Drug Treatment of Type 2 Diabetes

Question 1

Glucagon-like peptide-1 analogs

• Exenatide for example
  
  • Administered s.c. injection …-… mins before last meal of day
  • Facilitates glucose control by:
    
    • Augmenting … response
    • Suppresses pancreatic release of … helping stop the liver overproducing glucose
    • Slows down gastric …
    • Reduces … and promote … via hypothalamic receptors
    • Reduces liver … content

Answer 1

• Exenatide for example
  
  • Administered s.c. injection 30-60 mins before last meal of day
  • Facilitates glucose control by:
    
    • Augmenting pancreas response
    • Suppresses pancreatic release of glucagon helping stop the liver overproducing glucose
    • Slows down gastric emptying
    • Reduces appetite and promote satiety via hypothalamic receptors
    • Reduces liver fat content

Question 2

Insulin - Net Effect is what? (in what 3 types of cell/tissue?)

Answer 2

Net effect is to cause hypoglycemia and increase fuel storage in muscle, fat tissue and liver

Question 3

Thiazolidinediones - Glitazones

• … now only remaining approved
• It activates … proliferator-activated receptor-y (PPAR-y)
  
  • PPARs involved in … of insulin-responsive genes and in regulation of adipocyte … metabolism

Answer 3

• Pioglitazone now only remaining approved
• It activates peroxisome proliferator-activated receptor-y (PPAR-y)
• PPARs involved in transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism

Question 4

• Pioglitazone subject to interactions - why?
• May lower … … level containing ethinyl estradiol and norethindrone

Answer 4

• Due to liver metabolism
• May lower oral contraceptive levels containing ethinyl estradiol and norethindrone

Question 5

Insulin Action

• Insulin affects all major … pathways
  
  • carbohydrate, fat, protein
• Major target tissues are: (3)

Answer 5

• Insulin affects all major metabolic pathways
  
  • carbohydrate, fat, protein
• Major target tissues are:
  
  • Liver, adipose, and skeletal muscle

Question 6

Effects of SGLT2 inhibitors

• Inhibition of renal tubular Na+-glucose cotransporter -> reversal of hyperglycaemia -> reversal of “gluco…”
  
  • Increased Insulin … in muscle, increase GLUT… translocation, increased insulin signalling
  • Increased sensitivity in liver - decreased glucose-…-…
  • Decreased gluco… - decreased Cori cycle - decreased PEP carboykinase
  • Improved …cell function

Answer 6

• Inhibition of renal tubular Na+-glucose cotransporter -> reversal of hyperglycaemia -> reversal of “glucotoxicity”
  
  • Increased Insulin sensitivity in muscle, increase GLUT4 translocation, increased insulin signalling
  • Increased sensitivity in liver - decreased glucose-6-phosphatase
  • Decreased gluconeogenesis - decreased Cori cycle - decreased PEP carboykinase
  • Improved beta cell function

Question 7

How does glucose cause insulin release?

• Glucose in bloodstream - picked up by beta cell using GLUT-… transporter - glucose into beta cell - metabolised by … - increase ATP levels inside cell - inhibits ATP sensitive … channels - close them - potassium ions cannot leave cell - stuck inside - change voltage of cell - open voltage dependent calcium channels - calcium ions outside cell enter - contribute … charge to depolarise cell - also involved in … process - calcium ions cause insulin granules to move to plasma membrane - release insulin into bloodstream

Answer 7

Glucose in bloodstream - picked up by beta cell using GLUT-2 transporter - glucose into beta cell - metabolised by glycolysis - increase ATP levels inside cell - inhibits ATP sensitive potassium channels - close them - potassium ions cannot leave cell - stuck inside - change voltage of cell - open voltage dependent calcium channels - calcium ions outside cell enter - contribute positive charge to depolarise cell - also involved in exocytosis process - calcium ions cause insulin granules to move to plasma membrane - release insulin into bloodstream

Question 8

Sulphonylureas - T2 diabetes

• Examples include:
  
  • Gliclazide, glipizide, glimepride
• All are … active
• Are they bound to anything?

