Consultant, Pediatric Endocrinologist, King AbdulAziz University Hospital, Jeddah.
Diabetes mellitus type 2 Is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency & hyperglycemia It is rapidly increasing in the developed world Has characterized the increase as an epidemic Unlike type 1 diabetes, there is little tendency toward ketoacidosis in Type 2 diabetes, though it is not unknown Complex and multi-factorial metabolic changes lead to damage & function impairment of many organs, most importantly the cardiovascular system Criteria for the Diagnosis of Diabetes Symptoms of diabetes plus random plasma glucose concentration 200 mg/dl (11.1 mmol/l). The classic symptoms of diabetes include: polyuria, polydepsia, and unexplained weight loss. OR FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h. OR 2-h PG 200 mg/dl (11.1 mmol/l) during OGTT The test should be performed as described by W HO using a glucose load containing equivalent of 75-g anhydrous glucose dissolved in water. Pathophysiology Insulin resistance means that body cells do not respond appropriately when insulin is present Other important contributing factors: increased hepatic glucose production (e.g., from glycogen degradation), especially at inappropriate times decreased insulin-mediated glucose transport in (primarily) muscles & adipose tissues (receptor and post-receptor defects) impaired beta-cell functionloss of early phase of insulin release in response to hyperglycemic stimuli Underlying causes of type 2 diabetes Obesity Insulin resistance -cell defect Impaired glucose tolerance Early diabetes Late diabetes Hyperinsulinaemia Decreased insulin secretion -cell failure Adapted from Saltiel AR. J Clin Invest 2000;106:163164. Obesity & Type 2 Diabetes
Too large meals ! Too high Calories ! Sedentary life style!!
Normal The progressive nature of type 2 diabetes Impaired glucose tolerance Type 2 diabetes Fasting plasma glucose Insulin sensitivity Insulin secretion Insulin sensitive Normal insulin secretion Normoglycaemia Hyperglycaemia -cell exhaustion Insulin resistance Late type 2 diabetes complications Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867876. Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1S7. Insulin resistance Type 2 Obesity& Insulin resistance Genetic susceptibility Type 2 Diabetes in Children Clinical presentation Children with type 2 diabetes are usually diagnosed over age of 10 years Middle to late puberty Milder symptoms than type 1 with mild polydepsia, polyuria, little or no weight loss Glucosuria with / without ketonuria Up to 33% have ketonuria at diagnosis 525% of patients with type 2 diabetes have ketoacidosis at presentation Associated problems with type 2 DM Obesity Insulin resistance Hyperinsulinism Arterial hypertension Hyperlipidemia Acanthosis Nigerians Macro & microangiopathy PCOS
Acanthosis Nigricans Acanthosis nigricans is a cutaneous finding frequently in darker- skinned obese individuals Characterized by velvety hyperpigmented patches most prominent in intertriginous areas and is present in as many as 90% of children with type II diabetes Screening for type 2 DM in Children & Adolescents
Why to screen for type 2 DM?
As in adults, a substantantial number of children with type 2 can be detected in A symptomatic state In type 2, there is a prolonged latency period without symptoms during which abnormality can be detected Only children at risk for the presence or development of type 2 should be screened
Criteria of screening for Type 2 DM in Children & Adolescents
1. overweight which is defined as (WHO) body mass index (BMI) > 85 th percentile for age and sex weight for height > 85 th % ile weight >120 th % ile of ideal (50%) for height Plus two of the following risk factors: 2. Family history of type 2 DM in first or second-degree relative
Criteria of screening for Type 2 DM in Children & Adolescents
2. Race/ethnicity (Pima Indian, African- American, Hispanic, Asian / Pacific Islander) 3. Signs of insulin resistance or conditions associated with insulin resistance acanthosis nigricans polycystic ovary syndrome hypertension dyslipidemia Diabetic retinopathy Leading cause of blindness in working-age adults 1 Diabetic nephropathy Leading cause of end-stage renal disease 2 Cardiovascular disease Stroke 1.2- to 1.8-fold increase in stroke 3 Diabetic neuropathy Leading cause of non-traumatic lower extremity amputations 5 75% diabetic patients die from CV events 4
Type 2 diabetes is NOT a mild disease 1 Fong DS, et al. Diabetes Care 2003;26 (Suppl. 1):S99S102. 2 Molitch ME, et al. Diabetes Care 2003;26 (Suppl. 1):S94S98. 3 Kannel WB, et al. Am Heart J 1990;120:672676. 4 Gray RP & Yudkin JS. In Textbook of Diabetes 1997. 5 Mayfield JA, et al. Diabetes Care 2003;26 (Suppl. 1):S78S79.
