Download Concepts in the natural history of diabetes.

Concepts in the natural history of
diabetes.
Dr H Oosthuizen
Pathogenesis of Type 1 diabetes.
Autoimmune Type 1 Diabetes
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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
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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.
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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.
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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.
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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.
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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).
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Symptoms are mild, gradual onset. Classic
diabetic symptoms may be present.
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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
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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?
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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
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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