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Concepts in the natural history of diabetes. Dr H Oosthuizen Pathogenesis of Type 1 diabetes. Autoimmune Type 1 Diabetes Beta cells destroyed via autoimmune mechanism. Genetically predisposed people:triggering factor = production of islet cell Ab. Islet cell Ab destroy Beta cells. Insulin production decreases. Pathogenesis of Type 1 diabetes. Autoimmune Type 1 Diabetes Viruses + other environmental agents have been shown to be triggering factors. Viruses can damage beta cells by: 1.Direct invasion. 2.Triggering an auto immune response. Pathogenesis of Type 1 diabetes. Autoimmune Type 1 Diabetes Implicated viruses: mumps, intrauterine rubella, coxsackie B virus, echo virus, gytomegalo virus and herpes virus. Chemical substances that reduce diabetes: alloxan, streptozotosin and dietary nitroamides. Pathogenesis of Type 1 diabetes. Idiopathic Type 1 Diabetes No known aetiology. Permanent insulinopaenia. This form is strongly inherited. Not HLA associated. Clinical features of Type 1 diabetes. Presents acutely. Symptoms due to hyperglycaemia (thirst, polyuria, tiredness,weight loss). Ketone production - abdominal pain, nausea and vomiting. Other symptoms: blurred vision, repeated infections. No chronic complications at diagnosis, may only be apparent 5-10 years post diagnosis. Incidence of Type 1 diabetes. Incidence peaks at 11-13 years. Seasonal variation: lowest rates in spring and summer. Geographical variation: Japan has a very low incidence. 10% of Type 1 diabetics are over 65 years of age. Type 2 diabetes. Patients frequently undiagnosed for many years. May present with hyperglycaemia symptoms. Coma is rare in type 2 diabetes. May progress to an absolute state of insulin deficiency. Pathogenesis of Type 2 diabetes. 1. 2. 3. 4. Cause: a combination of impaired insulin secretion and insensitivity of target tissues to insulin. Impaired insulin secretion due to beta cell malfunction can be associated with: Incorrect secretion pattern. Ratio of proinsulin to insulin. Amyloid deposits. Slow destruction of beta cells Mechanisms for insulin resistance. 1. Receptor numbers are decreased. (Often seen in obese and aged patients.) 2. 3. Receptor structure is abnormal. Insulin resistance at post receptor events. Clinical features of Type 2 diabetes. Diagnosis due to presence of complications.(At least 30% patients have complications at diagnosis). Symptoms are mild, gradual onset. Classic diabetic symptoms may be present. Type 2 diabetics are usually: over 40 years, fat (“apple obesity”) and no ketones are present. Insulin Secretion in Non-Diabetics and Type 2 Diabetics Insulin Secretion (pmol/min) 800 Normal Type 2 DM 700 600 500 400 300 200 100 06:00 O'MEARA et al. Am. J. Medicine, 1990;89 10:00 14:00 18:00 22:00 Clock Time (Hours) 02:00 06:00 Glucose Contributions to HbA1c HbA1c = Postprandial Glucose, Influenced by: Fasting Glucose, Influenced by: Hepatic glucose production Hepatic insulin sensitivity to + Preprandial glucose Glucose load from meal Insulin secretion Insulin sensitivity in peripheral tissues and liver Postprandial glucose Most of the day may be postprandial HbA1c = FPG + PPG Postprandial from the time glucose starts to rise until it comes down again Time period up to 2.5 h after a meal – normal individuals 1.5 h Testing of PPG recommended 2h after the start of a meal Possible Pathogenesis of Diabetic Complications Overall Glycemic Control (HbA1c) Hyperglycemic "Peaks" Acute toxicity Fasting/Preprandial glucose elevations Chronic toxicity Tissue lesion Complications Which glucose variable? Fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and HbA1c all have pros and cons Where feasible, HbA1c should be the standard measurement by which to gauge risk and treatment efficacy FPG and PPG are useful to adjust daily treatment to monitor for hypoglycaemia for confirmation as haemoglobin metabolism problems may mask true HbA1c levels if there is a lack of resources for HbA1c measurement Age-Adj usted Rel ati ve Ri sk Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study 120 100 80 60 40 20 0 < 22 22- 23- 24- 2522.9 23.8 24.9 26.9 27- 2928.9 30.9 BMI (kg/m2) Colditz GA, et al. Ann Intern Med. 1995;122:481-486. 3132.9 33- > 35 34.9 Lessons from UKPDS: Better control means fewer complications EVERY 1% reduction in HBA1C REDUCED RISK* Deaths from diabetes Heart attacks 1% Microvascular complications Peripheral vascular disorders UKPDS 35. BMJ 2000; 321: 405-12 *p<0.000 1