14. Drug treatment of type 2 diabetes

Question 1

Insulin action

Answer 1

Affects all major metabolic pathways - carbohydrate, fat, protein
Major target tissues are liver, adipose and skeletal muscle

Question 2

Insulin effects on hepatic cells

Answer 2

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

Question 3

insulin effects on muscle cells

Answer 3

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 4

insulin effects on adipocytes

Answer 4

increase glucose uptake, increase triglyceride synthesis; decrease FFA and glycerol release

Question 5

Net effect of insulin

Answer 5

causes hypoglycemia and increase fuel storage in muscle, fat tissue and liver

Question 6

Treatments

Answer 6

Diet, exercise, treatments for obesity and dyslipidaemia

Metformin and TZDs for insulin resistance

SGLT-2 inhibitors to block renal glucose absorption

GLP-1 analogues and DDP-4 inhibitors for beta-cell dysfunction

insulin replacement for loss of beta-cell mass

Question 7

Describe sulfonylureas

Answer 7

E.g. gliclazide, glipizide, glimepiride
All orally active
All bound to plasma protein (90-99%)

Cause release of insulin

Question 8

Pharmacodynamics of sulfonylureas

Answer 8

Primary mechanism of action
	• stimulates endogenous insulin release
	• binding site on ATP-sensitive K-channel to inhibiting the opening of the channel similar to ATP
Secondary mechanisms of actions
Evidence these drugs :
	• Sensitize ß-cells to glucose
	• Decrease lipolysis
Decrease clearance of insulin by the liver

Question 9

Therapeutic uses of sulfonylureas

Answer 9

Useful in Type-2 DM only
best patient is
• over 40 yrs. Old
• DM duration less than 10 yrs.
• daily insulin (if taking) less than 40 units
can be used in combination with other anti-diabetic drugs
Major side effect: Hypoglycaemia

Question 10

What is the golden standard drug for type 2 diabetes?

Answer 10

Metformin

Question 11

How are biguanides different from sulfonylureas?

Answer 11

Differ from sulfonylureas 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 12

What is the primary mechanism of action of biguanide drugs (metformin)?

Answer 12

AMPK part of second messenger system of insulin. Metformin is bypassing insulin by activating AMPK directly or bypassing AMPK-independent insulin pathways in hepatocytes.

AMPK then increases expression of SHP, a nuclear transcription factor, which then turns off expression of PEPCK and G6Pase involved in hepatic gluconeogenesis

Question 13

How does metformin enhance peripheral glucose uptake?

Answer 13

Increased GLUT 4 translocation through AMPK

Heart muscle metabolic changes by p38 MAPCK and PKC-dependent mechanisms and independent of AMPK

Question 14

What are some other non-primary mechanisms of metformin?

Answer 14

Increases insulin sensitivity
(Possibly through improved insulin binding to insulin receptors)

Enhances peripheral glucose uptake

Increases fatty acid oxidation via decreasing insulin-induced suppression of fatty acid oxidation

Decreases glucose absorption from GI tract (minor)

Question 15

What are the properties of metformin?

Answer 15

• orally active
• does not bind plasma proteins
• excreted unchanged in urine
• half-life 1.3 - 4.5 h
• often combined in a single pill with other anti-diabetic medications
• also used for polycystic ovary syndrome

Question 16

Adverse effects and toxicity of biguanides

Answer 16

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 17

Contraindications for metformin

Answer 17

hepatic disease
 past history of lactic acidosis (any cause)
 cardiac failure
 chronic hypoxic lung disease 
 causes metabolic acidosis

Question 18

Describe thiazolidinediones

Answer 18

Troglitazone was first ‘glitazone’ approved for use in NIDDM; off the market now due to hepatic failures.

Rosiglitazone now off the market due to CVS damage

Pioglitazone now only one remaining approved

Activate peroxisome proliferator-activated receptor-g (PPARg)

PPARs involved in transcription of insulin-responsive genes and in regulation of adipocyte lipid metabolism

Question 19

Glitazone pharmacodynamics

Answer 19

In presence of endogenous or exogenous insulin glitazones will:

• 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

monotherapy or with other anti-diabetic medications

Question 20

Adverse reactions and drug interactions of glitazone

Answer 20

Glitazones
-fluid retention (promotes amiloride-sensitive sodium ion reabsorption in renal collecting ducts) causing, edema, mild anemia

• 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

Pioglitazone subject to interactions due to liver metabolism.
-may lower oral contraceptives levels containing ethinyl estradiol and norethindrone

Question 21

Effects/characteristics of GLP-1

Answer 21

Increase glucose-dependent insulin secretion

Decrease glucagon secretion and hepatic glucose output

Regulates gastric emptying
Decreases rate of nutrient absorption

Decrease food intake

Decrease plasma glucose acutely to near-normal levels

Not resistant to DPP-IV degradation

Short duration in plasma

Question 22

Give an example of GLP-1 and when is it administered?

Answer 22

Exenatide for example administered s.c. injection 30 to 60 mins before last meal of day

Adjuvant therapy for type II diabetic on metformin, a sulfonylurea, thiazolidinediones, or a combination of these drugs who have not been able to achieve adequate control of blood glucose

Question 23

How does exanatide facilitate glucose control?

Answer 23

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 24

What are the side effects of exanetide?

Answer 24

Side effects are mainly gastrointestinal in nature including acid or sour stomach, belching, diarrhea, heartburn etc.

Question 25

Describe exanatide

Answer 25

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 26

Describe Dipeptidyl peptidase-4 (DPP-4) inhibitors

Answer 26

Class of oral hypoglycemic agents

Mechanism of action is via increased levels of Incretins GLP-1 and GIP

Drugs in this class include vildagliptin (reversible), sitagliptin (reversible) and saxagliptin (covalently bound)

Question 27

What is the effect of increased incretins?

Answer 27

Increased Incretins:

• Inhibit glucagon release
• Increase glucose-induced insulin secretion
• Decrease gastric emptying
• Reduce hepatic glucose production
• Improved peripheral glucose utilisation

Question 28

DDP IV inhibitors

Answer 28

Orally active
Few side effects
Modest elevations of incretins
Weight neutral no gastrointestinal side effects
Cancer risk?
DPP-IV enzyme known to be involved in suppression of certain malignancies as it functions as a tumor suppressor
Not yet seen with drugs in long-term preclinical studies

Question 29

Describe SGLTs

Answer 29

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 30

SGLT2 inhibitors

Answer 30

Dapagliflozin-approved for use in Europe April 2012

IC50 for SGLT2 is less than 1/1000 of the IC50 for SGLT1

Canagliflozin-approved by FDA 10th January 2013 to treat Type 2 diabetes in adults

Question 31

Effects of SGLT2 inhibitors

Answer 31

inhibition of renal tubular Na+-glucose cotransporters
This reverses hyperglycaemia
This reverses glucotoxicity

Increased insulin sensitivity in muscle results in increased GLUT4 translocation and increased insulin signalling

increased insulin sensitivty in liver due to decreased G6P

Decreased gluconeogenesis by decreasing Cori cycle and decreased PEP carboxykinase

Improved beta cell function

Question 32

Side effects of SGLT2 inhibitors

Answer 32

Rapid weight loss (due to glycosuria (up to 70 g/day)
Tiredness
Osmotic diuretic so dehydration
Can worsen urinary tract infections and thrush