Blood Glucose Control

Glucose uniporters (odd)

Km

• half the conc to work at max capacity

• low → always working (high glucose affinity)

• high → works under specific env (e.g. GLUT4 & hyperglycaemia)

normal blood glucose ranges

• 3.4-6.7

• ruminants = 2.3-4.4

GLUT1 (3-7 Km)

• Basal glucose uptake

• Ubiquitous expression

GLUT3 (lowest (1.4) Km)

• Basal glucose uptake

• Brain and placenta → need the most glucose

Glucose uniporters (even)

Km

• half the conc to work at max capacity

• low → always working (high glucose affinity)

• high → works under specific env (e.g. GLUT4 & hyperglycaemia)

GLUT2 (highest Km) - nec for insulin release

• Glucose sensing role in beta cells

• High capacity, low affinity → only activated when hyperglycaemic

GLUT4 (5 Km) - nec for insulin uptake

• Insulin responsive glucose transporter

• Muscle, fat, heart, hippocampus

Na+ glucose symporters (SGLTs)

SGLT1

• Small intestine → glucose absorption

SGLT2

• Kidney → glucose resorption in PCT

GLUT4 → responding to insulin signalling (insulin-induced glucose uptake)

• Skeletal muscle, fat, cardiac muscle

Sequestered within GSVs (GLUT4 storage vesicles) in cytoplasm

1. Activation of PI3K pathway in response to insulin signalling

2. AS160 phosphorylated → stimulates GSV translocation to CSM

3. GLUT4 at CSM → facilitated diffusion of glucose into cells

   • GLUT4 translocation in skeletal muscle also stimulated by exercise mediated mechanisms

Insulin receptors

• RTKs expressed by most cells

  • esp. liver, muscle, adipose

• Expressed as preformed dimer

  • other RTKs dimerise to respond to ligand

• 2 isoforms

• INSR-A → mitogenic actions

  • Foetal development

  • Cancers

• INSR-B → metabolic actions

  • Exon 11 positive → longer chain (12 more amino acids)

  • Found in higher amounts → normal glucose homeostasis

• Ligands: IGF 1 + 2

  • INSR-A higher affinity

  • Upon binding → V shape → T shape

  • Enables autophosphorylation and activation of intracellular pathways

Insulin Signalling Pathways

• Metabolic effects (INSR-B) → PI3K signalling pathway

  • Phospho-ino-sitide 3 kinase

  • Increased glucose uptake and metab

  • Glycogen, protein, lipid (FA) synthesis

• Mitogenic effects (INSR-A) → MAPK pathway

Insulin synthesis

• RER → Golgi → secretory granules

• Preproinsulin (110) → proinsulin (86) → mature insulin(51) → insulin hexamers

• Preproinsulin (RER) → A, B, C chains, signal peptide

• Proinsulin (RER) → A, B, C chains

• Insulin (Golgi) → A, B chains

  • C chain longer ½ life than insulin used to check for insulin levels in blood

• Insulin hexamers (secretory granules)

  • B cells are granular due to high conc of secretory granules

    • Increased insulin concentration causes insulin monomers to dimerise

    • Presence of zinc causes dimerised insulin → hexamers

• Insulin hexamers dissociate in blood → release active zinc free insulin monomers

monomers → dimerise →(zinc)→ hexamers → monomers

Stimuli for insulin secretion

• Glucose sensing GLUT2 expressed on beta cells → facilitate entry of glucose

• Glycolysis → glucose → pyruvate

• Krebs → ATP production

• high ATP binds → ATP sensitive K+ channels CLOSE→ membrane depolarisation [K+ cannot leave - increase in PD]

• Voltage gated Ca2+ channels open

• Insulin exocytosis (secretory granules) and secretion

Insulin biphasic secretion

• First phase

  • Rapid and transient

  • Uses readily releasable pool of secretory granules

• Second phase

  • Gradual increase in insulin secretion sustained for as long as glucose stimuls remains

