LT5 Second line drugs for T2D and obesity

Question 1

What are the established ORAL hypoglycaemic agents?

Answer 1

Sulphonylureas
Incretins
Meglitinides
TZD
Acarbose

Question 2

What do SU end in?

Answer 2

-ide

Question 3

What do SU structure have in common?

Answer 3

All sulphonylurea class of drugs contrain a central S-arylsulphonylurea structure with a p-substituent on the phenyl ring and alternative groups terminating the urea N end group

Gives a variety of pharmacological properties

Question 4

What is the mechanism of action for sulphonylureas?

Answer 4

SUs bind to SUR1 subunit of the K_ATP channel

This binding inhibits K_ATP channel = allowing depolarization of the beta-cell

Causing Ca2+ influx and thus vesicle secretion

SUs mimck the action of ATP

Question 5

How were sulphonylureas discovered?

Answer 5

People were looking for anti-bacterial drugs

SUs were a derivative but had little anti-bacterial efficacy

Reserachers notived animals that were dosed with them became hypoglycaemic

Question 6

When will SUs not work?

Answer 6

SUs only work if there are functional beta-cells that can release insulin

They will not work in T1D

Question 7

How are meglitinides different to sulphonylureas?

Answer 7

They have faster onset and shorter duration of action than SUs because they ahve a weaker binding efficiency and faster dissociation constant

Typically taken just before a meal to control postprandial (after meal) blood glucose spikes

Question 8

What is the mechanism of action of Meglitinides?

Answer 8

Same mechanism to SUs

Binds to the allosteric site on SUR1 of the K_ATP channel

Question 9

What are the problems with sulphonylureas?

Answer 9

Not very potent on their own = only small decrease in HbA1c

Cause weight gain (like insulin)

Risk of hypoglycaemia because not glucose-dependent

Only work if beta-cells are functioning (not in T1D)

May enhance beta-cell dailure due to extra strain of chronic insulin production

Question 10

What are the problems with Meglitinides?

Answer 10

Similar side effects to SUs but seem to cause less weight gain and have lower risk fo hypoglycaemia compared to SUs

Weaker side effects probably due to fast acting response and their rapid degradation

Question 11

Why would Meglitinides need to be used if they are almost the same as SUs?

Answer 11

Used in patients with allergy to sulphur contianing drugs

Or that have side effects with SUs

Question 12

What is another name for TZD?

Answer 12

Thiazolidinediones

or Glitazones

Question 13

What do TZD/glitazones do?

Answer 13

Induce glucose and fatty acid uptake into fat cells

While in obese mice they promoted dramatic glucose lowering

Question 14

What is the mechanism of action of TZD/glitazones?

Answer 14

TZD bind PPAR-Υ (transcription factor)

Regulates the transcriptio nof may genes involved in lipid and carbohydrate metabolism

Results in increased lipogenesis and glucose uptake in fat, liver and muscle

With some reduction in glucose production in liver

Question 15

Why is it good that TZD/glitazones cause adipose proliferation?

Answer 15

Helps store nutrients in adipose, instead of elsewhere

Question 16

Where is PPAR-Y predominantly found?

Answer 16

Adipose

But some expression in liver and muscle

Question 17

What other mechanism have been propsed for TZD/glitazones?

Answer 17

Activation of AMPK and modulation of mitochondria (like Metformin)

Question 18

What are the problems with TZD/glitazones?

Answer 18

First TZD ws withdrawn due to heptaotoxicity (LIVER issues)

Often used in combination with SUs so hypoglycaemia risk is increased

Increased incidence of heart failure in chronically treated patients
5% of patients experience oedema

Very EXPENSIVE

Question 19

Name the two TZD/glitazones being used?

Answer 19

Tosiglitazone is being phased out

Pioglitazone is only one used in UK in new patients

Question 20

What is Acarbose?

Answer 20

alpha-glucosidase inhibitor

alpha-glucosidase = a membrane-bound enzyme primarily found in the small intestine’s brush border, responsible for breaking down complex carbohydrates (like starch and disaccharides) into simpler sugars like glucose for absorption

Inhibiting this enzyme reduces glucose absorption and postprandial blood sugar spikes, used in the treatment of diabetes.

Question 21

What is the mechanism of action of Acarbose?

Answer 21

Competitive inhibition of alpha-glucosidase

Stops enzyme form breaking down copmlex carbs = less glucose released

Slows carbohydrate digestion and absorption

Question 22

What is the problem with Acarbose?

Answer 22

Reduced rate of digestion of polysaccharides in proximal small intesine

Reduced HbA1c very small

No weight alteraitons though!