Answer 8

• Examples include:
  
  • Gliclazide, glipizide, glimepride
• All are orally active
• All bound to plasma protein (90-99%)

Question 9

Type 2 diabetes: treatment options

• Tackle …dysfunction:
  
  • ​Sulphonylureas, GLP-1 analogues, DDP-4 inhibitors (these … insulin release)
• … resistance reduction:
  
  • … and TZD’s
• … glucose absorption:
  
  • SGLT-2 inhibitors
• Loss of … mass:
  
  • Insulin replacement
• Lifestyle changes such as … and …, also treat underlying conditions such as … and … associated with T2 diabetes

Answer 9

• Tackle B-cell dysfunction:
  
  • ​Sulphonylureas, GLP-1 analogues, DDP-4 inhibitors (increase insulin release)
• Insulin resistance reduction:
  
  • Metformin and TZD’s
• Renal glucose absorption:
  
  • SGLT-2 inhibitors
• Loss of B-cell mass:
  
  • Insulin replacement
• Lifestyle changes such as exercise and diet, also treat underlying conditions such as obesity and dyslipidaemia associated with T2 diabetes

Question 10

Drugs that lower blood glucose levels in T2 diabetes are usually trying to mimic or enhance …

Answer 10

insulin

Question 11

Side effects of SGLT2 inhibitors

• Rapid weight … (Due to glycosuria (up to 70g/day))
• Tiredness
• Osmotic diuretic so …
• Can worsen … infections and …

Answer 11

• Rapid weight loss (Due to glycosuria (up to 70g/day))
• Tiredness
• Osmotic diuretic so dehydration
• Can worsen UTI and thrush

Question 12

Glitazones (Thiazolidinediones) can be used in …, but more commonly used with other anti diabetic medications

Answer 12

Glitazones (Thiazolidinediones) can be used in monotherapy, but more commonly used with other anti diabetic medications

Question 13

Give 2 examples of SGLT2 inhibitors

Answer 13

Dapagliflozin and Canagliflozin

Question 14

Dipeptidyl peptidase-4 (DPP-4) Inhibitors

• Oral … agents
• Mechanism of action is via increased levels of Incretins …-1 and G…
• Increased Incretins
  
  • Inhibit … release
  • Increase glucose-induced … secretion
  • Decrease gastric …
  • Reduce … glucose production
  • Improved … glucose utilisation

Answer 14

• Oral hypoglycemic agents
• Mechanism of action is via increased levels of Incretics GLP-1 and GIP
• Increased Incretins
  
  • Inhibit glucagon release
  • Increase glucose-induced insulin secretion
  • Decrease gastric emptying
  • Reduce hepatic glucose production
  • Improved peripheral glucose utilisation

Question 15

Glucagon-like peptide-1 analogs are an adjuvant therapy for type II diabetic on …, a …, …. or a combination of these drugs

Answer 15

Glucagon-like peptide-1 analogs are an adjuvant therapy for type II diabetic on metformin, a sulfonylurea, thiazolidinediones or a combination of these drugs

Question 16

SGLT2 Inhibitors

• Dapagliflozin
  
  • IC50 for SGLT2 is 1/… of the IC50 for SGLT1
• Canagliflozin
  
  • IC50 for SGLT2 is less than 1/… of the 1C50 for SGLT1
• Why is this important?

Answer 16

• Dapagliflozin
  
  • IC50 for SGLT2 is 1/1200 of the IC50 for SGLT1
• Canagliflozin
  
  • IC50 for SGLT2 is less than 1/160 of the 1C50 for SGLT1
• Important because it is specific for SGLT2 and will have very little effect on SGLT1

Question 17

Exenatide

• … plasma concentration
• Strong effects on …
• … only (So far)
• New … formulation in clinical trials - neutralizes the acid in local area protecting against breakdown while also enhancing absorption

Answer 17

• High plasma concentration
• Strong effects on receptors
• Injectables only (So far)
• New oral formulation in clinical trials - neutralizes the acid in local area protecting against breakdown while also enhancing absorption

Question 18

Gliclazide, glipizide, glimepride are examples of what class of drug?

Answer 18

Sulphonylureas

Question 19

Glitazone pharmacokinetics

• Pioglitazone: what is the daily dosage?
  
