L12.1 Metabolic Syndrome

Question 1

Target BP range of different diseases

Answer 1

• Different disease → Target BP range would be different

Question 2

Metabolic syndrome

Answer 2

• Combination of disorders → ↑ risk of cardiovascular disease &diabetes

Question 3

Signs and symptoms of metabolic syndrome

Answer 3

• Fasting hyperglycaemia
• High BP
• Midriff fat deposition (from aging)
• ↓HDL
• ↑Triglycerides

Question 4

How is the metabolic syndrome managed

Answer 4

• Controlling glucose → key to manging it (symptoms not shown in absence of insulin resistance)

Question 5

Exo/endo/HPA functions of pancreas

Answer 5

• Exocrine
  
  • Acinar cells
  • Bile
• Endocrine Islets of langerhans
  
  • β-cells prod insulin
  • α-cells prod glucagon
  • Delta-cells → somatostatin (involved in satiety and controls GIT)
• Controls outside HPA
  
  • Responds directly to plasma glucose levels

Question 6

HPA pancreas response to blood glucose

Answer 6

• Glucose homeostasis
• HPA action: ↓blood glucose → release Adrenaline/glucocorticoid from adrenal medulla/cortex → stimulate liver to release glucose
  
  • ONLY when blood glucose is low, NO HPA action when blood glucose is high

Question 7

Insulin secretion

Answer 7

• Biphasic response
  
  • 1st phase: Release of stored hormones (spike)
  • 2nd phase: Continued release of stored hormone & new synthesis

Question 8

Type 1 and 2 diabetes mellitus

Answer 8

• Type 1: Absolute lack
  
  • Islet cells destroyed → no insulin secretion
  • Glucose change → pre-dispose to other co-morbidities
• Type 2: Relative lack
  
  • Impaired secretion and insulin resistance
  • Lack 1st phase insulin response

Question 9

Diabetes characterised as

Answer 9

• Chronic disturbed carbohydrate AND lipid metabolism
  
  • LDL/HDL ratio altered as a result of glucose intolerance → Atherosclerosis
• Important to be monitored and controlled as best as possible

Question 10

Aim of treatment

Answer 10

• To control glucose homeostasis (4-8mmol/L)
• ↓acute and chronic complications
• Restore metabolism

Question 11

Treatment options

Answer 11

• 1st line = lifestyle modifications
• Type 1:Lack of insulin → hard to treat
  
  • Could use stem cells, islet transplantations…
• Type 2:
  
  • Oral hypoglycaemic agents
  • Small peptides

Question 12

Targeting insulin secretion

Answer 12

• GLUT2 transporter on β-cells expressed on cell surface
  
  • Glucose → G6P → ATP (oxidative phos) → inhibits ATP-sensitive K channels → depol → Ca influx (VG Ca channels) → stimulate secretory granules → release insulin

Question 13

How does insulin work

Answer 13

• Accelerates glucose movement from blood into cells
  
  • Through cell surface tyrosine kinase R
  • Recruits GLUT 4 transporter to cell membrane (normally GLUT 4 in subcellular vesicular structures)

Question 14

Targetting ATP-sensitive channels - Meglitinides

Answer 14

• Repaglinide
• Mech: Selectivity for β-cells KATP channels
  
  • Helps 1st phase secretion

Question 15

Repaglinide pharmacokinetics and A.E

Answer 15

• Pharmacokinetics:
  
  • Oral abs
  • Rapid onset/offset
  • 1/2 life = 3hrs
  • Able to taken accordingly with meals
• A.E
  
  • Less risk of hypoglycemia & weight gain thank sulphonylureas (SUR *1st class of drug)

Question 16

Targetting ATP-sensitive channels - Biguanides

Answer 16

• Metformin
• Mech:
  
  • ↑glucose utilisation and ↓hepatic glucose prod
  • ↓LDL and TG
  • By activating AMPK

Question 17

Metformin pharmacokinetics and A.E

Answer 17

• Pharmacokinetics
  
  • 1/2 life = 3hrs
  • Able to be taken with meals
  • Excreted unchanged in urine
  • Req functioning kidney but many diabetics have kidney dysfunction
• A.E
  
  • GIT
  • No weight gain (may have weight loss)
  • Lactic acidosis (from ↑AMPK)
  • Contraindicated in impaired renal function

Question 18

Incretins regulating glucose homeostasis

Answer 18

• Incretins are glucagon-like peptides (GLP) released from ingestion of food
• Acts on α & β cells
  
  • β-cells → ↑insulin secretion and glucose uptake
  • α-cells → ↓glucacgon → ↓hepatic glucose

Question 19

Targetting incretins - DPP-4i

Answer 19

• DPP-4 responsible for inactivating incretin
• Sitagliptin (DPP-4i)
  
  • ↑GLP1
  • Adjunct to diet and exercise

Question 20

Sitaglipin A.E

Answer 20

• Upper resp tract infections
• Headaches
• Hypoglycaemia when combined with insulin/secretagogues
• Allergic/hypersensitivity
• Pancreatitis

Question 21

GLP 1 agonists

Answer 21

• Exenatide (synthetic) - s.c. injections
• Mech:
  
  • Potentiate glucose-mediated insulin secretion
  • Supress glucagon release
  • Slow gastric emptying
  • Loss of appetite (CNS effect)

Question 22

Exenatide A.E

Answer 22

• Nausea, vom, diarrohea
• Weight loss → anorexia
• AB formation → immune rxn, pancreatitis
• Endocrine neoplasias (↑endocrine cancers)

Question 23

a-glucosidase inhibitor

Answer 23

• Slow abs of starches
• Acarbose
  
  • Blocks enz in gut that promotes digestion and abs of starches in SI
  • Pharmacokinetics
    
    • Not abs from GIT → doesn’t get into bloodstream, acts LOCALLY

Question 24

Acarbose A.E

Answer 24

• Abdominal discomfort
• Loose stool
• Contraindicated in patients with inflammatory bowel disease/cirrhosis