Frequent GI side effects = increased gas production

3 times a day dosing = after every meal

EXPENSIVE

Question 23

Is Acabose a good drug?

Answer 23

Minimal health benefits

Major GI side effects

Really only used if patients have serious difficulty in reducing calorie intake

Question 24

What are the two more recent hypoglycaemia agents?

Answer 24

Incretins (incretin modulating drugs)

SGLT2 inhibitors

Question 25

Name the two incretins

Answer 25

Gastric inhibitory polypeptide (GIP) Glucagon-like peptide-1 (GLP-1)

Question 26

Why are the half-lives of incretins too short for clinical use?

Answer 26

Because these peptides are normally rapidly degraded in blood by DPP4 So used DPP4 inhibitors and more stable GLP-1 peptide mimetics

Question 27

What are the advantages of incretins?

Answer 27

Beneficial effects on satiety and gastric emptying (not just pancreas targeting) Only act in the presence of glucose = so lower risk of hypoglycaemia

Question 28

When is GLP-1 secretion triggered?

Answer 28

When food is ingested GLP-1 is secreted from intestinal L-cells

Question 29

Where does GLP-1 act in humans?

Answer 29

Beta-cells = enhances glucose-dependent insulin secretion in pancreas Alpha-cells = suppresses post-prandial glucagon secretion Liver = reduces HGP Stomach = slows rate of gatric emptying Brain = promotes satiety and reduces appetite

Question 30

Where are the two SGLT found?

Answer 30

SGLT2 is located in segment1 of proximal tubule SLGT1 is located in distal segment 2/3 of primal tubuil (decending into Loop of Henlee)

Question 31

What is the mechanism of action of SGLT2 inhibitors?

Answer 31

Glucose pass from bloodstream into nephron SGLT2 normall reabsorbs glucose from nephron back into bloodstream Inhibitors block SGLT2 reabsorbing glucose Glucose is excreted in the urine ad blood glucose decreases

Question 32

What are the (dis)advantages of SGLT2 inhibitors?

Answer 32

Result in more glucose being excreted in urine (weight control) Lowers blod glucose = independent of insulin so low risk of hypoglycaemia Only a few issues of UTI in the clinical trials = good

Question 33

What are the names of SGLT2 inhibitors?

Answer 33

-flozins

Question 34

What other systems can SGLT2 inhibitors impact?

Answer 34

More than just glucose transport Reduced adverse cardiac event end point by 14% Thi sis unlikely to be due to simple glucose lowering (as metformin does not have same effect with same glucose lower) Haemodynamic effects = specifically reduced blood pressure and decreased extracellular volume Potential to benefit kidneys as well

Question 35

Hearing about this SGLT2 inhibitors beneficial effect on CV death, what did NICE say?

Answer 35

SGLT2 inhibitors can now be considered a first like therapy option if Metformin is contraindicated or cannot be tolerated BUT increased reptorts of diabetic ketoacidosis in people taking any of currently available SGLT2 inhibitors

Question 36

What are the last resort drugs?

Answer 36

Insulin because it has such a narrow therapeutic window (only used if oral agents lose efficacy) Acarbose because it has such bad side effects for so little benefit

Question 37

What needs future research?

Answer 37

Develop drugs to replace, improve or mimic insulin action Need to bypass the issue of INSULIN RESISTANCE

Question 38

What is always consdiere a first option in treatment and prevention of T2D?

Answer 38

LIFESTYLE changes

Question 39

Why is targeting obesity important for T2D prevention?*** [potential essay question]

Question 40

How can we prevent/trat obesity-diabetes?

Answer 40

Lifestyle changes = total diet replacement Psychological therapies = cognitive behavioural therapy (not able to deliver on mass scale bc expensive) Bariatric surgery = effective but risk (limited to surgeon/theatre availability) Therapeutic agents to reduce body weight = decrease consumption/absorption of food and/or increase energy expenditure

Question 41

What do noradrenergics do?

Answer 41

Appetite supressant Inhibit noradrenaline uptake CV side effects = short term use

Question 42

What do serotonergics do?

Answer 42

Appretite supresant Act on Serotonin uptake and release Induced heart disease = no longer prescribed in US and UK

Question 43

What is fen-phen?

Answer 43

Combination of a noradrenergic and a serotonergic appetite supressant Very effective BUT causes potentialy fatal pulmonary hypertension and heart valve problems FDA withdrew it in 1997

Question 44

What do sibutramines do?