  • Plasma levels peak about … hr
  • Plasma half-life is …-… hr; active metabolites (t1/2 = …-… hr)
  • Liver metabolism and excreted in faeces (…/3) and urine (…/3)

Answer 19

• Pioglitazone: taken once or twice a day orally
• Plasma levels peak about 3 hr
• Plasma half-life is 3-7 hr; active metabolites (t1/2 = 16-24 hr)
• Liver metabolism and excreted in faeces (2/3) and urine (1/3)

Question 20

Pioglitazone is the only remaining approved …

Answer 20

Glitazones (thiazolidinediones)

Question 21

Metformin - mechanism of action

• The exact mechanism is unknown but does involve primarily suppression of hepatic glucose production through …
  
  • Inhibition of mitochondrial complex …
    
    • … ATP synthesis (… is an energy intensive process)
    • … AMP:ATP ratio inhibits fructose-1,6-bisphosphate
  • Activating …-activated protein kinase (AMPK)
    
    • AMPK increases expression of the nuclear transcription factor SHP which in turn … the expression of hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase

Answer 21

• The exact mechanism is unknown but does involve primarily suppression of hepatic glucose production through gluconeogenesis
  
  • Inhibition of mitochondrial complex I
    
    • Decrease ATP synthesis (gluconeogenesis is an energy intensive process)
    • Increase AMP:ATP ratio inhibits fructose-1,6-bisphosphate
  • Activating AMP-activated protein kinase (AMPK)
    
    • AMPK increases expression of the nuclear transcription factor SHP which in turn inhibits the expression of hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase

Question 22

Type 2 diabetes - A moving target

• As you get impaired glucose … which is increasing, for example in …, basal … glucose levels increase and also ones after your meal increase (known as …) - until a diagnosis of T2 diabetes

Answer 22

As you get impaired glucose tolerance which is increasing, for example in obesity, basal plasma glucose levels increase and also ones after your meal increase (known as postprandial) - until a diagnosis of T2 diabetes

Question 23

Insulin Effects - Muscle cells

• increases GLUT-… translocation to the membrane and hence increase … uptake, … oxidation, … synthesis, amino acid uptake, protein synthesis
• decreases …, amino acid …

Answer 23

• increases GLUT-4 translocation to the membrane and hence increase glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis
• decreases glycogenolysis, amino acid release

Question 24

Insulin Effects - Hepatic cells

• decreases gluco… ,glyco…, keto…, (increases … synthesis)

Answer 24

Hepatic cells

• decreases gluconeogenesis, glycogenolysis, ketogenesis, (increases glycogen synthesis)

Question 26

_Insulin Effects - Adipocytes_ • increase ... uptake, increase ... synthesis; decrease FFA (what is this?) and ... release

Answer 26

• increase **glucose** uptake, increase **triglyceride** synthesis; decrease **Free Fatty Acids** and **glycerol** release

Question 27

_How do Sulphonylureas work?_ * Inhibit ...-sensitive potassium channels - bind to site on these channels - close it - same effect of ATP - build up of K+ in cell - ... cell - opening of ... ... calcium channels - insulin release * Overall - they are ... beta cells and cause release of insulin ... of glucose - directly affect the channel to inhibit opening and increase intracellular levels of ...

Answer 27

* Inhibit **ATP**-sensitive potassium channels - bind to site on these channels - close it - same effect of ATP - build up of K+ in cell - **depolarise** cell - opening of **voltage** **gated** calcium channels - insulin release * Overall - they are **depolarising** beta cells and cause release of insulin **independently** of glucose - directly affect the channel to inhibit opening and increase intracellular levels of **potassium**

Question 28

_Glucagon-like peptide-1 analogs_ * What are they? How do they work?

Answer 28

* GLP-1’s (incretin mimetics) * This type of medication works by increasing the levels of hormones called ‘**incretins**’. These hormones help the body produce more insulin only when needed and reduce the amount of glucose being produced by the liver when it’s not needed.

Question 29

_Metformin - oral antihyperglycemic_ * Differ from ... and meglitinides both chemically and in mechanism of action * Biguanides do not stimulate ...release or cause ... * Biguanides appear to increase glucose uptake in ... and decrease glucose production by ...

