concepts in the natural history of diabetes. dr h oosthuizen
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Concepts in the natural history of diabetes.
Dr H Oosthuizen
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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.
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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.
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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.
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Pathogenesis of Type 1 diabetes.Idiopathic Type 1 Diabetes No known aetiology. Permanent insulinopaenia. This form is strongly inherited. Not HLA associated.
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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.
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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.
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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.
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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
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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.
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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.
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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
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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 =
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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
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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
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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
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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
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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%