Answer 44

Appetite suppresants Selectively inhibit re-uptake or NorA, serotonin and dopamine Decreases food intake and may also increase themogenesis Modest weight loss (4.5kg in 1 year) Major side effects = cardiovascular events and strokes Withdrawn

Question 45

What do Rimonabants do?

Answer 45

Appretite suppresant Antagonist of CB1 receptors = high levels in the hypothalamus Useful to counteract obesity and potential effectiveness against addition (smoking, drugs, etc) Improve short-term memory Serious psychiatric side effects = severe depresion and anxiety Withdrawn

Question 46

What does Lorcaserin do?

Answer 46

Appetite suppressants Agonist at 5HT2c receptors (serotonergics act on 5HT2b) Inferior weight loss efficacy compared to Rimoonabant or subutramine Heart valve problems and increased cancer = withdrawn

Question 47

What does Qsymia do?

Answer 47

Appretite suppresant Combination therapy Weight loss in obese rats = better than sibutramine or rimonabant Rejected by EMA

Question 48

What does Contrave do?

Answer 48

Appreitite suppressant Bupropion = dopamine reuptake inhibitor also activates POMC neurones Naltrexone = opiod antagonist acts to usppress POMC inhibition Together = may reduce cravings via reward pathway CV side effects

Question 49

What was the first drug for obesity treatment that was aproved?

Answer 49

Liraglutaide = GLP-1 RA GLP-1 = satiety peptide Higher doses than used for diabetes produces significant weight loss 2014 = approved by FDA Mechanism for anti-obesity action unclear Some concerns remain regarding increased risk of thyroid and pancreatic cancer

Question 50

What is the name of the dual incretin agonist?

Answer 50

Mounjaro/Tirsepatide

Question 51

What is GIP responsible for?

Answer 51

Main incretin hormone in HEALTHY people = responsible for most incretin effects Insulin response after GIP secretion in T2D = strongly REDUCED So GIP nor as good as diabetes target

Question 52

Who is Mounjaro (GLP1-RA) given to?

Answer 52

High BMI people with weight-related health problems such as, Pre diabetes High bp High cholesterol Heart problems

Question 53

Why is it an issue to give GLP-1 receptor agonists?

Answer 53

This medicine is meant to be used together with a reduced-calorie diet and increase physical actiivity If they come off the drug and don't change lifestyle habits = then will just put the weight back on OR will have to take the drug forever, not being able to enjoy food because of the reduced appetite

Question 54

What is the target weight loss where health benefits are seen?

Answer 54

Health benefits are seen starting at 5% body weight reduction

Question 55

What are the current issues with GLP-1 receptor agonists?

Answer 55

They are still very expensive = could bankrupt the NHS Evidence suggets when stop treatment = weight comes back Side effects still unclear = evidence of MALNUTRITION if sustained treatment but not proper nutrition They are injections = self-administraiton is more difficult

Question 56

What paradox was seen with GIP?

Answer 56

BOTH GIPR agonists and antagonists worked on the receptor to reduce hyperglycaemia, when combined with GLP-1RA = could be T2D treatment Both enhanced GLP-1 action on glucose control and weight loss

Question 57

What does Orlistat do?

Answer 57

Inhibits pancreatic lipase = decreases triglyceride absorption Reduction efficiency of fat adsorption in small intestine Side effects = cramping, bloating, flatulence, abdominal pain an ddiarrhoea

Question 58

What do you need to take alongside Orlistat?

Answer 58

Vitamine supplements because losing fat soluble vitamins

Question 59

Why is Orlistat not really worth it?

Answer 59

Because not very effective over long-term = 3kg in 1 year And then tend to reboud weight after

Question 60

What are the 3 type of bariatric surgery?

Answer 60

Adjustable gastric band = band limits food entry to stomach Roux-en-Y gastric bypass = (accelerates GI transit of food) re-route, bypassing most of stomach an dpart of small intestine Vertical sleeve gastrectomy = reduces size of stromach (lowering food intake and gastric emptying increases)

Question 61

Overall effect of bariatric surgery?

Answer 61

Substantial weight loss in 1 year = 50%-60% Increased satiety and reduced hunger So very effective against obesity and T2D Improves glucose homeostasis and insulin sensitivity before wieght loss occurs

Question 62

What are potential mechanisms happen in bariatric surgery to cause glucose control (happens before weight loss)?

Answer 62

Altered GI physiology Marked increase in GLP-1 after most surgeries Pancreatic beta-cell function improves (possibly because of GLP-1) Changes in adipokine levels Change on gut microbiota in rodents and human

Question 63

What is the "thrifty genotype"?

