Lecture 18/19 - Diabetes

Question 1

Diabetes insipidus

Answer 1

defective antidiuretic hormone signalling causing production of large volumes of dilute urine and need to increase fluid intake to compensate

Question 2

diabetes mellitus

Answer 2

group of metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both

Question 3

Type 1 diabetes mellitus

Answer 3

associated with autoimmune damage to the pancreas and loss of insulin-producing beta cells so reduced blood insulin

Question 4

Type 2 diabetes mellitus

Answer 4

insulin resistance and elevated blood insulin but reduced tissue responses

Question 5

risks and consequences of diabetes (1)

Answer 5

many linked to vascular pathology, particularly atherosclerosis formation
most of the elevated mortality risk from diabetes comes from atherosclerosis diseases (CHD and stroke)
diabetes linked to elevated low-density lipoprotein cholesterol, elevated triglycerides and hypertension, all risk factors for atheroma formation

Question 6

risks and consequences of diabetes (2)

Answer 6

Diabetic retinopathy linked to damage to small blood vessels in retina followed by neovascularisation and vascular inflammation
diabetic nephropathy linked to damage to renal vasculature - eventual loss of filtrate function of kidney
loss of sensation commonly results in amputations

Question 7

physiology of insulin: mechanism of release

Answer 7

oral glucose administration -> more insulin release than iv administration

Question 8

Insulin resistance

Answer 8

blood glucose conc higher than expected based on blood insulin concentration
Insulin resistance (IR) - normal fasting glucose conc, normal oral glucose tolerance, maintained by elevated insulin conc
Impaired glucose tolerance (IGT) - normal fasting glucose conc, impaired oral glucose conc, hyperinsulinemia
type 2 diabetes (T2D) - elevated fasting glucose conc, impaired oral glucose tolerance

Question 9

treatment of diabetes

Answer 9

control of acute symptoms, prevention of hypoglycaemia, reduce risk of long term complicates with elevated blood glucose conc

Question 10

treatment of type 1 diabetes

Answer 10

insulin-dependent - treatments based on providing a source of insulin
insulin side effects: hypoglycaemia, infection around the pump, lipohypertrophy (anabolic effect on adipose tissue)

Question 11

treatment of type 2 diabetes (T2DM)

Answer 11

lifestyle changes
metformin
metformin + other therapies

Question 12

T2DM (biguanides)

Answer 12

only metformin used clinically
most widely used oral medication
diverse cellular targets: improving insulin sensitivity by increasing glucose uptake/usage. no change in insulin secretion
liver: decreased gluconeogenesis, decreased FA production
adipose tissue: reduced lipolysis and lipogenesis
skeletal muscle: increased glucose uptake; increased glycogen synthesis
GI system: reduced carbohydrate absorption, reduced appetite.
the overall effect - reduced blood glucose conc

Question 13

T2DM (incretins)

Answer 13

synthetic analogues of GLP-1; administered by injection
agonists of GLP1 receptors
increase insulin secretion from pancreatic beta cells
inhibit glucagon secretion
dipeptidyl peptidase 4 inhibitors - inhibit breakdown of endogenous incretins

Question 14

T2DM (SGLT2 inhibitors)

Answer 14

SGLT-2 is normally responsible for filtering out around 90% of glucose from the filtrate in the kidney nephron. Inhibitors are therefore used to reduce glucose reabsorption into the PCT leading to urinary glucose excretion and osmotic diuresis.
glucose reabsorbed by sodium-glucose co-transporters (SGLTs) in the proximal tubule
SGLT2 inhibitors inhibit glucose uptake
glucose lost in the urine

Question 15

T2DM (sulphonylureas)

Answer 15

block of KATP channels by sulphonylureas depolarises beta cells and releases insulin independently of blood glucose
elevated blood insulin conc overcomes insulin resistance
hypoglycaemia is a major risk - insulin release despite blood conc being low

Question 16

Peroxisome proliferator-activated receptor-y (PPAR-y) agonist

Answer 16

They have a multitude of effects mainly on improving insulin sensitivity in the lipid and in the muscle some effects on the liver. Overall, reduces insulin resistance and improves fatty acid uptake.
Ligands for PPAR-γ regulate adipocyte production, secretion of fatty acids and glucose metabolism.
Agents binding to PPAR-γ result in increased insulin sensitivity in adipocytes, hepatocytes and skeletal muscle.