Answer 29

* Differ from **sulfonylureas** and meglitinides both chemically and in mechanism of action * Biguanides do not stimulate **insulin** release or cause **hypoglycemia** * Biguanides appear to increase glucose uptake in **muscle** and decrease glucose production by **liver**

Question 30

_Glucagon-like peptide-1 vs Glucagon-like peptide-1 analogs (Exenatide)_ * Identical in almost all of the effects except duration in plasma following sc injection (what is it for each?) and whether it is resistant to DPP-IV degradation (which one is?)

Answer 30

* Identical in almost all of the effects except duration in plasma following sc injection **(GLP-1 has a short duration, Exendatide has a long duration (analog))** and whether it is resistant to DPP-IV degradation **(GLP-1 analog - Exenatide is resistant)**

Question 31

_Metformin contraindications_ * ... disease * Past history of lactic ... (any cause) * ... failure * Chronic ... lung disease * Causes metabolic ...

Answer 31

* **Hepatic** disease * Past history of **lactic acidosis** (any cause) * **Cardiac** failure * Chronic **hypoxic** lung disease * Causes metabolic **acidosis**

Question 32

Biguanides are a type of medication used to treat what?

Answer 32

Treat T2 Diabetes (Metformin)

Question 33

_Adverse effects and drug interactions_ * Glitazones * ...retention (promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts) causing ..., mild ... * Dose-related weight ... * Safety in ... and ... not determined * Do not cause lactic ..., even in patients with renal impairment * Liver ... may require regular blood tests

Answer 33

* Glitazones * **Fluid** retention (promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts) causing **oedema**, **mild anaemia** * Dose-related weight **gain** * Safety in **pregnancy** and **lactation** not determined * Do not cause lactic **acidosis**, even in patients with renal impairment * Liver **damage** may require regular blood tests

Question 34

* Non diabetic patients - insulin sensitive or not? * Type 2 diabetes - insulin sensitive or not?

Answer 34

* **Non diabetic - very insulin sensitive** - beta cells don't produce much as they don't need to be that high to lower BG levels * **Impaired glucose tolerance - normally associated with obesity - insulin sensitivity decreases** - body increases insulin concentration - T2 diabetes - tackle with exercise, weight and drugs - can eventually get beta cell failure - end up on insulin as beta cells do not function to produce enough insulin to lower BG levels

Question 35

_Glucagon Like Peptide (GLP) -1_ * Do they increase glucose-dependent insulin secretion? * Decrease glucagon secretion and hepatic glucose output? * Regulates gastric emptying and decrease rate of nutrient absorption? * Decrease food intake? * Decrease plasma glucose acutely to near-normal levels? * Resistant to DPP-IV degradation? * Duration in plasma is ...

Answer 35

* Do they increase glucose-dependent insulin secretion? **- yes** * Decrease glucagon secretion and hepatic glucose output? **- yes** * Regulates gastric emptying and decrease rate of nutrient absorption? **- yes** * Decrease food intake? **- yes** * Decrease plasma glucose acutely to near-normal levels? **- yes** * Resistant to DPP-IV degradation? **- no** * Duration in plasma is **short**

Question 36

_Treating T2 diabetes - overview_ ​

Answer 36

* Initially - diagnosis * Increase physical activity, weight control, diabetic education, healthy eating * Pharmacological intervention - gold standard drug - metformin - target HbA1c levels - 3 months monotherapy - failure = dual therapy - consider what you go for - dependent on patient * Usually dual therapy with one of 5 options before using insulin * If dual therapy does not work - try triple therapy * Not working - start considering injectable therapy

Question 37

_Pharmacodynamics of Sulphonylureas_ * Primary mechanism of action * Stimulates ... ... release * Binding site on ATP-sensitive ...-channel to inhibiting the opening of the channel similar to ATP * Secondary mechanisms of action * Evidence these drugs: * Sensitize ...-cells to glucose * Decrease lipo... * Decrease ... of insulin by the liver

Answer 37

* Primary mechanism of action * Stimulates **endogenous** **insulin** release * Binding site on ATP-sensitive **K**-channel * Secondary mechanisms of action * Evidence these drugs: * Sensitize **B**-cells to glucose * Decrease **lipolysis** * Decrease **clearance** of insulin by the liver

Question 38

In presence of endogenous or exogenous insulin glitazones will: * Decrease gluconeogenesis, glucose output, and triglyceride production in ... * Increase glucose uptake and utilization in ... muscle * Increase glucose uptake and decrease fatty acid output in ... ... * Cause differentiation of ...

