1. Outpatient Management, co -morbidities & complications of Type 1 Diabetes Mellitus Prof. Abdulmoein Al-Agha, Consultant, Pediatric Endocrinologist, King Abdulaziz University Hospital, Jeddah, KSA Available at my website: aagha,kau.edu.sa

2. Education Glycemic targets Insulin therapy Glucose monitoring Nutrition Hypoglycaemia Immunization Psychology Comorbidities Complications Overview

3. Type 1 DM Autoimmune destruction of the pancreatic islet cell Hallmark = lymphocytic infiltration of islets Progresses over months - years Leads to insulin deficiency initially Later may also be associated with glucagon deficiency

4. Goals of T1DM Management Utilize intensive therapy aimed at near- normal BG and A1C levels Prevent diabetic ketoacidosis and severe hypoglycemia Achieve the highest quality of life compatible with the daily demands of diabetes management Achieve normal growth and physical development and psychological maturation Establish realistic goals adapted to each individual’s circumstances

5. Education Education, from diagnosis onwards, is complex, touching on a range of issues medical and social It is best done by a multidisciplinary team trained in paediatric diabetes Education topics should include: – Prevention, detection and treatment of hypoglycaemia – Insulin action and administration – Dosage adjustment – Blood glucose (BG) and Ketone testing – Sick-day management – Prevention of DKA – Nutrition and exercise

6. Self-monitoring of blood glucose is an essential part of management of type 1 diabetes Subcutaneous continuous glucose sensors allow detection of asymptomatic hypoglycemia and hyperglycemia Subcutaneous continuous glucose sensors may have a beneficial role in children and adolescents but evidence is not as strong as in adults Glucose Monitoring

7. MONITORING STRATEGIES Self Blood Glucose Monitoring – 4-6 / day – Affected by anemia, hemoglobinopathy Urine Testing – Ketones - PRN Glycosylated Hemoglobin - HbA1 C - quarterly Blood lipids - annually Thyroid function – annually Urine micro albumin – annually Dilated fundoscopic – annually

8. *Postprandial monitoring is rarely done in young children except for those on pump therapy for whom targets are not available A1C = Glycated Haemoglobin; FPG = Fasting Plasma Glucose; PG = Plasma Glucose; N/A = Not Available Glycemic Targets Age (years) A1C (%)FPG / premeal PG (mmol/L) 2-hour pc PG (mmol/L) Considerations <6<8.0%6.0-10.0N/A* Caution is required to minimize hypoglycemia because of the potential association between severe hypoglycemia and later cognitive impairment. Consider target of <8.5% if excessive hypoglycaemia occurs 6-12≤7.5%4.0-10.0N/A Targets should be graduated to the child’s age. Consider target of <8.0% if excessive hypoglycaemia occurs 13-18≤7.0%4.0-7.05.0-10.0 Appropriate for most adolescents

9. Continuous Glucose Monitoring

11. Interstitial Fluid Measurement Interstitial fluid glucose (G2) is almost always comparable with blood glucose (G1)

12. Insulin Therapy

13. 1921 Banting Best Insulin was the first discovered (late 1920's) which won the doctor and medical student who discovered it the Nobel Prize (Banting and Best)

14. Banting & Best

16. Types of Insulin for Use in T1DM

17. Rapid (lispro, aspart, glulisine) Hours Long (glargine) Short (regular) Intermediate (NPH) Long (detemir) Insulin Level 0 2 4 6 8 10 12 14 16 18 20 22 24 Pharmacokinetics of Insulin Products Adapted from Hirsch I. N Engl J Med. 2005;352:174-183.

19. FDA approves Afrezza to treat diabetes June 30, 2014 -- Millions of people with type 1 or type 2 diabetes will have another treatment option now that the FDA has approved an inhaled insulin, called Afrezza, the rapid-acting insulin is taken before each mealtype 2 diabetes

20. Insulin is the mainstay of medical management The choice of insulin regimen depends on many factors: – Child’s age – Duration of diabetes – Family lifestyle – Socioeconomic factors – Family, patient, and physician preferences Insulin Therapy

21. Everyone has different needs

22. Insulin regimens Frequently used regimens Two injections daily mixture of short and intermediate-acting insulin (before breakfast and before evening meal) Three injections daily using a mixture of short and intermediate acting insulin before breakfast & dinner short-acting insulin alone before Lunch Basal-bolus regimen short-acting insulin 20-30 min before main meals intermediate or long-acting insulin at bedtime Insulin pump

23. 2 Vs 3 Daily insulin injections profiles 8101214 16 182022242468 Time BreakfastLunchEvening meal Short acting insulin injection Long Acting insulin injection 2 x daily 3 x daily

24. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Glargine or detemir Plasma insulin Basal/Bolus Treatment Program With Rapid- Acting and Long-Acting Analogs Bed Rapid (lispro, aspart, glulisine)

26. Intensive insulin therapy What was considered "intensive therapy" in the DCCT is now considered to be standard therapy for management of type 1 diabetes Intensive insulin therapy (three or more injections per day or continuous subcutaneous insulin infusion with an insulin pump) is successful only if the patient is: – fully committed to it – has good understanding of the regimen – is supported by a health care team with sufficient expertise to educate the patient and to continuously monitor his or her progress

27. Physiologic Multiple Injection Regimens: The Basal-Bolus Insulin Concept Basal insulin – Controls glucose production between meals and overnight – Usually ~50% of daily needs Bolus insulin (mealtime or prandial) – Limits hyperglycemia after meals – Immediate rise and sharp peak at 1 hour post-meal – 10% to 20% of total daily insulin requirement at each meal Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

