insulin or eat a snack with exercise Frequent blood sugar checks and prompt treatment of low blood sugar will prevent serious lows Recognizing high blood sugar Frequent Urination Extreme Thirst Blurred Vision Drowsiness Hunger Nausea Severe untreated hyperglycemia for many hours to days can cause dehydration and diabetic ketoacidosis 14

15 Treatment of high blood sugar Check blood glucose Check urine ketones if blood sugar > 300 mg/dl and advised by parent (ketones are breakdown products of fats that accumulate in states of insulin deficiency) Give insulin ( correction dose ) as advised by parent Give non-sugary fluids, as advised by parent Prevention of high blood sugar High blood sugars often occur because of mismatch between insulin and food. High blood sugar after meals usually occurs because of inadequate premeal bolus insulin - increase for next time High fasting blood sugar or blood sugar right before a meal usually occurs because of inadequate longacting or basal insulin - if this is a pattern, basal insulin can be increased The stress of illness raises blood sugar. Insulin doses often need to be temporarily increased in times of illness. 15

Hemoglobin A1c is the gold standard measurement for assessment of diabetes management Hemoglobin A1c specifically refers to the Amadori product Of the N-terminal valine of each beta chain of HbA with

16 Hemoglobin A1c is the gold standard measurement for assessment of diabetes management Hemoglobin A1c specifically refers to the Amadori product Of the N-terminal valine of each beta chain of HbA with glucose Glucose + Hemoglobin A Schiff Base (reversible) Amadori Product It is a reliable index of average blood glucose concentrations over the preceding 6 8 weeks. Relationship of A1c to Blood Sugar 16

end-stage renal disease 3 Cardiovascular Disease Diabetic Neuropathy Leading cause of

17 Leading cause of blindness in working age adults 1 Diabetic Retinopathy Stroke 2- to 4- fold increase in cardiovascular mortality and stroke 2 Diabetic Nephropathy Leading cause of end-stage renal disease 3 Cardiovascular Disease Diabetic Neuropathy Leading cause of non-traumatic lower extremity amputations 4 Relationship of Diabetes Complications to Hemoglobin A1c 17

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19 Intensive N (%) Standard N (%) HR (95% CI) P Primary 352 (6.86) 371 (7.23) 0.90 ( ) 0.16 Secondary Mortality 257 (5.01) 203 (3.96) 1.22 ( ) 0.04 Nonfatal MI 186 (3.63) 235 (4.59) 0.76 ( ) Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 ( ) 0.74 CVD Death 135 (2.63) 94 (1.83) 1.35 ( ) 0.02 CHF 152 (2.96) 124 (2.42) 1.18 ( ) 0.17 In people with type 2 diabetes at high risk for CVD, with an A1C of 7.5% or more, a therapeutic strategy that targets an A1C <6% vs % increases mortality over 3.5 years There is no significant effect of the glycemic intervention on the primary outcome at this time Ongoing follow-up and ongoing analyses (both epidemiologic & within baseline subgroups) will add further insight and generate more hypotheses 19

20 Coping with diabetes A diagnosis of type 1 diabetes is a big deal Feelings of sadness, guilt, loneliness, and blame are common It s important for the patient and the whole family (and support network) to be able to talk about their feelings about diabetes Insulin treatment in type 1 diabetes: Replacement treatment Background or basal insulin given over 24 hours Meal-related, or bolus, or prandial insulin is given to cover the carbohydrates in the food Insulin can be given by multiple injections or by pump With injections, 1 shot is long-acting basal insulin, usually glargine (lantus) insulin. Additional shorts of rapid-acting insulin (lispro-humalog or aspartnovolog) are given right before meals and snacks. With the pump, only rapid acting insulin is used. Basal insulin is given in small increments all day long and bolus insulin is given through the pump s catheter right before meals and snacks. 20

21 Insulin Injections or Insulin Pump Food in type 1 diabetes There is NO such thing as a diabetic diet. People with type 1 diabetes eat normally and cover the carbohydrates in food with insulin. This is called carbohydrate counting. People with type 1 diabetes have an individualized insulin:carbohydrate ratio that helps guide how much insulin to take with each meal and snack. 21