Answer 38

* Decrease gluconeogenesis, glucose output, and triglyceride production in **liver** * Increase glucose uptake and utilization in **skeletal** muscle * Increase glucose uptake and decrease fatty acid output in **adipose tissue** * Cause differentiation of **adipocytes**

Question 39

_Therapeutic uses of sulphonylureas_ * Useful in Type-2 Diabetes * Can be used in combination with other anti-diabetic drugs * Major side effect: Hypoglycemia * Drug interaction: * Potentiate * Allopurinol * Aspirin * Alcohol * Decrease glucose tolerance * Oral contraceptives * Corticosteroids

Question 40

Side effects of glucagon-like peptide-1 analogs are mainly ... in nature including ... (4)

Answer 40

Side effects of glucagon-like peptide-1 analogs are mainly **gastrointestinal** in nature including **acid or sour stomach, belching, diarrhea, heartburn etc**

Question 41

_Metformin - secondary mechanisms of action_ * Increases insulin ... * Possibly through improved insulin binding to insulin receptors * Enhances peripheral glucose uptake * Increased GLUT ... translocation through AMPK * ... muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK * Increases fatty acid ... via decreasing insulin-induced suppression of fatty acid ... * Decreases glucose absorption from ...

Answer 41

* Increases insulin **sensitivity** * Possibly through improved insulin binding to insulin receptors * Enhances peripheral glucose uptake * Increased GLUT **4** translocation through AMPK * **Heart** muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK * Increases fatty acid **oxidation** via decreasing insulin-induced suppression of fatty acid **oxidation** * Decreases glucose absorption from **GI tract**

Question 42

_Sodium-glucose transporter (SGLT) protein inhibitors_ * SGLT1 found in ... intestine (to absorb glucose) and proxmal ... tubule of the nephron * SGLT2 found in proximal ... tubule * 100% of glucose has to be reabsorbed along the nephron, 90% by SGLT... * Therefore blocking this transporter does what?

Answer 42

* SGLT1 found in **small** intestine (to absorb glucose) and proximal **straight** tubule of the nephron * SGLT2 found in proximal **convoluted** tubule * 100% of glucose has to be reabsorbed along the nephron, 90% by **SGLT2** * Therefore blocking this transporter **causes blood glucose to be eliminated through the kidney**

Question 43

_Adverse effects and toxicity of biguanides_ * Metformin produces ... ... only rarely * More frequent in patients with ... impairment * More common side effects include ... (5) * Vitamin ... and fo... absorption decreased with chronic metformin * Myocardial infarction or septicemia mandate immediate stoppage - why?

Answer 43

* Metformin produces **lactic acidemia** only rarely * More frequent in patients with **renal** impairment * **Nausea, abdominal discomfort, diarrhea, metallic taste, anorexia more common** * Vitamin **B12** and **folate** absorption decreased with chronic metformin * Myocardial infarction or septicemia mandate immediate stoppage **(associated renal dysfunction)**

Question 44

_DPP IV inhibitors_ * Drugs in this class include ...gliptin (Reversible), ...gliptin (Reversible) and ...gliptin (covalently bound) * ... active * Side effects? * Modest elevations of ... * Weight ..., no ... side effects

Answer 44

* Drugs in this class include **vildagliptin** (Reversible), **sitagliptin** (Reversible) and **savagliptin** (covalently bound) * **Orally** active * **Few side effects** * Modest elevations of **incretins** * Weight **neutral**, no **GI** side effects

Question 45

_Properties of Metformin_ * ... active * Does not bind plasma ... * Excreted unchanged in ... * Half-life ...-... hr * Often combined in a single pill with what? * Also used for ... ... syndrome

Answer 45

* **Orally** active * Does not bind plasma **proteins** * Excreted unchanged in **urine** * Half-life **1.3-4.5** hr * Often combined in a single pill **with other anti-diabetic medications** * Also used for **polycystic ovary** syndrome