2018B12 Outline the normal physiological control of blood glucose in a non-diabetic adult.

Glucose

·  6 carbon monosaccharide for energy production

·  Brain, RBCs are obligate glucose users (brain can use ketones too)

·  Tight control of blood glucose level necessary (~3-6mM)

Summary of glucose control

·  Multiple systems

o ↑BGL: glucagon, cortisol, catecholamines, growth hormone

o ↓BGL: insulin

·  Ratio of activity determines effect (especially insulin:glucagon)

·  Each system is subject to negative feedback (e.g. ↑BGL -> ↑insulin -> ↓BGL)

·  Liver buffers [glucose] – able to store and release glucose

·  Skeletal muscle and liver store glucose but buffer poorly

Glycolysis (GL)

·  Hexokinase

Gluconeogenesis (GNG)

·  From pyruvate, lactate, fructose, amino acids, glycerol

·  Note glucose 6 phosphatase mainly expressed in liver > renal cortex

Glycogenolysis (GGL)

·  Glycogen phosphorylase

Glycogenesis (GG)

·  Glycogen synthase

Lipolysis (LL)

·  Hormone-sensitive lipase

De novo lipogenesis (DNL)

·  Lipoprotein lipase, acetyl-CoA carboxylase, fatty acid synthase

Ketogenesis (KG)

·  Acetyl-CoA thiolase

Source

·  Pancreatic islet β cells

Stimuli for release

·  Major: ↑BGL

·  Minor: ↑[amino acids], ↑[fatty acids])

·  GIT secretagogues (e.g. GLP-1, GIP)

Pattern of secretion

·  Mechanism: ↑BGL -> ↑ATP -> ↑inhibition of K channel -> depolarisation -> ↑Ca²⁺ > exocytosis

·  Constitutive: 15 milli-Units per minute

·  1^st phase inducible: preformed insulin, onset 2 mins, duration 15 mins

·  2^nd phase inducible: newly synthesized, onset 15 mins, duration 2-3 hours

Liver effect

·  ↑GL, ↑GG

·  ↓GNG, ↑DNL

Skeletal muscle effect

·  ↑GLUT4 expression

·  ↑GL, ↑GG

·  ↓GNG, ↑DNL

Adipose effect

·  ↑GLUT4 expression, ↑glucose uptake -> glycerol

Negative feedback loop

·  ↑BGL -> ↑insulin -> ↓BGL

Source

·  Pancreatic islet α-cells

Stimulus for release

·  ↓BGL

·  Adrenaline (β₂)

·  GIT secretagogues (GIP, CCK)

Inhibition of release

·  Tonic release of GABA from activated β-cells (i.e. interlock mechanism)

Effects

·  Liver: opposite to insulin

·  Muscle: opposite (but does NOT cause GGL)

·  Adipose: opposite to insulin

Source

·  Zona fasciculata of adrenal cortex

Stimuli for release

·  ↓BGL sensed by hypothalamus independent of pancreas

·  Physical stress e.g. trauma, surgery, burns, exercise

·  Mental stress, anxiety etc.

HPA axis

Liver effect

·  ↑GNG ++, ↑LL

·  ↓GL, ↓GGL, ↓DNL

Skeletal muscle effect

·  ↑proteolysis -> amino acids -> hepatic GNG

·  ↓GG, ↓GL

Visceral adipose effect

·  ↓glucose uptake -> glycerol

·  ↑LL, ↓DNL

Subcut adipose effect

·  ↑glucose uptake -> glycerol

·  ↑DNL, ↓LL

Source

·  Adrenal medulla

Stimuli for release

·  ↓BGL sensed by hypothalamus independent of pancreas

·  Other physical and psychological stressors

Liver effects

·  β₂ adrenoceptor: ↑GGL, ↑GNG

Skeletal muscle effects

·  β₂: ↑GGL

Adipose effects

·  β₁ white fat -> ↓glucose uptake

·  β₃ brown fat -> insertion of uncoupling protein -> production of heat without ATP

Source

·  Anterior pituitary
(production stimulated by corticotrophin-releasing hormone)

Stimuli for release

·  ↓BGL sensed by hypothalamus independent of pancreas -> ↑CRH release

·  ↓plasma fatty acids

·  Protein deficiency

·  (multiple other factors)

Metabolic effect

·  Insulin resistance -> ↓GL, ↑GNG

·  ↑(LL), ↑FFA utilisation

·  ↑Protein synthesis