28. Relative Risk of Progression of Diabetes Complications by Mean HbA1c: based on DCCT Data 15 13 11 9 7 5 3 1 67891011 Level of Diabetes Control = HbA 1c Retinopaty Nephropaty Neuropathy Microalbuminuria 12

29. Advantages of intensive insulin therapy Gain of 15.3 years of complication free living compared to conventional therapy Disadvantages of intensive insulin therapy Hypoglycemia Peaked profiles result in uncontrolled glycaemic excursions Injection issues Variability of absorption from different sites of injection Patients’ fear of multiple injections Weight gain

30. Hyperglycemia Microangiopathic complications Hypoglycemia Neuronal loss Poor school performance seizures

31. All children with type 1 diabetes should receive counselling from a registered dietitian experienced in pediatric diabetes Children with diabetes should follow a healthy diet as recommended for children without diabetes There is no evidence that one form of nutrition therapy is superior to another in attaining age- appropriate glycaemic targets Nutrition

32. Use of insulin to carbohydrate ratios may be beneficial but is not required The effect of protein and fat on glucose absorption must also be considered Nutrition therapy should be individualized (based on the child’s nutritional needs, eating habits, lifestyle, ability, and interest) and must ensure normal growth and development without compromising glycaemic control Nutrition

33. Hypoglycaemia Hypoglycaemia is a major obstacle for children with type 1 diabetes and can affect their ability to achieve glycemic targets All families should understand the importance of hypoglycemia (severity and frequency) along with treatment and follow up strategies Frequent use of continuous glucose monitoring in a clinical care setting may reduce episodes of hypoglycaemia

34. There is no evidence in children that one insulin regimen or mode of administration is superior to another for reducing non-severe hypoglycaemia In children, the use of mini-doses of glucagon has been shown to be useful in the home management of mild or impending hypoglycemia associated with inability or refusal to take oral carbohydrate Dose = 10 mcg x (years of age) Dose range 20 – 150 mcg Hypoglycaemia

35. For children, and particularly adolescents, there is a need to identify psychological disorders associated with diabetes and to intervene early to minimize the impact over the course of development The risks increase exponentially during adolescence Children and adolescents with diabetes have significant risks for psychological problems: – Depression – Anxiety – Eating disorders – Externalizing disorders Psychological Issues

36.  Children with persistently poor glycemic control (e.g. A1C >10%) should be assessed by a specialized pediatric diabetes team for a comprehensive interdisciplinary assessment and referred for psychosocial support as indicated [Grade D, Consensus].  Intensive family and individualized psychological interventions aimed at improving glycemic control should be considered to improve chronically poor metabolic control [Grade A, Level 1A].

37. Occurs in 15 to 30% of individuals with type 1 diabetes Risk for AITD during the first decade of diabetes is directly related to the presence or absence of thyroid antibodies Hypothyroidism is most likely to develop in girls at puberty Hyperthyroidism also may occur more frequently in association with type 1 diabetes than in the general population Autoimmune Thyroid Disease

38. Is rare, even in those with type 1 diabetes Targeted screening is required in those with unexplained recurrent hypoglycaemia and decreasing insulin requirements Addison’s Disease

39. Celiac disease can be identified in 4 - 9% of children with type 1 diabetes 60 to 70% of these children, the disease is asymptomatic There is good evidence that treatment of classic or atypical celiac disease with a gluten-free diet improves: – Intestinal and extra-intestinal symptoms – Prevents the long-term squeal of untreated disease Universal screening for and treatment of asymptomatic celiac disease remains controversial Celiac Disease

40. Screening for Comorbid Conditions

41. COMPLICATIONS Acute Chronic HypoglycemiaNeuropathy HyperglycemiaRetinopathy Ketoacidosis Nephropathy

42. Nephropathy, retinopathy, neuropathy and hypertension are relatively rare in paediatric diabetes Screening efforts should focus most attention on post-pubertal patients with longer duration and poorer control of their diabetes Diabetes Complications

43. Screening for microalbuminuria (MAU) should be performed annually, commencing at 12 years of age in children with type 1 diabetes >5 years` duration [Grade D, Consensus]. A first morning urine albumin to creatinine ratio (ACR) has high sensitivity and specificity for the detection of microalbuminuria (MAU) Treatment is indicated only for those adolescents with persistent microalbuminuria Nephropathy

44. Retinopathy is rare in prepubertal children with type 1 diabetes and in post pubertal adolescents with good metabolic control Age ≥15 yrs + DM of 5 years Begin annual screening If…. DM 5-10 yrs + normal eye exam + good glycemic control Screen every 2 years Retinopathy

45. Microangiopathic complications from DM can occur by the time of diagnosis but typically 10 – 15 yr

46. Neuropathy is mostly subclinical in children Prospective nerve conduction studies and autonomic neuropathy assessment studies have demonstrated increased prevalence of abnormalities overtime Vibration and monofilament testing have suboptimal sensitivity and specificity in adolescents Neuropathy

47. Children with type 1 diabetes who are 95th percentile for age and gender) and/or a family history of dyslipidemia or premature CVD Dyslipidemia

48. Up to 16% of adolescents with type 1 diabetes have hypertension Screen blood pressure at least twice / year Treat according to the guidelines for children without diabetes Hypertension