Answer 63

Certain genetic traits were beneficial for survival in ancient human populations have become deterimental in modern society Specifically genes promoting efficient storage of fat and glucose = helped humans survive during periods of food scarcity These same genetic traits may predispose individuals to metabolic disorders

Question 64

What are variants in the FTO gene associated with?

Answer 64

FTO (fat mass and obesity-associated) gene Genetic variants in the FTO gene have been strongly associated with increased body mass index (BMI) and a higher risk of obesity.

Question 65

What are adipokines?

Answer 65

Signalling proteins/peptides secretd by adipose tissue Regulate funciton i nmost major organs = metbolism, satiety and nutrient homeostasis

Question 66

What are some of the best studied adipokines?

Answer 66

Apelin RBP4 Leptin Adiponectin TNF-a IL-6 PAI-1

Question 67

What occurs in obesity to adipokines?

Answer 67

Altered production of adipokines Higher levels of leptin and leptin resistance in obesity = contributes to hunger pangs Low levels of adiponectin in obesity = this molecule is anti-diabetic and anti-CVD

Question 68

What drug was proposed to reverse leptin resistance?

Answer 68

Celastrol

Question 69

How does Celastrol potentially increase leptin sensitivity?

Answer 69

Celastrol enhances leptin sensitivity in the HYPOTHALAMUS Inhibits leptin-negative regulators like PTP1B and TCPTP in the hypothalamus Potentially stimulating fat consumption and reducing ER stress, which is a key factor in leptin resistance

Question 70

Why does Celastrol have no effect in ob/ob and db/db mice?

Answer 70

Since ob/ob and db/db mice either lack leptin or cannot respond to it, their leptin signaling pathways are dysfunctional. Celastrol is believed to work, in part, by activating leptin signaling and influencing the hypothalamus to reduce food intake and increase energy expenditure. It also has anti-inflammatory properties and may modulate other metabolic pathways that help regulate body weight and inflammation.

Question 71

What is wrong with Celastrol?

Answer 71

Toxicity is still an issue

Question 72

What is an alternative to calorie restriction?

Answer 72

Targeting energy expenditure

Question 73

Equation for energy expendiure

Answer 73

Energy expenditure = heat produced + work done

Question 74

What 3 things cause energy expenditure?

Answer 74

Metabolism = obligatory energy expenditure Physical activity Adaptive thermogenesis

Question 75

Define adaptive thermogenesis

Answer 75

Heat production by organism in response to change in the environmental temperature or diet

Question 76

Where does adaptive thermogenesis occur?

Answer 76

Brown adipose tissue and skeletal muscle

Question 77

What induces adaptive thermogenesis?

Answer 77

Cold-induced = shivering (skeletal muscle) or non-shivering (brown fat) Diet-induced = feeding increases energy expenditure (brown fat)

Question 78

What is the best described mechanism for adaptive thermogenesis?

Answer 78

In mammals = uncoupled ATP production VIa uncoupling protein 1 (UCP1)

Question 79

Why is ATP production not 100% efficient?

Answer 79

Because of proton leak = reduces amount of ATP produced and dissipates free energy as heat (e.g during exercise)

Question 80

How does uncoupling work in brown adipose tissue (BAT)?

Answer 80

Regulated proton leak in BAT by UCP1 = inner mitochondrial transmembrane protein Allows proton to re-enter mitochondrial matrix from intermembrane space = short circuit proton gradient So no generate of ATP Heat is generated by proton movement and there is increased flux through ETC

Question 81

What activates UCP1 in brown adipose tissue?

Answer 81

Long chain fatty acids when broken down by beta-oxidation Cold exposure or overfeeding → sympathetic nervous system activation → norepinephrine release. This activates β3-adrenergic receptors in brown fat → lipolysis. Lipolysis releases LCFAs from stored triglycerides, which: Fuel β-oxidation for electron transport Activate UCP1 to enable proton leak and heat production

Question 82

What is the primary function of adaptive thermogenesis in BAT?

Answer 82

Generate body heat in animals or newborns that do not shiver

Question 83

What happens when BAT and UCP1 are 'removed'?

Answer 83

Induces obesity primarily because it impairs adaptive thermogenesis, reducing energy expenditure, especially in response to cold, high-fat diets, or overnutrition.

Question 84

Can uncoupling be a therapeutic target?***

Answer 84

Yes, but DNP was not safe because produced hyperthermia So perhaps lower DNP dose Research these 3 drugs for uncoupling??? SkQ compounds MitoQ BAM15