Type II Diabetes Flashcards
Type 2 Diabetes
insulin resistance rather than deficiency
more common form (90%)
strongly linked to prevalence of obesity
management initially by diet & exercise - changing variable demand that body has for glucose
Insulin replacement therapy
not first line treatment as the disease is caused by insulin resistance → mechanisms to use the insulin are disrupted
Acute consequences of T2D
Thirst, excess urine production
Blurred vision
Weight loss, fatigue
Itching – thrush infections
Chronic consequences of T2D
Cardiovascular disease (atherosclerosis, heart disease, stroke)
Kidney disease
Eye problems (retinopathy)
Peripheral neuropathy
Poor peripheral circulation leading to lower limb amputation
Mechanisms of T2D
Inadequate secretion of insulin or reduced efficacy of insulin at its receptor or combination of the two
Associated with increased release of glucose from liver, increased breakdown of lipids in adipose tissue (releases more glucose - positive feedback), high glucagon levels in blood
Treatment of T2D
Diet
Exercise
Medication → if improvement fails with diet and exercise
Insulin → depends on patient, whether they have functional pancreatic beta cells
Biguanides (metformin)
Considered to be a sensitising agent: improves insulin resistance
Main effects are:
Reduction in hepatic glucose synthesis (gluconeogenesis)
Increase in glucose uptake into skeletal muscle - increase in GLUT4 transporter expression within skeletal muscle cells → more glucose taken up into stores
Additional effects
Reduces absorption of carbohydrate
Increases oxidation of fatty acids
Reduces circulating levels of LDL and VLDL
Increase insulin sensitivity, decrease glucose in blood
Metformin - mechanism of action
first-line treatment in most new cases of T2D
Activation of AMP-kinase pathway in hepatic cells
Downstream signalling → Reduced expression of genes involved in gluconeogenesis so reduced production of new glucose
Metformin - advantages
no weight gain, low risk of hypoglycaemia (blood sugar too low)
Metformin - adverse effects
gastrointestinal disturbances, risk of lactic acidosis
Contraindicated in liver and kidney disease → due to effects on hepatic cells
Sulphonylureas
First widely used oral anti-diabetic agents
Main compounds: tolbutamide, glibenclamide, glipizide
Considered to be secretagogues: enhance insulin secretion from β-cells
only useful in T2D with strong “insulin resistance”
Require functional β-cells
Sulphpnylureas - mechanism of action
Concentration-dependent block of ATP-sensitive K+ channel (Kir6.2) - causes block of this channel, enhancing effect that already happens normally
Depolarisation of β-cell membrane
Influx of Ca2+ via L-type channels
Enhanced release of insulin from vesicular stores
Tolbutamide
fast-acting, short-duration, low potency
Glibenclamide
slow-acting, long-duration, high potency
Glipizide
medium-acting, long-duration, moderate potency
Sulphpnylureas - adverse effects
hypoglycaemia (depending on PK) → can push too far the other way, weight gain
Possibility of β-cell exhaustion? - if cells are overworked, they can die, may overexert pancreatic beta cells
Meglitinides
Main compounds: repaglinide, nateglinide
Also considered to be secretagogues; different chemical structure but same mechanism:
Block of Kir6.2 potassium channel
Increase in insulin secretion
Meglitinides - action
More potent than sulphonylureas and more selective for β-cells → less likely to block Kir6.2 channels in other cells so lessn toxicity
Rapid-acting and short-duration; can be taken orally prior to a meal to reduce post-prandial rise in blood glucose
Low risk of hypoglycaemia, no weight gain
Thiazolidinediones (TZDs)
Main compounds: rosiglitazone, pioglitazone
Considered to be sensitising agents; improve insulin resistance
Main effects of TZDs
reduced hepatic glucose output
Increased glucose uptake into skeletal muscle by enhancing effectiveness of endogenous insulin
Maximum effect only achieved after 1-2 months - take a while to balance out within body
Additional effects of TZDs
reduced serum insulin and fatty acid levels, decline in triglycerides, slight increase in LDL and HDL
TZD mechanism of action
Enhance gene transcription
Peroxisome proliferator-activated receptor-g (PPARg) agonists
Complexes with another nuclear receptor (retinoid X receptor)
Altered expression of multiple genes
