Diabetes Mellitus Zhao-xiaojuan

Introduction Diabetes mellitus is a heterogeneous group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

Introduction The chronic hyperglycemia of diabetes is associated with long- term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

Symptoms Polyuria Polydipsia (thirst) Weight loss Weakness Polyphagia Blurred vision Recurrent infection Impairment of growth

Criteria for diagnosis of diabetes (WHO1999) Symptoms of diabetes + Casual plasma glucose ≥ 1.1mmol/l(200mg/dl) Or FPG ≥ 7.0mmol/l (126mg/dl) Or 2-hPG ≥ 11.1mmol/l

Diagnostic Criteria WHO1999 IGT - FPG<7mmol/L - 2-h PG≥7.8mmol/L and <11.1mmol/L IFG - FPG≥6.1mmol/L and <7.0mmol/L

Laboratory Findings Urinary glucose Urinary ketone Blood glucose (FPG and 2-hPG) HbA1c and FA(fructosamine) OGTT Insulin / CP releasing test

Classification (1) Type 1 diabetes β-cell destruction, usually leading to absolute deficiency Immune-mediated diabetes Idiopathic diabetes Type 2 diabetes Ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance

Classification (2) Other specific types of diabetes Due to other causes, e.g.,genetic defects in insulin action, diseases of the exocrine pancreas, drug or chemical induced Gestational diabetes mellitus(GDM) diagnosed during pregnancy

Etiologic classification of diabetes mellitus(1) I.Type 1diabetes (  -cell destruction, usually leading to absolute insulin deficiency ) A. immune mediated B. Idiopathic II.Type 2diabetes ( may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance ) III.Other specific types A. genetic defects of  -cell function 1. Chromosome 12, HNF-1  (MODY3) 2. Chromosome 7, glucokinase (MODY2) 3. Chromosome 20, HNF-4  (MODY1) 4. Mitochondrial DNA 5. Others B. Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson- Mendenhall syndrome 4. Lipoatrophic disease 5. Others C. Diseases of the exocrine pancreas 1. Pancreatitis 2. Trauma / pancreatectomy 3. Neoplasia 4. Cystic fibrosis 5. Hemochromatosis 6. Fibrocalculous pancreatopathy 7. Others

Etiologic classification of diabetes mellitus(2) D. Endocrinopathies 1. Acromegaly 2. Cushing’s syndrome 3. Glucagonoma 4. Pheochromocytoma 5. Hyperthyroidism 6. Somatostatinoma 7. Aldosteronoma 8. Others E. Drud- or chemical-induced 1. Vacor 2. Pentamidine 3. Nicotinic acid 4. Glucocorticoid 5. Thyroid hormone 6. Diazoxide 7.  -adrenergic agonists 8. Thiazides 9. Dilantin 10.  -Interferon 11. Others F. Infections 1. Congenital rubella 2. Cytomegalovirus 3. Others

Etiologic classification of diabetes mellitus(3) G. Uncommon forms of immune- mediated diabetes 1. “Stiff-man” syndrome 2. Anti-insulin receptor antibodies 3. Others H. Other genetic syndromes sometimes associated with diabetes 1. Down’s syndrome 2. Klinefelter’s syndrome 3. Turner’s syndrome 4. Wolfram’s syndrome 5. Friedreich’s ataxia 6. Huntington’s chorea 7. Laurence-moon-Biedl syndrome 8. Myotonic dystrophy 9. Porphyria 10. Prader-Willi syndrome 11. Others IV. Gestational diabetes mellitus ( GDM ) Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin dose not, of itself, classify the patient.

Type 1 DM Generally <30 years Rapid onset Moderate to severe symptoms Significant weight loss Lean Ketonuria or keto-acidosis Low fasting or post-prandial C-peptide Immune markers(anti-GAD,ICA,IA-2)

Type 2 DM Generally ＞ 40 years Slowly onset Not severe symptoms Obese Ketoacidosis seldom occur Nonketotic hyperosmolar syndrome Normal or elevated C-peptide levels Genetic predisposition

Pathophysiological model for development of obesity and T2DM Beta-cell defect Intra-uterin growth retardation Insulin Resistance genes Obesity genes Insulin Resistance + Intraabdominal obesity IGT T2DM Western lifestyle Glucose toxicity Metabolic Insulin Resistance (FFA) Year

