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.
2.

Receptor numbers are decreased. (Often

seen in obese and aged patients.)

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

800 Insulin Secretion (pmol/min) 700 600 500 400 300 200 100 06:00
O'MEARA et al. Am. J. Medicine, 1990;89

Normal Type 2 DM

10:00

14:00 18:00 22:00 Clock Time (Hours)

02:00

06:00

Glucose Contributions to HbA1c

HbA1c =
Fasting Glucose, Influenced by:
Hepatic

Postprandial Glucose, Influenced by:

glucose production sensitivity to insulin

Preprandial

Hepatic

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" Fasting/Preprandial glucose elevations

Acute toxicity

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

Link Between Obesity and Type 2 Diabetes: Nurses Health Study

Age-Adjusted Relative Risk

120 100 80 60 40 20 0 < 22 22- 23- 24- 25- 27- 2922.9 23.8 24.9 26.9 28.9 30.9 BMI (kg/m2) 31- 33- > 35 32.9 34.9

Colditz GA, et al. Ann Intern Med. 1995;122:481-486.

Lessons from UKPDS: Better control means fewer complications

EVERY 1% reduction in HBA1C Deaths from diabetes REDUCED RISK*

Heart attacks
Microvascular complications Peripheral vascular disorders
UKPDS 35. BMJ 2000; 321: 405-12 *p<0.000 1

1%