- Lipoprotein lipase
- Fatty acid transporter protein
- Adipocyte fatty acid binding protein
- Glucose transporter 4
- Several others
- PPARg predominantly expressed in adipose tissue; also muscle and liver - increase GLUT4 in 3 key glucose storage cells
Advantages of TZDs
effective in most cases of T2D
low risk of hypoglycaemia
Adverse effects of TZDs
risk of heart failure, weight gain, oedema, expensive
- Rosiglitazone and troglitazone withdrawn due to heart and liver problems
- Pioglitazone may elevate risk of bladder cancer (still licensed) also increases risk of bone fractires in women
- Contraindicated in heart failure and pregnancy
Alpha-glucosidase inhibitors
-act on the gut
Main compounds: acarbose, miglitol
Alpha-glucosidase inhibitors - mechanism of action
No direct effect on insulin secretion or sensitivity → acting prior to this process by slowing down carbohydrate absorption hence increase in blood glucose
Only effective when insulin secretion / sensitivity is marginally impaired - less effective for severe T2D
Adverse effects of alpha-glucosidase inhibitors
Diarrhoea
Flatulence
Abdominal cramps
Incretin hormones
Insulin secretion is more pronounced following oral vs i.v. administration of glucose; suggests GI involvement
Incretins are metabolic hormones produced in GI tract
Prepare beta cells to start secreting insulin before substantial blood glucose increase
GLP-1 and GIP stimulate release of insulin from β-cells following a meal but prior to increase in blood glucose
Also inhibit glucagon release, reduce absorption of nutrients by slowing gastric emptying, and reduce food intake → feel full for longer
Glucagon-like peptide 1 (GLP-1)
29 AA peptide secreted by epithelial cells throughout GI tract
Glucagon-like insulinotropic peptide (GIP)
42 AA peptide secreted from epithelial cells in duodenum
Gliptins
Main compounds: sitagliptin, vildagliptin, saxagliptin
Competitive inhibitors of dipeptidylpeptidase-4 (DPP-4); responsible for metabolism of GLP-1 and GIP → target this pathway → acts to decrease levels of GLP-1 and GIP
Gliptins - mechanism of action
Reduce blood glucose by: inhibiting metabolism of incretins, decrease in glucagon release, increase in insulin release
Gliptins - side effects
Well-tolerated: little hypoglycaemia, no weight gain
GLP-1 receptor agonists
Main compounds: exenatide, liraglutide, lixisenatide, semaglutide
GLP-1 receptor agonists - mechanism of action
Increase insulin release from β-cells; reduce glucagon release from a-cells
Slow gastric emptying; promote satiety
Degraded in GI tract, admin by s.c. injection → peptide structure
Well-tolerated: little hypoglycaemia, significant weight loss (up to 8kg) → not necessarily healthy to lose so much weight in one go
Used in conjunction with insulin to optimise control, limit insulin dose, and reduce likelihood of weight gain leading to progression of the disease
Glifozins
Main compounds: dapagliflozin, canaglifozin, empaglifozin
Glifozins - mechanism of action
Block the sodium-glucose co-transporter 2 (SGLT2) on proximal convoluted tubule of nephron
SGLT2 responsible for reabsorption of 90% of glucose from urinary filtrate
Inhibition causes significant excretion of plasma glucose
May also be useful in type 1 diabetes
Glifozins - side effects
Well-tolerated: no hypoglycaemia, moderate weight loss (not as extreme)
Insulin
Most patients with T2D will eventually require insulin therapy
Long-acting formulation (i.e. glargine, detemir) taken once daily (at night)
Oral antidiabetic medications continued
Insulin is treatment of choice in pregnant women
Weight gain is a problem with insulin use in T2D
Insulin sensitisers
Metformin
Thisazolidinediones
Incretin mimetics
Gliptins
GLP-1 agonists
Replacement therapy
Insulin
Insulin secretagogues
Sulphonylureas
Meglitinides
Others
⍺-glucosidase inhibitors
Glifozins
Combination therapy
Most treatments for T2D can be used in combination when initial therapy fails or where symptoms are severe
However, there are some exceptions:
Sulphonylureas and meglitinides should not be combined due to risk of sustained hypoglycaemia
Thiazolidinediones should not be combined with long-acting insulin due to risk of peripheral oedema, weight gain and congestive heart failure
Insulin secretagogues should not be combined with rapid-acting pre-prandial insulin due to risk of severe acute hypoglycaemia
