inital steps in the regulation of the blood glucose concentration (gylcemia)

process by which an organism constantly maintains the internal conditions necessary for life

maintains the stability of the human body’s internal environment in response to changes in external conditions

communication between organs essential

the nervous and endocrine systems provide the majority of the communication:

• nervous influx through the nerves

• hormones carried by the blood

always 3 interdependent elements in a regulatory mechanism

• receptor (senses variation)

• input goes via the afferent pathway

• regulation center (integrates variation)

• output sent along the efferent pathway

• effector (response organ)

difficult: one mechanism can affect others, mechanisms can be redundant (allows preservation of life)

existence of a variation range for the parameter that is acceptable for the organism

0.8 - 1.26 g/L (4.5 - 7 mM)

• organs/tissue: control in organs and organic fluids (blood) for all elements needed for living, an important role of the hypothalamus (hunger, thirst, body temperature)

• cell: control of enzymes activity/transport (inflow/backflow)

• nervous cells: sensory cells capable of detecting variations and responding by the production of action potentials

• endocrine cells: humoral answer is enough to control the change of a variable (insulin vs. glucagon)

cell body in the central nervous system

single neuron from CNS to effector organs

NT = Acetylcholine (stimulatory)

effector organ skeletal muscle

two neuron chain from CNS to effector organs

sympathetic: ganglion with Ach preganglionic & Norepinephrine postganglionic

or adrenal medulla (Ach preganglionic and epinephrine/norepinephrine in blood vessels)

parasympathetic: lightly myelinated preganglionic axon —> ganglion (ACh) —>unmyelinated postganglionic axon (ACh)

stimulatory or inhibitory depending on NT and receptor

longest cranial nerve

contains motor and sensory fibers and has the widest distribution in the body

The hypothalamus very important nervous integrator center with an endocrine function

pituitary gland is under the control of the hypothalamus

controls other endocrine glands (thyroid, adrenal glands, mammary glands, gonads)

hormones secreted: thyroid, parathyroids, adrenal glands, ovary, testis, thymus, and pancreas (insulin & glucagon)

but also from the digestive tract, adipose tissue, stomach

locally secreted by cells, acts on nearby cells

paracrine or autocrine mode

secreted in the bloodstream by endocrine glands (insulin)

endocrine mode

hormone released into venous circulation—>goes through heart, lungs & then to target organ

—>at the level of target reduced quantity

lipophilic

can pass membrane by passive diffusion

binds to receptors in cytoplasm

translocation in the nucleus as active TF

activates transcription and translation of certain gene

new protein—>induces answer in the target tissue

long process

the ligand binds the surface receptor

intracellular signaling

signal transduction (via second messanger)

cellular response

changes in gene expression

fast and late response

enteric nervous system (receptor) first organ sensing glucose, stimulated by bacteria

nervous and endocrine signals (integration centers)

autonomic nervous system

energy homeostasis (liver, muscle, pancreas, adipose tissue —>effectors)

1-3% of body weight

high diversity in bacteria species in the mouth, intestine, skin, urogenital tract

less in stomach: unfriendly acidic environment

biggest families: firmicutes, bacteroidetes

varies between populations & individuals

but functional redundancy —> central metabolic pathways (carbohydrate and AA metabolism)

sterile gastrointestinal tract during pregnancy

upon birth, the gut is exposed to microbes from the mother’s reproductive tract & environment (different if cesarean or vaginal delivery)

upon first 2 years often variations in the composition of gut microbiota

then solid food —> gut microbiota more diverse and stable

in old age, gut microbiota alters drastically, with less diversity

geographical location, region-specific diet

host genetics

exposure to antibiotics, feeding type

use of prebiotics/probiotics

age/health

mode of delivery, hospital environment

food for bacteria

only metabolized by the gut bacteria, not the human host

increase bacterial growth

live bacteria

active bacterial cultures

renew microbiota after long antibiotic therapy

combination of pro and prebiotics

• breaking down food compounds

• resistance to pathogens (protection)

