1. Concepts in the natural history of diabetes.
Dr H Oosthuizen

2. 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.

3. 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.

4. 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.

5. Pathogenesis of Type 1 diabetes.
Idiopathic Type 1 Diabetes
No known aetiology.
Permanent insulinopaenia.
This form is strongly inherited.
Not HLA associated.

6. 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.

7. Incidence of Type 1 diabetes.
Incidence peaks at 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.

11. Natural history of patients with type 2 diabetes
Natural history of patients with type 2 diabetes...Problems before you see them
Content Points:
People with type 2 diabetes are at high risk for atherosclerosis and consequent CVD. Part of this risk is thought to be due to insulin resistance and resultant hyperinsulinemia as the pancreas secretes extra insulin to overcome the resistance of muscle and fat to insulin.
There is evidence that hyperglycemia is one factor that may cause oxidation of compounds and contribute to endothelial dysfunction and, subsequently, CVD.36
Many individuals who are insulin resistant or who have type 2 diabetes are not diagnosed until they have sustained cardiovascular damage from hyperglycemia and hyperinsulinemia. Prediabetics (people with impaired glucose tolerance or IGT), without chronic hyperglycemia, have a 2-fold increase in risk of coronary artery disease compared with normal subjects. By the time a person has developed full-blown type 2 diabetes, their risk has increased to 3-fold greater than normal.37
In an effort to decrease the high level of morbidity and mortality and to facilitate early diagnosis, the American Diabetes Association has recently revised their guidelines by lowering the fasting plasma glucose level at which diabetes is diagnosed from 140 mg/L to 126 mg/L.38
Physicians need to be aggressive in diagnosing and treating type 2 diabetes to reduce risk of cardiovascular events.

12. 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.

13. Pathogenesis of Type 2 diabetes.
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

14. Mechanisms for insulin resistance.
Receptor numbers are decreased. (Often seen in obese and aged patients.)
Receptor structure is abnormal.
Insulin resistance at post receptor events.

15. 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.

18. Insulin Secretion in Non-Diabetics
and Type 2 Diabetics
Clock Time (Hours)
06:00
Normal
Type 2 DM
10:00
14:00
18:00
22:00
02:00
800
700
600
500
400
300
200
100
Insulin Secretion (pmol/min)
O'MEARA et al. Am. J. Medicine, 1990;89

19. Glucose Contributions to HbA1c+
Postprandial Glucose,
Influenced by:
Preprandial glucose
Glucose load from meal
Insulin secretion
Insulin sensitivity in peripheral tissues and liver
Fasting Glucose,
Hepatic glucose production
Hepatic sensitivity to insulin
HbA1c =

20. 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

21. Possible Pathogenesis of Diabetic Complications
Overall Glycemic Control (HbA1c)
Hyperglycemic "Peaks"
Fasting/Preprandial glucose elevations
Acute toxicity
Chronic toxicity
Tissue lesion
Complications

22. 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

23. Link Between Obesity and Type 2 Diabetes: Nurses’ Health Study
Colditz GA, et al. Ann Intern Med. 1995;122:

24. Lessons from UKPDS: Better control means fewer complications
EVERY 1%
reduction in HBA1C
REDUCED RISK* 1%
-21%
Deaths from diabetes
-14%
Heart attacks
Lessons from UKPDS: better control means fewer complications
The UKPDS has proven beyond doubt that intensive glycaemic control is strongly associated with significant clinical benefits for patients with type 2 diabetes. In an epidemiological analysis of the UKPDS cohort every 1% decrease in HbA1C was associated with clinically important reductions in the incidence of
diabetes-related death ( 21%)
myocardial infarction ( 14%)
microvascular complications ( 37%)
peripheral vascular disease ( 43%)
There is no lower limit beyond which reductions in HbA1C cease to be of benefit. Taking diabetes-related death as an example, this means that:
 HbA1C of 2% delivers a 42% reduction in risk
 HbA1C of 3% delivers a 63% reduction in risk, and so on.
Therefore, the greater the reduction in HbA1C, the greater the protection against complications.
Stratton MI Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:
-37%
Microvascular complications
-43%
Peripheral vascular disorders
*p<0.0001
UKPDS 35. BMJ 2000; 321: