Diabetes - anatomy, pathophysiology

What is the type of diabetes characterised by no insulin?

Type 1 diabetes

What is the type of diabetes characterised by an inability to respond to insulin as pancreas doesn’t make enough to meet the demand?

Type 2 diabetes

What is the usual blood glucose fluctuations in a person without diabetes?

Very little fluctuations, generally stays around 5mmol/L

What organs use the most energy?

Heart and kidney, followed by brain

What is the order of organs energy usage?

heart > kidney > brain. > liver > skeletal muscle > adipose tissue > residual

Why does skeletal muscle not use much energy?

Not using much energy usually but will increase if exercising e.g., at the gym, running a marathon

Why does the kidney require so much energy?

Uses lots of active transport to reabsorb ions

Where does active transport to reabsorb ions, glucose, amino acids and bicarbonate in the kidney occur?

Proximal tubule, loop of Henle, distal tubule, collecting duct

Where in the kidney does the majority of reabsorption of filtrate occur?

Proximal tubules

What is active transport powered by in the kidney?

Na+ K+ ATPase

What roles does Na+ K+ ATPase in the kidneys?

Establishes ion gradients and drives co-transporters

What does kidney reabsorption rely on/

Aerobic respiration - requires lots of blood supply

What energy source do the kidneys mostly use?

Beta oxidation of fatty acids e.g, palmitate producing 106 molecules of ATP

What area of the kidneys has one of the highest oxygen consumptions in the body?

Proximal tubules

What does the brain/neurons rely on for energy?

Glucose

How does a neuron use energy?

• Maintaining resting potential

• Propagation of action potential

• Releasing neurotransmitter vesicles

• Post-synaptic actions of neurotransmitters

• Recycling neurotransmitters and vesicles

• All of the above use ATPase pump

What can be signs of hypoglycaemia in type 1 diabetes?

Slurred speech, cognitive impairment, stumbling

Why does type 1 diabetes have cognitive symptoms in hypoglycaemia?

Brain cannot get the glucose it needs so stops working properly

Where does the majority of glucose in the blood come from?

Food or liver

What type of activity uses glucose/glycogen in muscles as an energy source?

Anaerobic e.g., sprinting

What is the graph showing glucose usage after eating and the different stages?

• Glucose from food used for the first few hours, is also being moved into muscle and liver to be stored as glycogen

• If stores are full, triglycerides made and put into liver and adipose tissue

• At around 4 hours - stored glucose from the liver begins to work, about a days worth of

• Newly made glucose begins to take over at 24 hour mark, Gluconeogenesis occurs and can keep going for days-weeks

In starvation, where is the glucose from for the brain to use?

Uses fat initially, then carbon for glucose from muscle cells amino acids

In general, what energy source will organs use?

• Brain = always glucose

• Kidney = fatty acids

• Those that switch will e.g., if more glucose, will use glucose

What organ tops up glucose in between meals?

Liver

What is a diagram showing the glucose flux after an overnight fats?

Most diverted towards the brain

What is the graph showing the blood glucose variations in a non-diabetic vs a diabetic?

Much higher, wider variations after a meal, maximum for transporters is around 20 so may have lots of glucose left in the urine

What effect do SGLT2 drugs have due to making the body absorb less glucose?

Urinate more frequently

What is a side effect of SGLT2 drugs making patients urinate more?

Increase susceptibility to lower UTI infections

What is the term to describe the metabolic disease characterised by raised plasma glucose levels?

Diabetes

What is diabetes caused by?

Failure of insulin and regulation of metabolism, can switch off fatty acid release from fat stores also

What are the 2 main complications from hyperglycaemia?

Microvascular and macrovascular

What are examples of microvascular damage caused by hyperglycaemia?

Blindness, limb amputations, kidney failure

What are examples of macrovascular damage caused by hyperglycaemia?

Heart attacks, strokes

Why does microvascular complications occur?

Damage to endothelial lining of small blood vessels

What are the 3 mechanisms for endothelial damage?

• Sorbitol production using NADPH which increases oxidative stress and reduces vasoelasticity

• Glycation of proteins alters cellular interactions and extracellular matrix

• Acetyl CoA makes fatty acids which makes diacyl glycerol - signalling molecule which alters cellular interactions signalling

How do macrovascular complications occur from hyperglycaemia?

increases free fatty acids, leading to plaque deposition in arterial walls and increases FAOx which can lead to oxidative stress

What diseases is diabetes an independent risk factor for?

Coronary artery disease, cerebrovascular disease, peripheral vascular disease

What can diabetes be a cormorbid risk factor for?

Obesity, hypertension, hyperlipidaemia, altered platelet function

When does macrovascular disease present in type 2 diabetes?

At diagnosis

When does macrovascular disease present in type 1 diabetes?

Age and duration of diabetes correlates with degree

What do most treatments for diabetes target?

Hyperglycaemia

Why is glucose used as a target in diabetes?

Easily measurable, key to target

What is a diagram comparing type 1 and 2 diabetes?

• T1 is early onset, type 2 is later

• Lean physique in type 1, obese in type 2

• Treatment for type 1 is insulin, type 2 is diet, drugs and insulin

What is the defect in type 1 diabetes?

Autoimmune destruction of Beta cells

What is the main defect in type 2 diabetes?

Insulin resistance or defective insulin secretion

How does the autoimmune response in type 1 diabetes start?

Antibody mediated immune destruction of beta cells from islets of Langerhans, progressive loss occurs over months and years and usually appeared in adolescence where hyperglycaemia noticed when 80-90% of beta cells lost

What is post-meal insulin release like in type 1 diabetes?

Spike occurs a lot later than usual

What is the usual graph showing post-meal insulin release?

Stable first peak that spikes quickly before second phase release

What accounts for 1/3 of susceptibility for type 1 diabetes?

Genetic factors

What are some candidates for environmental factors affecting type 1 diabetes?

• Viruses - mumps, rubella, retroviruses

• Specific drugs or chemicals - specific nitrosamines in smoked and cured meats, coffee

• Dietary constituents - cow milk in infancy

• Reduced exposure to microorganisms in early childhood

What are some major complications of type 1 diabetes?

• Chronic hyperglycaemia effects

• Hypoglycaemia from over administering insulin

• Diabetes ketoacidosis

What can be a cause of hypoglycaemia in type 1 diabetes?

Patient over administering too much insulin - an acute state

What is the term to describe uncontrolled glucose and fatty acid oxidation levels in diabetes, where ketone bodies enter the brain in diabetes?

Diabetes ketoacidosis

What is the issue with ketone bodies entering the brain in diabetic ketoacidosis?

NOT needed in the brain and can make the blood very acidic, leading to coma and death

What is the diagram showing usual usage of glucose in the fasting state in an individual WITHOUT diabetes?

Low plasma glucose levels, Triglycerides broke down and used in liver to make glucose, Gluconeogenesis also occurs

What happens in the fed state in a normal person without diabetes?

No lipolysis occurs, insulin from pancreas switches off Gluconeogenesis etc and reduces plasma glucose levels

What happens in high plasma glucose levels/fed state in diabetes?

Insulin doesn’t work, lipolysis uncontrolled and keeps going, plasma glucose and ketone bodies remain high, Gluconeogenesis keeps going

What processes are uncontrolled that lead to diabetic ketoacidosis?

Lipolysis and beta oxidation, also high blood glucose

What causes type 2 diabetes?

Hyperglycaemia and high free fatty acids, glucose unable to exert effects on liver and adipose

What happens to beta cells in type 2 diabetes?

Produce more insulin to try and overcome insulin resistance, until they are overwhelmed and insulin cannot switch off

What causes insulin resistance in type 2 diabetes?

• Strong genetic components e.g., in twins and in indigenous populations

• Environment is key!! Lifestyle, exercise and DIET

What are some reasons that cause insulin resistance?

Ectopic lipid accumulation, cellular stress responses, inflammation

How does ectopic lipid accumulation cause insulin resistance?

Lipids in the wrong place - should usually be in adipose tissue, liver and muscle triglycerides have less insulin sensitivity, accumulates lipid mediators and can alter protein phosphorylation

How do cellular stress responses cause insulin resistance?

Mitochondrial and protein producing machinery break down, alters insulin signalling pathways - downstream of ectopic lipid accumulation

How does inflammation cause insulin resistance?

Macrophages in adipose tissue accumulate in lipid, when it becomes too full leaks triglycerides into surrounding tissue and secretes inflammatory cytokines such as TNF alpha and alters insulin signalling pathways in muscle and liver

What is a graph showing history of type 2 diabetes before/after diagnosis?

• Insulin can be raised for years before dipping

• Beta cell number slowly decreases

• Fasting glucose and postmeal glucose both steadily rise

• Insulin resistance increases over time

What can microvascular damage lead to in diabetes?

Retina, kidney and nerve damage

What does diabetic retinopathy lead to ultimately?

Blindness

Related to the retina, what are diabetic patients offered more frequently?

Free eye tests

What can diabetic nephropathy lead to?

End stage renal failure

What can diabetic neuropathy lead to?

Debilitating neuropathy and lead to diabetic foot

What is peripheral neuropathy caused by?

Endothelial damage, wall thickening leads to ischaemia and neural death, segmental demylinisation and slowing of nerve conduction occurs

What are the.2 different types of diabetic peripheral neuropathies?

Somatic and autonomic

What are the somatic symptoms of diabetic peripheral neuropathies?

Parathesias, including numbness and tingling, impaired pain, termpature, light touch, two-point discrimination and vibratory sensation

What are autonomic symptoms of diabetic peripheral neuropathies?

• Vasomotor functions e.g., postural hypotension

• GI function - gastric atony, postprandial and nocturnal diarrhoea

• Genitourinary function - Paralytic bladder/incomplete voiding, impotence

• Cranial nerve - impaired pupillary response s

What can patients be unaware of. For foot problems in diabetic foot ulcers?

Poorly fitting shoes, improper weight baring or iinfections