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. Cause: a combination of impaired insulin secretion and

insensitivity of target tissues to insulin.2. Impaired insulin secretion due to beta cell malfunction

can be associated with:3. Incorrect secretion pattern.4. Ratio of proinsulin to insulin.5. Amyloid deposits.6. Slow destruction of beta cells

Mechanisms for insulin resistance.1. Receptor numbers are decreased. (Often

seen in obese and aged patients.)

2. Receptor structure is abnormal.

3. 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 Insulin Secretion in Non-DiabeticsNon-Diabeticsand Type 2 Diabeticsand Type 2 Diabetics

Clock Time (Hours)06:00

Normal

Type 2 DM

10:00 14:00 18:00 22:00 02:00 06:00

800

700

600

500

400

300

200

100Insu

lin S

ecre

tion

(pm

ol/m

in)

O'MEARA et al. Am. J. Medicine, 1990;89

Glucose Contributions to HbAGlucose Contributions to HbA1c1cGlucose Contributions to HbAGlucose Contributions to HbA1c1c

++

Postprandial Glucose,

Influenced by:

Preprandial glucose Glucose load from meal Insulin secretion Insulin sensitivity in

peripheral tissues and liver

Fasting Glucose,Influenced by: Hepatic glucose

production Hepatic sensitivity to

insulin

HbA1c =HbA1c =

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

Hyperglycemic "Peaks"

Hyperglycemic "Peaks"

Fasting/Preprandial glucose elevationsFasting/Preprandial glucose elevations

Acute toxicityAcute toxicity Chronic toxicityChronic toxicity

Tissue lesionTissue lesion

ComplicationsComplications

Overall Glycemic Control (HbA1c)Overall Glycemic Control (HbA1c)

Possible Pathogenesis of Diabetic Possible Pathogenesis of Diabetic ComplicationsComplications

Possible Pathogenesis of Diabetic Possible Pathogenesis of Diabetic ComplicationsComplications

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

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

0

20

40

60

80

100

120

<22 22-22.9

23-23.8

24-24.9

25-26.9

27-28.9

29-30.9

31-32.9

33-34.9

>35

BMI (kg/m2)

Age

-Adj

uste

d Re

lativ

e Ri

sk

EVERY 1%

reduction in HBA1C

REDUCED RISK*

1%

Deaths from diabetes

Heart attacks

Microvascular complications

Peripheral vascular disorders

UKPDS 35. BMJ 2000; 321: 405-12

Lessons from UKPDS:Better control means fewer complications

-37%

-43%

*p<0.0001

-14%

-21%