immune syetem Essay

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LECTURE 2: Diabetes
Dr Simon J Dunmore

What is Diabetes Mellitus and how is it diagnosed?
It is a disease characterised by hyperglycaemia (= high blood glucose)
WHO defines this as a fasting plasma glucose ³ 7.0 mmol/l (2 separate measurements)
Or ³ 11.1 mmol/l 2hrs after an Oral Glucose Tolerance Test (OGTT): 75g glucose given orally, at t=0 hrs, to fasting subject
Not to be confused with diabetes insipidus
A Brief History of Diabetes (1)
15th c BC - Known in Ancient Egypt
1st c AD Aretaeus of Cappadocia named it diabhths
“Diabetes is a strange disease, which fortunately is not very frequent. It consists in the flesh and bones running together into urine…. The disease was called diabetes, as though it were a siphon….”
5th c AD - Indians recognised different types
10th c - Arabic physicians provide accurate clinical descriptions and described complications
17th/18th c English physicians describe role of “sugar”
A Brief History of Diabetes (2)
19th c- Role of liver in diabetes recognised late 19th c - Minkowski & Von Mering - role of pancreas (pancreatectomized dogs)
20th c
De Meyer - named “Insuline”
Opie - recognised lesions in islets (amyloid plaque - later realized only in type 2)
Various impure insulin preps
1921 Banting, Best, Collip & McLeod - Active Insulin

Other types of diabetes
1. MODY
Maturity Onset Diabetes of the Young single gene defects (autosomal recessive) in genes associated with glucose control of insulin secretion or beta-cell development
2. Gestational diabetes
Type 2-like, occurring during pregnancy
May lead to later type 2 diabetes after pregnancy

Insulin
Peptide Hormone
Secreted by beta-cells
Acts on insulin receptors on cell surface of target tissues (primarily skeletal muscle, adipose tissue, liver)
Stimulates anabolic processes: glycogen synthesis, fatty acid and triacylglycerol synthesis, protein (specific) synthesis

How insulin deficiency ± insulin resistance leads to diabetes
1. Type 1 diabetes is characterised by near/complete loss of beta cells – becomes clinically overt when around 80% of beta cells lost
2. Type 2 diabetes is characterised by insulin resistance but this is not sufficient on its own to result in diabetes many people are obese and insulin resistant but can overcome the resistance by secreting more insulin – hyperinsulinaemia
Type 2 diabetes develops when individuals can no longer secrete enough insulin (due to eg genetic factors such as TCF7L2) – relative insulin deficiency

Causes of Diabetes
Type 1: Autoimmunity
May be initiated by virus infections, dietary factors eg cow’s milk, toxins…
Type 2: Inheritance; obesity
Strongly genetic (90-100% concordance in identical twin studies)
Many genetic risk factors identified (eg see Florez JC (2008) The Genetics of Type 2 Diabetes: A Realistic Appraisal in 2008. J Clin Endocrinol Metab 93: 4633–4642)
80% of type 2 diabetes patients are obese (especially centrally obese – “apple shape”!)
Insulin resistance is a feature of obesity
Dietary factors eg fatty acids (esp saturated) contribute to beta-cell failure and insulin deficiency
Amyloid accumulation in/around beta-cells may destroy them
Adipose tissue produces adipokines (eg leptin, resistin, adiponectin (low), visfatin) which may contribute to insulin deficiency as well as insulin resistance

This is a diagrammatic representation of human amylin and the synthetic amylin analog, pramlintide. Human amylin has a tendency to aggregate, form insoluble particles and stick to surfaces.
The analog, pramlintide, differs from human amylin at three amino acid sites (proline at 25, 28, and 29) and this molecule overcomes these disadvantages of human amylin. Studies have shown that pramlintide has the full biological spectrum of, and potency equal to or better than,…