Central Glucose Homeostasis

Role of the brain in Glucose Homeostasis:

objectives::

  1. illustrate sensory inputs of glucose regulation

  2. to introduce the brain as a sensor of the body’s nutrient status

    a. autonomic NS and neurocircuits

    b. hypoglycemia counterregulation

    c. glucose-sensing neurons

  3. to introduce the brain as a sensor of hormone inputs to regulate energy and glucose homeostasis

  4. to provide a research example: Brainstem homeostasis

  5. to introduce gut-brain interaction in the regulation of glucose metabolism

Glucose sensory input:

afferents get sent to the brainstem caused from taste receptors, GI tract, an d portal and mesenteric veins where they then project to the hypothalamus

  • GI tract vagal affarents project to the NTS

Neural outflow

  • glucose acts as a stiulus for glucosensing elements. The glucosensing elements then transduce information into neural signals to control glycemia.

    • glucose sensing elements include the portal mesenteric vein, hindbrain and hypothalamus…these can lead to autonomic and nueroendocrine motor neurons causing secretion of hormones such as E/NE, glucagon, or glucocorticoids

Autonomic NS: Sympathetic and Parasympathetic

Sympathetic NS = activated via stresss, cold, low BP, low blood sugar

  • acts to increase blood glucose

    • inhibit insulin secretion and stimulate glucagon secretion

    • increase hepatic glucose production (glycogenolysis and gluconeogenesis)

    • mobilize fatty acids

    • stiulate cortisol secretion

Parasympathetic NS = tonic acitvity, acetylcholine

  • acts to decrease blood sugar

    • stimulate insulin secretion, and decrease hepatic glucose production

Counter-regulation of hypoglycemia: you want to increase glucose levels

  • increase glucagon, epinephrine, cortisol

  • decrease insulin

Glucose sensing neurons: Can be inhibitory or excitatory

  • these neurons are found in the lateral, arcuate, ventromedial and hypothalamic nuclei

  • they play a role in coordinating metabolism, behavior and future planning

ventromedial hypothalamus glucose-sensing mechanims during hypoglycemia:

*when glucose is low both GE and GI neurons lead to stimulating glucose

  • Glucose excited neuron (GE)

    • decreased ATP: ADP leading to opening of kATP channel and hyperpolarization of the GE cell. This prevents release of GABA thus removing inhibition on the sympathetic NS and promoting glucose production and mobilization

  • Glucose inhibited neuron (GI)

    • increase firing when glucose is low, increase AMPK levels and cause an increase in NO production. NO inactivates the CFTR channel leading to depolarization of the neuron and exocytosis of glutamate. Glutamate activates neurons. inthe PVN and lateral hypothalamus overall causing SNS activation and increased glucagon release

Negative feedback control of glucose homeostasis:

  • insulin, glucagon, Hypothalamic regulation (ie: low glucose cause increase), feeding and satiety signals

The brain senses hormone inputs to regulate energy and glucose homeostasis:

AGRP and NPY = promote hunger

  • leptin inhibits AGRP to decrease feeding

  • insulin inhibits AGRP to decrease feeding

POMC = suppress hunger - insulin and GLP-1 act here

  • insulin and GLP-1 activate this to stop feeding behaviour

Insulin, leptin, and GLP-1 all lead to decreased glucose production

  • insulin on AGRP, leptin and GLP-1 on POMC

Nutritional and hormonal signals converge on kATP channels

  • plays a central role in regulating energy balance - the body is able to response to both immediate needs and long term energy storage signals

CNS Hormones:

insulin lowers glucose production actingin the hypothalamus and the hindrbrain

leptin lowers glucose production

GLP-1 lowers glcuose production

CNS glucagon lowers glucose production (this contrasts in the periphery)

Resistin increases glucose production

Manipulating hindbrain glycine levels: therapeutic target for obesity and diabetes

  • glycine is an inhibitory neurotransmitter that helps regulate glucose homeostasis

  • The role of the GlyT1 is to clear glycine - hence by inhibiting it you increase extracellular levels of glycine. When you inhibit GlyT1 this lowers glucose production and body weight

  • you would want to inhibit the GlyT1 (glycine transporter 1) as this would help improve insulin signalling, as higher levels of glycine would then be able to act on NMDA receptors to further control neuronal circuits within the hindbrain to allow for decreased food intake and decreased weigth gain - improve glucose tolerance and lowering of hepatic glucose levels

Gut-Brain interactions:

There is crosstalk between the brain and the gut, where nutrient sensing lowers food intake and glucose production

  • GLP-1 agonists = treatment for type 2 diabetes an overwieght patients