  • Reserve pool of secretory granules and de novo insulin synthesis

Other factors regulating insulin secretion

Molecule Type	Example Molecules	Effect on Insulin	Notes
Incretins	GLP-1 (Glucagon-like peptide) GIP (Gastric inhibitory polypeptide)	↑ Increases	Released after meals; enhance glucose-stimulated insulin secretion
Hormones (chronic)	Melatonin, Oestrogen, Leptin, GH, Glucocorticoids	↑/↓ Modulate	Long-term regulators; effects vary with context
Neurotransmitters	ACh, NE, Epinephrine, Dopamine, 5-HT, GABA	↑ or ↓ (varies)	ACh ↑ (via vagus); NE/Epi ↓ (via α2 receptors); GABA ↓

Insulin linked disorders

• equine metabolic sydrome

  • due to insulin resistance (mimics type 2)

  • need to lower blood glucose → resensitisation (Met-formin - inhibition → gluconeogenesis)

  • thyroxine improves insulin sensativity

• type 1 diabetes (decreased beta cell mass)

• type 2 diabetes

• Diabetes as a consequence (secondary) of other conditions

• Diabetes as a consequence (secondary) of other conditions

  • Cushings → mobilise more glucose in blood → insulin resistance + cortisol impairs glucose uptake

  • Pancreatitis

    • damage to beta cells?

  • Acromegaly

    • GH antagonist of insulin

      • reduces translocation of GLUT-4

      • inhibits insulin signalling

      • lipolysis → desensitisation

    • GH → Liver → IGF-1

    • IGF → ligand of insulin receptor → desensitisation of receptors

  • Pregnancy (gestational diabetes)

    • placental hormones → causes insulin resistance

  • Insulinoma

Insulin resistance - mechanisms

• skeletal muscle

• hepatic

• adipose

• compensatory hyperinsulinaemia (overactive Beta cells)→ desensitisation

Diglyceride accumulation = insulin resistance

• skeletal muscle

  • Chronic hyperglycaemia → diglyceride (di-acyl-glycerol) accumulation → reduces insulin signalling

• hepatic

  • Excess glucose → full glycogen reserves → lipogenesis prioritised → diglyceride accumulation → reduces insulin signalling

  • Reduced insulin → excess glucose (positive feedback)

• adipose

  • Failure to suppress lipolysis → exacerbates muscle and liver insulin resistance (more circulating diglycerides)

Equine metabolic syndrome

Clinical signs

• Mare infertility

• Recurring acute laminitis

• Abnormal fat deposits

Treatment

• Resolve laminitis

• Low calorie hay, more exercise

Type 2 diabetes - cat breed overrepresentation

Other risk factors?

Burmese cats

• Advancing age

• Obesity

• Male sex

• Indoor confinement (low physical activity)

Type 1 diabetes clinical signs

• Abnormal gait (cats)

• Cataracts

• Chronic infections

• Muscle wasting

Sites of action- glucose lowering agents

• GLP-1 agonists (clinical trials)

  • GLP-1 increases insulin levels → weight loss

• SGLTs (esp SGLT2)

• Metformin (prevents gluconeogenesis in liver)

Cells and hormones secreted by Islets of Langerhans

1. Alpha cells → glucagon

2. Beta cells → insulin

3. Delta cells → somatostatin

   • Inhibits insulin, glucagon, somatotropin, thyrotropin

4. Gamma (/PP/F) cells → pancreatic polypeptide

   • Stimulated by vagal + enteric output

   • Inhibits gastric emptying and biliary function

   • Sat-iety hormone

5. Epsilon cells → ghrelin

   • Stimulates GH production

   • Sustains Beta cell viability, inhibits acinar cells

   • Involved in pancreatic development

   • Promotes fat storage, increases food intake

   • Rare in pancreas

Interrelationship between alpha, beta, delta cells

• Insulin secretion finetuned by somatostatin

  • High blood glucose → insulin secretion → somatostatin inhibits glucagon

  • Beta cells can also inhibit alpha cells

  • Alpha cells cannot directly inhibit beta cells

  • Alpha cells can directly PROMOTE beta cells

  • Somatostatin secretion stimulated by glucagon and beta cell electrical coupling

• High glucose, high amino acids, low free fatty acids → promotes insulin + somatostatin secretion

• Low glucose, high fatty acids, high ketones → promotes glucagon

Glucagon production

(similar to POMC)

