Diabetes mellitus 2 (Block 5) Flashcards by Daisy-Kate Jackson

Prevalence of Type 2 diabetes

Most common form (90%)
Increased 9-fold in the past 30 years
Strongly linked to prevalence of obesity
Usually presents in 40+ year olds

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Acute consequences of T2D

Thirst and excess urine production
Blurred vision
Weight loss
Fatigue
Itching (thrush infections)

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Chronic consequences of T2D

Cardiovascular disease
Kidney disease
Eye problems
Peripheral neuropathy
Poor peripheral circulation leading to lower limb amputation

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Treatment of T2D (BROADEST strokes)

Can be managed by diet and exercised but eventually drug therapy is required
Insulin replacement isn’t first line treatment

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By how much can T2D reduce life expectancy?

10 years

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What type of disorder is T2D?

Metabolic

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Mechanisms of T2D

Inadequate secretion or reduced efficacy of insulin or combination of both
Increased release of glucose (+ve feedback mechanism of glucose = not safe)

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Links of T2D

Link to obesity (mechanisms unclear)
Potential genetic predisposition (lots of genes, each with small effect)
Strong influence of ethnicity

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Biguanides compounds - main effects

Reduction in hepatic glucose synthesis (gluconeogenesis)
Increase in glucose uptake into skeletal muscle

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Biguanides compounds - additional effects

Reduces absorption of carbohydrate
Increases oxidation of fatty acids
Reduces circulating levels of LDL and VLDL

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Only biguanide compound in use

Metformin

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Metformin

1st line treatment in most new cases of T2D

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Metformin - mechanism of action

Activation of AMP-kinase in hepatic cells
Reduced expression of genes involved in gluconeogenesis

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Advantages of metformin

no weight gain, low risk of hypoglycaemia

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Adverse effects of metformin

gastrointestinal disturbances, risk of lactic acidosis gastrointestinal disturbances, risk of lactic acidosis

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Who is metformin NOT given to?

Patients with liver and/or kidney disease

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Sulphonylureas compounds

First widely used oral anti-diabetic agents
Considered to be secretagogues, meaning they enhance insulin secretion from beta cells

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Main sulphonylureas

Tolbutamide
Glibenclamide
Glipizide

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Main mechanism of action of sulphylureas

Concentration-dependent block of ATP-sensitive K+ channel (Kir6.2)
Depolarisation of β-cell membrane
Influx of Ca2+ via L-type channels
Enhanced release of insulin from vesicular stores

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When are Sulphonyureas useful?

When there is strong insulin resistance
Functional beta cells

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Sulphonylureas - Tolbutamide

Fast acting
Short duration
Low potency

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Sulphonylureas - Glibenclamide

Slow acting
Long duration
High potency

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Sulphonylureas - Glipizide

Medium acting
Long duration
Moderate potency

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Sulphonylureas - adverse effects

Hypoglycaemia (depending on PK)
Weight gain
Potential beta cell exhaustion (?? They’re trying to work this one out)

Meglitinides compounds

Considered secretogues, different chemical structure to sulphylureas but same mechanism + more potent and more selective Raping acting and short duration; taken orally prior to a meal to reduce post-prandial rise in blood glucose

Meglitinides example compounds

Repaglinide Nateglinide

Advantages of Meglitinides

Low risk of hypoglycaemia No weight gain

Thiazolinediones (TZDs)

Considered sensitising agents; improve insulin resistance

TZDs - main effects

Reduced hepatic glucose output Increased glucose uptake into skeletal muscle by enhancing effectiveness of endogenous insulin

TZDs - additional effects

reduced serum insulin and fatty acid levels, decline in triglycerides, slight increase in LDL and HDL.

TZDs - examples

Rogislitazone Pioglitazone

Disadvantage of TZDs

Maximum effects only achieved after one month

How do TZDs work?

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists Complexes with another nuclear receptor (retinoid X receptor) Altered expression of multiple genes

Advantage of TZDs

Low risk of hypoglycaemia

Adverse effects of TZDs

risk of heart failure, weight gain, oedema, expensive

Why was rosiglitazone withdrawn?

Heart and liver problems

What does pioglitazone elevate risks of?

Bladder cancer Bone fractures in women

Alpha-glucosidase inhibitors

Inhibitors of alpha-glucosidase enzyme in gut, delay carbohydrate absorption, reduce post-prandial increase in blood glucose No direct effect on insulin secretion or sensitivity Only effective when insulin secretion / sensitivity is marginally impaired

Alpha-glucosidase inhibitors - main examples

Acarbose Miglitol

Adverse effects of Alpha-glucosidase inhibitors

Diarrhoea Flatulence Abdominal cramps

Incretin hormones

Metabolic hormones produced in the GI tract, eg Glucagon-like peptide 1 (GLP-1) and Glucagon-like insulinotropic peptide (GIP)

GLP-1

22 AA peptide secreted by epithelial cells throughout GI tract

GIP

42 AA peptide secreted by epithelial cells throughout GI tract

Function of GIP and GLP-1

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

Gliptins

Competitive inhibitors of dipeptidylpeptidase-4 (DPP-4); responsible for metabolism of GLP-1 and GIP

Mechanism of Gliptins (how d they reduce blood glucose?)

Inhibiting metabolism of incretins, decrease in glucagon release, increase in insulin release

Advantages of Gliptins

Well-tolerated Little to no hypoglycaemia No weight gain

Main example compounds of Gliptins

Sitagliptin Vildagliptin Saxagliptin

GLP-1 receptor agonists

Mimic the action of GLP-1 in pancreas and brain; longer-acting than GLP-1 Increase insulin release from β-cells; reduce glucagon release from alpha-cells Slow gastric emptying; promote satiety Degraded in GI tract, admin by s.c. injection

Mai example compounds of GLP-1 receptor agonists

Exenatide Liraglutide Lixisenatide

Advantages of GLP-1 receptor agonists

Well-tolerated Little hypoglycaemia

Adverse effects of GLP-1 receptor agonists

Significant weight loss (up to 8kg)

What can GLP-1 receptor agonists be given in conjunction with?

Insulin; optimises control, limits insulin does, and reduces likelihood of weight gain

Glifozins

Block the sodium-glucose co-transporter 2 (SGLT2) on proximal convoluted tubule of nephron

SLGLT2

Responsible for reabsorption of 90% of glucose from urinary filtrate

What does the inhibition of SGLT2 cause?

Significant excretion of plasma glucose -> blood glucose levels decrease

Advantages of Glifozins

Well-tolerated No hypoglycaemia Only moderate weight loss May also be useful in T1D

Main example compounds of Glifozins

Dapagliflozin Canaglifozin Empaglifozin

Uses of insulin in T2D

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