Disorder of glycemia: etiological types clinical stages Stages Types Normoglycemia Hyperglycemia Diabetes mellitus Type 1 Type 2 Other specific types Gestational diabetes Normal glucose tolerance IGT and/or IFG Not insulin requiring Insulin requiring for control Insulin requiring for survival

Acute,life-threatening consequences Hyperglycemia with ketoacidosis Nonketotic hyperosmolar syndrome

Microvascular complications Retinopathy Nephropathy Peripheral neuropathy Autonomic neuropathy

Macrovascular complications Atherosclerotic cardiovascular disease Peripheral vascular disease cerebrovascular disease

Others Hypertension Abnormalities of lipoprotein metabolism Periodontal disease

Potential chronic complications of elevated HbA1c goodpoor control RISK Microalbuminuria Mild Retinopathy Mild Neuropathy Albuminuria Macular Edema Proliferative Retinopathy Peridontal Disease Impotence Gastroparesis Depression Foot Ulcers Angina Heart Attack Coronary Bypass Surgery Stroke Blindness Amputation Dialysis Kidney Transplant

The Aims of Treatment Relief of hyperglycemic symptoms Correction of hyperglycemia, ketonuria and hyperlipidemia Establishment and maintenance of a desirable body weight, and in children normal growth and development Avoidance of acute metabolic disturbance Prevent or delay the onset of the long-term complications

Targets for control OptimalFairPoor Plasma glucose (mmol/L) FPG 2-hPG  7.0  10.0 >7.0 >10.0 HbA1c(%) < 6.2< >8.0 Blood pressure (mmHg) <130/80>130/80- <160/95 >160/95 BMI (kg/m 2 ) Male female <25 <24 <27 <26  27  26 Total cholesterol (mmol/L) <4.5  4.5  6.0 HDL- cholesterol (mmol/L) > <0.9 Triglycerides (mmol/L) <1.5<2.2  2.2 LDL- cholesterol (mmol/L) < >4.4

Management Essentials of management Monitoring of glucose levels Food planning Physical activity Treatment of hyperglycemia

2. Monitoring of Glucose Levels Blood glucose levels - before each meal - at bedtime Urine glucose testing Urine ketone tests (should be performed during illness or when blood glucose is  20mmol/L )

3. Food Planning Weight control %of the total dietary energy should come from complex carbohydrates % form fats and oils % from protein. Restrict alcohol intake. Restrict salt intake to below 7g/d.

4. Physical Activity Physical activity play an important role in the management of diabetes particularly in T2DM. Physical activity improves insulin sensitivity, thus improving glycemic control, and may help with weight reduction Do sparingly avoid sedentary activities Do regularly participate in leisure activities and recreational sports Do every day adopt healthy lifestyle habits

5. Drug Treatment If the patient is very symptomatic or has a very high blood glucose level, diet and lifestyle changes are unlikely to achieve target values. In this instance, pharmacological therapy should be started without delay.

Treatment Sulphonylureas Biguanides  -Glucosidase inhibitors Thiazolidinediones Glinides Insulin Combination therapy

1. Sulphonylureas Chlorpropamide Tolbutamide Glibenclamide Glipizide Gliclazide Gliguidone Glimepiride

2. Biguanides Metformin Phenformin Buformin

3.  -Glucosidase inhibitors Acarbose Voglibose Miglitol

4. Thiazolidinediones Rosiglitazone Pioglitazone Ciglitazone

5. Glinides Nateglinide repaglinide

6. Insulin Insulin is the most efficacious pharmacologic treatment for patients with diabetes

6. Insulin Indication Preparation Therapy Adverse reaction

Management Algorithm for Overweight and Obese T2DM Diet Exercise and weight control Failure Add biguanide, TZD or  -glucosidase inhibitors Failure Combine two of these or add sulphonylurea or glinide Add insulin or change to insulin Check adherance at each step

Management Algorithm for Non-Obese T2DM Failure Add sulphonylurea, biguanide,  - glucosidase inhibitors or glinide Combine sulphonylurea or glinide with biguande and/or  -glucosidase inhibitors and/or add TZD Add insulin or change to insulin Check adherance at each step