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Normal glucose regulation:

-          Beta cells: produce insulin, lowers blood sugar, stimulates glycogenesis in liver

-          Alpha cells: produce glucagon, raises blood glucose, stimulates glycogenolysis, promotes glucogenesis

Insulin action:

-          Binds to insuin receptors on target cells

-          Activates PI3K-Akt signalling pathway

-          Triggers GLUT 4 translocations

-          Glucose enters cells

GLUT 1:

-          Basal ganglia glucose uptake

-          Many tissues

GLUT 2:

-          Liver and pancreatic beta cells

-          Glucose sensor

GLUT 4:

-          Insulin-responsive

-          Skeletal muscle and adipose tissue

-          Increase glucose uptake ~ 10-20 fold

Type 1 diabetes:

-          Autoimmune beta cell destruction

-          Absolute insulin deficiency

Type 2 diabetes:

-          Insulin resistance

-          With or without beta cells dysfunction

Other types of diabetes:

-          Gestational diabetes

-          Monogenic diabetes

-          Secondary diabetes (steroid induced)

Type 1 pathophysiology:

-          Autoimmune destruction of pancreatic beta cells

-          Absolute insulin deficiency

-          Genetic suseptability (HLA genes)

-          Environmental triggers

Type 1 cellular impact:

-          Insulin receptor signalling absent

-          PI3-Akt pathway not activated

-          GLUT 4 transporters remain intracellular

-          Reduced glucose uptake into cells

Type 1 metabolic consequences:

-          Cells cannot access glucose

-          Cellular energy deficit

-          Lipolysis

-          Ketone production

-          Metabolic acidosis

-          Risk of diabetic ketoacidosis

Type 1 hyperglycaemia:

-          Osmotic diuresis

-          Glucose in urine draws water out

-          Fluid loss

-          Dehydration

-          Electrolyte loss

-          Reduced blood volume

-          Reduced blood pressure

-          Reduced tissue perfusion

Type 1 Ketoacidosis:

-          Metabolic acidosis

-          Reduced blood ph

-          Disrupted enzyme activity and cellular function

-          Deep rapid breathing

-          Impaired brain function

-          Confusion

-          Reduced consciousness

-          Potential coma

Type 1 potassium imbalance

-          Total body potassium depletion

-          Insulin therapy shifts potassium back into cells

-          Hypokalaemia risk

-          Life threatening cardiac arrhythmias

Type 2 pathophysiology stages:

-          Insulin resistance

-          Compensatory hyperinsulinemia

-          Free fatty acids

-          B cell dysfunction and apoptosis

Insulin resistance:

-          Muscle, liver and adipose tissue respond poorly

-          Reduced GLUT 4 translocation

-          Reduced glucose uptake

Compensatory Hyperinsulinemia

-          Pancreas secretes more insulin

-          Temporary beta cell hyperplasia/hypertrophy

-          Glucose initially normal

Free fatty acids:

-          Impair insulin signalling

-          Increase hepatic glucose production

-          Promote beta cell stress

Beta cell dysfunction and apoptosis:

-          Relative then absolute insulin deficiency

-          Sustained hyperglycaemia

Symptoms of diabetes:

-          Polyuria

-          Polydipsia

-          Polyphagia

-          Fatigue

-          Blurred vision

-          Slow wound healing

-          Unexplained weight changes

Diagnosis of diabetes:

-          HbA1c: reflects average bg over 2-3 months/ >6.5% indicates diabetes

-          Fasting plasma glucose: bg after 8hr fast / >7.mmol/L indicates diabetes

-          Oral glucose tolerance test: bg measured before and 2hrs after sugary drink/ >11.1mmol/L at 2 hrs indicates diabetes

Diabetes management:

-          Lifestyle modifications: balanced diet, physical activity, weight management

-          Self monitoring w glucometer

Insulin therapy:

-          T1: lifelong

-          T2: may be added when meds are sufficient

Metformin

-          First line medication for T2

-          Improves insulin sensitivity

-          Reduces hepatic glucose production

-          Supports weight management

Long term complications of diabetes:

-          Formation of AGEs

-          Oxidative stress

-          Activation of inflammatory pathways

-          Direct blood vessel injury

Microvascular complications of diabetes

-          Thickening of basement membrane

-          Endothelial dysfunction

-          Reduced blood flow

Retinopathy:

-          Retinal blood vessel damage

-          Microaneurysms

-          Haemorrhages

-          Retinal ischemia

-          Neovascularisation

-          Vision loss

Nephropathy:

-          Glomerular capillary damage

-          Albuminuria

-          Chronic kidney disease

-          Kidney failure

Neuropathy:

-          Peripheral nerve damage

-          Numbness

-          Tingling

-          Burning pain

-          Autonomic neuropathy affects (digestion, heart rate, blood pressure)

Macrovascular changes of diabetes:

-          Accelerated atherosclerosis

-          Endothelial dysfunction

-          Vessel wall stiffening

-          Impaired blood flow and oxygen delivery

-          Risk of cardiovascular disease, stroke & peripheral artery disease