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Diabetes Mellitus (Type 1 Diabetes Mellitus (Diabetic Ketoacidosis…
Diabetes Mellitus
Type 1 Diabetes Mellitus
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Typical patient is young, lean with insulin DEFICIENCY
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Environmental factors: diet, enteroviruses, vitamin D deficiency
Associated with other autoimmune disease e.g. coeliac, autoimmune thyroid, Addison's disease, pernicious anaemia
Symptoms
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Polyuria - glucose draws water into urine by osmosis. Kidneys cannot reabsorb any more glucose as they have reached maximum absorptive capacity
Infections e.g. thrush, vaginal candidiasis, chest infection
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Diabetic Ketoacidosis
Increased production of acetyl-Co-A leads to ketone body production that exceeds the ability of peripheral tissues to oxidise them
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Due to the fat breakdown, patients become acidotic, anorexic, dehydrated and enter AKI, hyperglycaemia and death
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Biochemical presentations: Hyperglycaemia <50mmol/L, plasma ketones >3, urine ketones >2, plasma bicarbonate <15mmol/L, raised urea + creatinine due to renal failure
Signs: Hyperventilation to get rid of CO2 + reduce acidosis, dehydration, hypotension, tachycardia, coma
Management: Rehydration (3 litres in 3 hours), insulin to inhibit acidosis + ketogenesis + lipolysis, replacement of electrolytes (K+)
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Aetiology
T1D is associated with the following autoimmune diseases: hypothyroidism, Addison's, coeliac diease
The body produces the following antibodies which attack the beta cells: Anti GAD, pancreatic islet cell antibody, islet antigen-2 antibody + ZnT8
Only 30% concordance in identical twins so suggests that there are environmental factors contributing
Treatment
Insulin
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There is a risk of hypoglycaemia. This leads to cerebral dysfunction and adrenaline is released, causing sweating and tremor
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Aims
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Without treatment, patients with T1D can lose 10-20 years of life due to CV disease
LADA = latent autoimmune diabetes of adults, has slower progression and insulin treatment is required in later life
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Glucose
Liver performs gluconeogenesis from fat, protein and glycogen. 3 carbon precursors: lactate, alanine, glycerol
If blood glucose is high, liver will convert glucose to glycogen = glycogenesis, and in long term will make triglycerides
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If blood glucose is low, liver will convert glycogen to glucose = glycogenolysis, in long term liver will make glucose from lactate
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Brain is the major consumer of glucose. Brain cannot use free fatty acids as they cannot cross the blood brain barrier
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40% of ingested glucose goes to liver, 60% goes to muscle
Glucose Transport
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GLUT-4 is the channel in which glucose is taken up into muscle and adipose tissue following being stimulated by insulin
GLUT-2 is found in beta cells of pancreas. Low affinity - only allows glucose in when there is a high concentration of glucose. This allows GLUT-2 beta cells to detect high glucose levels and release insulin in response
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Type 2 Diabetes Mellitus
Epidemiology
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More prevalent in South Asian, African + Caribbean ancestry
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Aetiology
Polygenic disorder, so there is some genetic predisposition
Not autoimmune, not HLA associated
Associated with obesity, lack of exercise, calorie + alcohol excess
There is an association between low weight due to poor nutrition at birth to glucose intolerance later in life. Poor nutrition is thought to impair beta cell development and function, predisposing to diabetes later in life
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Risk Factors
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Obesity (> hypertriglyceridaemia,> cholesterol, <HDL)
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Cardiovascular problems e.g. MI, stroke
Pathophysiology
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Hyperglycaemia occurs due to inadequate suppression of gluconeogenesis and reduced uptake of glucose
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Hyperglycaemia is toxic to beta cells, reducing their mass and further exacerbating deterioration of glucose homeostasis
Insulin is still able to bind to receptor normally. Resistance arises due to a problem in the downstream signalling. Insulin resistance develops post receptor
There is amyloid deposition in the islets due to amyloid polypeptide which is co-secreted with insulin
Typically progresses from a preliminary phase (prediabetes) of impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) to fully established T2DM. This presents a critical window for lifestyle intervention
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Treatment
1st Line
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Lifestyle + dietary changes: stop smoking, lose weight, exercise
2nd Line
If HbA1c > 53, add a sulfonylurea e.g. oral Gliclazide to promote insulin secretion. Side effect is hypoglycaemia and weight gain
If HbA1c > 57 add isophane insulin, a long acting insulin
Oral metformin - reduces gluconeogenesis, increases cell sensitivity to insulin, reduces CVS risk
Side effects of metformin include diarrhoea, nausea, severe weight loss
Give incretin analogues (GLP-1 mimetic) as a last resort - these inhibit glucagon and augment release of insulin. These can cause weight loss
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Hormone Regulators
Insulin
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When there is insulin release, there will be a high level of C peptide in the blood due to cleavage of proinsulin
Glucagon
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Stimulates lipolysis, glycogenolysis and ketogenesis
Cortisol, adrenaline and GH have similar effects to glucagon
Types of Diabetes
Secondary
Endocrine disease e.g. Cushing's disease, acromegaly
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Maturity onset diabetes of youth (MODY) - autosomal dominant mutation alters beta cell function, presents in <25 yrs
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DEFINITION = Diabetes mellitus is a syndrome of chronic hyperglycaemia due to insulin deficiency, resistance or both. Diabetes mellitus is a vascular disease.