Prevention of type 2 DM Prevention of obesity (
.) Prevention of type 2 DM Public health measures 1. Media 2. School 3. Community 4. Family Increase physical activity Reduce caloric intake/obesity Decrease sedentary life style I. Computer 2. Video games 3. Television
Treatment of type 2 diabetes There are limited data available regarding management of type 2 diabetes in children As a result, the goals of treatment in type 2 diabetes in adults have been applied to children and adolescents These goals include: achieving psychological & physical well-being long term glycemic control defined as a fasting plasma glucose < 130mg/dL HbA 1c < 7% preventing microvascular & macrovascular complications
Initial treatment of type 2 DM, will vary depending on clinical presentation Wide range from A symptomatic hyperglycemia to DKA Children who are not ill at diagnosis can be managed with diet ,exercise & oral agents Children who are ill, dehydrated, presence of ketosis and acidosis need insulin therapy When stabilized, tapering of insulin gradually and introduction oral agents In all patients, identification & treatment of co- morbid conditions are important
How can insulin resistance be managed? Improve insulin resistance through: Diet Exercise Pharmacological intervention with agents that target insulin resistance Oral hypoglycemic agents Biguanides: Metformin The first oral agent used should be metformin. decrease hepatic glucose output enhance hepatic & muscle insulin sensitivity without a direct effect on b-cell function Sulfonylureas: chlorpropamide, gliclazide, glimepiride, glipizide, tolazamide, & tolbutamide promote insulin secretion from islet cells Thiazolidenediones: troglitazone, rosiglitazone improve peripheral insulin sensitivity Troglitazone has been associated with fatal hepatic failure; its use in children is not recommended
Metformin The first oral agent should be used in type 2 Metformin has advantage over sulfonylureas of a similar reduction in HbA1c without the risk of hypoglycemia Metformin normalizes ovulatory abnormalities in girls with PCOS Because of concerns about lactic acidosis, Metformin is contraindicated in patients with: impaired renal function should be discontinued with the administration of radiocontrast material. should not be used in patients with known hepatic disease, hypoxemic conditions, severe infections, or alcohol abuse Metformin The most common side effects of Metformin Gastrointestinal disturbances Because proper dosing in children has not been evaluated & because most patients are near or at adult weight, it is reasonable to use the doses recommended for adults If monotherapy with Metformin is not successful over a period of time (36 months), Some clinicians would add a sulfonylurea, whereas others might add insulin Sulfonylureas stimulate insulin secretion and reduce HbA 1c levels by 12% Sulfonylureas may cause weight gain and are associated with the highest incidence of hypoglycemia among the oral antidiabetic agents. Glucosidase inhibitors slow the hydrolysis of complex carbohydrates and carbohydrate absorption (acarbose and miglitol) The glucosidase inhibitors reduce HbA 1c by 0.50.9%
The thiazolidinediones improve peripheral insulin sensitivity & reduce HbA 1c by 0.51.5% The thiazolidinediones do not cause hypoglycemia when used as monotherapy, but may cause edema & weight gain The sulfonylureas, nonsulfonylureas, glucosidase inhibitors & thiazolidinediones have not received approval by FDA for use in the pediatric population