22 The Bad Old Days of Type 1 Diabetes Prior to or 2 injections of NPH and regular insulin per day Rigid rules for composition and timing of meals Urine tests for glucose Aggressive therapy unsafe and of unknown benefits Hemoglobin A1c 11-12% Inevitable eye and renal complications Inevitable noncompliance Advances in Type 1 Diabetes Treatment Evidence supporting glycemic control Means for achieving glycemic control Insulin analogues allowing basal/bolus therapy Carbohydrate counting Advances in monitoring Insulin delivery systems Integrated systems 22

Basal-Bolus Insulin Treatment of Type 1 Diabetes 2008 Use of insulin:carb ratios to normalize postprandial meal glucose and allow flexibility in timing and content of meals Use of corrective bolus to

23 Basal-Bolus Insulin Treatment of Type 1 Diabetes 2008 Use of insulin:carb ratios to normalize postprandial meal glucose and allow flexibility in timing and content of meals Use of corrective bolus to normalize glucose Peakless insulin simpifies sick day management, skipping meals, dieting Diabetes education promoting self-care especially day-to-day insulin dose adjustment Hemoglobin A1c % Eye and renal complications rare Noncompliance redefined Insulin Delivery Systems: Insulin Pens 23

24 Improved Blood Sugar Monitoring Technologic Advances Smaller meters Small blood sample (0.3 ul) Short test time (<5 secs) Self-contained strips Alternate site testing Non-Randomized Trials of CSII: Adolescents, Adults, Children Switching to CSII results in: Lower HbA1c Less Hypoglycemia Greater Patient Satisfaction 24

Insulin Delivery in Pump Compared to Multiple Daily Injections Lispro/aspart insulin is given in a programmable basal rate every few minutes.

25 Insulin Delivery in Pump Compared to Multiple Daily Injections Lispro/aspart insulin is given in a programmable basal rate every few minutes. Additional insulin is given in adjustable boluses to cover meal related glucose excursions. Programmable basal rate offers advantage over injected basal insulin as it can be modified as necessary leading to enhanced lifestyle flexibility, especially helpful in managing dawn phenomenon and exercise. CSII leads to more predictable insulin levels compared to MDI Dual-wave and square wave bolus offers greater ability to match insulin to food Early Insulin Pump 25

26 Continuous Subcutaneous Insulin Infusion (CSII MINIMED ANIMAS COZMO Closed-Loop Insulin Pump Implantable insulin pump coupled to glucose sensor Algorithm for insulin delivery based on glucose level 26

27 Experimental Treatment of Type 1 Diabetes Immune Therapy: Rituximab, anti-cd3, CTLA4Ig, SYK inhibitor, GAD vaccine Islet and Pancreas Transplant Closed loop system Stem Cell-based Therapy. Experimental Treatment of Type 1 Diabetes: The Challenge An intervention that can arrest the ongoing immune response and induce tolerance Beta cell replacement with tolerance to the graft mechanical or even more physiological replacement? Is hypoglycemia preventable? Markers for individuals at risk for complications and interventions that will block the effects of hyperglycemia directly or the associated abnormalities.. 27

28 Anti-CD3 Preservation of Beta Cell Function Drug treated Control AUC (pmol/ml/240 min) AUC (pmol/ml/240 min) Time (months) Time (months) Anti-CD20 Preservation of Beta Cell Function 28

Embryonic Stem Cell Research Somatic Cell

29 Embryonic Stem Cell Research Somatic Cell Nuclear Transfer Creation of ALS Neurons Induced Pleuripotential Stem Cells Type 1 diabetes is: A manageable condition A chronic condition Often challenging Entirely compatible with a happy and healthy childhood and family lif 29

Diabetes mellitus is a complex of syndromes characterized metabolically by hyperglycemia and altered glucose metabolism, and associated

Diabetes mellitus is a complex of syndromes characterized metabolically by hyperglycemia and altered glucose metabolism, and associated pathologically with specific microvascular and macrovascular complications.