• amino acid precursor → produces 9 regulated peptide hormones

• 6 subunits → 9 combinations

• PC1 expression

  • brain

  • enteroendocrine cells

• PC2 expression

  • Alpha cells → glucagon

Glucagon secretion

1. Hypoglycaemia

2. Decreased glycolysis → decreased respiration → decreased ATP

3. ATP sensitive K+ channels close

4. Depolarisation

5. Ca2+ influx (vgated channels open

6. Glucagon exocytosis

Stimuli for Glucagon Secretion

Endocrine

• GIP increases

• GLP-1 decreases

Paracrine

• insulin and somatostatin inhibition

Nutritional

• high amino acids

Sites of Glucagon Action

• Liver

  • Cholesterol clearance

  • Increase amino acid metabolism

  • Increase urea cycle

  • Beta oxidation

• Pancreas

  • Glucagon can directly promote insulin secretion

• Kidney

  • Increase GFR

• Intestine

  • Slows gastric emptying and peristalsis

• Heart

  • Positive inotrope + chronotrope

• Brain

  • Increased food intake, glucose metabolism

Brain use of glucose

• 20-25% blood glucose

• Can use ketone bodies when glucose scarce

Pancreas anatomy

• Compact

  • Dog, cat, pig, human

• Intermediate

  • Rodents → compact splenic, diffuse duodenal

• Diffuse

  • Rabbits → mesenteric type organ

Alpha beta delta cell distribution

Alpha

• Circumference

Beta

• Center

Delta

• Scattered throughout periphery

Metabolic effects of glucagon

• High glycogenolysis

  • Increase PKA → activates (phosphorylates) glycogen phosphorylase

  • G1P produced

  • high PKA activation → inhibits PP1 dephosphorylation = activation→ inhibits glycogen synthase

• glucose 6 phosphatase (G6P → blood glucose)

• High gluconeogenesis

  • Upregulate pyruvate carboxylase (PC)

  • Upregulate PEP carboxykinase (PEPCK)

  • Upregulate fructose 1, 6, bisphosphate (F16bpase)

  • Upregulates G6pase

• inhibition of glycolysis → inhibits PFK1 (6 → 1, 6) and pyruvate kinase (PEP → pyruvate)

Liver insulin metab effects

supressing gluconeogenesis and maximising glycogen storage

Decrease gluconeogenesis: downreg

• PC

• PEPCK

• fructose-1,6-biPase

• G-6-Pse

Increase glycogen storage

• increase glycogen synthase activity (glycogenesis)

  • increase dephosphorylation via PP1 - activates GS

  • inhibit PKA → therefore glycogen phosphorylase inhibited→ inhibiting glycogenolysis

• increase rate of glycolysis

  • upreg

  • glucokinase

  • PFK

  • PK

  • PD

Muscle insulin metab effects

glycogen storage and increasing glycolysis and protein synthesis

• GLUT 4 translocation

• increased amino acids uptake - protein synthesis

• increase glycogen synthase activity

  • increase dephosphorylation via PP1 - activates GS

  • inhibit PKA which activates glycogen phosphorylase

Adipose insulin metab effects

promotes storage of triglycerides

• translocation of GLUT 4 → cellular glucose uptake

• high rate of glycolysis (increase enzyme exp)

  • hexokinase

  • PFK

  • PK

  • PD

• lipogenesis → inhibit hormone-sensitive lipase and B oxidation

  • high activity of lipoprotein lipase (increases free uptake of fatty acuds

  • high PD

  • [ACC → acetyl coA carboxylase to make fatty acids] → FA intermediate

  • FAS (fatty acid synthase)

Blood glucose control overview

1. Phase 1 → food ingestion and digestion → increases blood glucose

   • Postprandial state → increase glycogen uptake and storage in skeletal muscle and liver

2. Phase 2 → Aftermeal

   • Hepatoglycogenolysis

   • Gluconeogenesis

3. Phase 3 → gluconeogenesis > glycogenolysis

   • Maintains blood glucose levels while utilising other sources

   • Beta oxidation in skeletal muscles

4. Phase 4 → no more meal

   • Brain begins supplementation with plasma ketone bodies → running out of gluconeogenic substrates

   • Only hepatic + renal gluconeogenesis occurs (conserving glucose for essential organs)

   • Intermediate starvation starts from day 24

5. Phase 5 → late stage intermediate starvation

   • Protein breakdown → supplies amino acids for glucose generation in liver

6. Phase 6 → starvation

   • High plasma ketone concentration

   • Body completely relies on ketone bodies → shuts down