• metabolism of therapeutics

• biosynthesis of vitamins and amino acids

• development & training of the immune system

• modification of the nervous system

• promotion of angiogenesis

• promotion fat storage

• modulation of bone-mass density

• protection against epithelial injury

Dissolution: broken down in the stomach

Absorption: of simple carbohydrates, most fats, and proteins in small intestine

Fermentation: of fiber-rich carbohydrates in the colon, transformed into beneficial compounds by bacteria (short-chain fatty acids, branched-chain fatty acids, non-starch polysaccharides, resistant starch, carbohydrates)

side products such as formate, carbon dioxide, and hydrogen gas are used by other species in cross-feeding

the more diverse, the healthier

dietary fibers are a source of complex carbohydrates

mucus reduction

dysbiosis (loose good bacteria)

toxins (like LPS)

barrier dysfunction / decreased gut motility

—>barrier or enterocytes more fragile (bacteria should not be in contact with blood to avoid immune response)

—>if crossing inflammation that can become systemic —>chronic diseases

altered intestinal microbiota can lead to chronic inflammation & metabolic dysfunction

exponential growth in prandial phase —>help to digest and signal to brain satiation

postprandial phase: small plateau, static

preprandial phase: decline, signal hunger to the host

digestion products and energy substrates (ATP, lactate, butyrate) can signal to vagal afferents

bioactive molecules (LPS, 5HT, indole) and mimetics of peptide hormones (ClpB) can stimulate satiety hormones (peptide tyrosine tyrosine PYY, glucagon-like peptide GLP1)

—>activate anorexigenic pathways (signal enough nutrients in the body)

digestive tract

enteric nervous system

endocrine pancreas

liver

skeletal muscles and adipose tissue

stomach: Ghrelin (hunger hormone), Leptin

small intestine: duodenum (CCK)

jejunum (APO AIV)

ileum (GLP1, PYY)

pancreas: Glucagon, insulin

> 500 million neurons (sensitives (chemo, mechano, thermo), interneurons, efferent)

independent, separate from the autonomic nervous system since it has its own independent reflex activity

capable of carrying reflexes and acting as an integrating center in the absence of CNS input

—>second brain

has vagal efferences and afferences

communicates with CNS via vagal pathway, parasympathetic (ACh), and splanchnic pathway sympathetic (NE)

—>acts autonomously & influences behavior by sending messages up the vagus nerve to the brain

Glucose-dependent insulinotropic peptide GIP

GLP1

—> Hormones from intestine stimulating the pancreas

—>increased insulin secretion, biosynthesis

—>increased ß-cell proliferation & cell survival

exocrine function: secretion of pancreatic enzymes through the Wirsung canal in the duodenum

endocrine function: secretion of pancreatic hormones in the blood

circulatory system linking the intestine, liver & pancreas

nutrients absorbed into the blood from the intestine go through the liver before entering the central circulation

for endocrine function

many capillaries to bring oxygen

many veins to release hormones into the circulation

2% of pancreas mass, 1-15 mio islets

each composed of 2000-4000 cells

hormones: ß cells (insulin), α cells (glucagon), δ cells (somatostatin), PP cells (pancreatic polypeptide)

hormone of the fed state, storage hormone, hypoglycemic hormone

—>glucose uptake in insulin-sensitive organs (stimulation of transport via GLUT4 in muscles and adipose tissue)

—>glucose storage in the liver and muscles (glycogen)

—>inhibition of lipolysis (fat) and neoglycolysis (liver)

—>action on CNS: insulin receptor implicated in the control of appetite—>increased production of satiety factors

glucose sensor GLUT2 (high Km) takes uo glucose converted quickly into G6P by glucokinase (high Km)

metabolized in mitochondria to ATP

inhibits K+ATP channel

depolarisation of the membrane

open voltage-gated calcium channels

fusion of insulin-containing vesicles with membrane (SNARE implicated, similar exocytosis as for neurotransmitter)

translocation & docking —> priming —> fusion (Ca2+ dependent)

1. phase: fast increase & peak in insulin secretion—> readily releasable pool RRP (<5%) next to membrane for fast fusion

2. phase: reserve pool deeper in the cell close to cytoskeleton—>less strong but long-lasting secretion

due to hormonal input (incretin)—>increased cAMP—>Ca2+ release

neural input (ACh)—>second messenger due to GPCR mechanism DAG & IP3 release Ca2+ from ER

but glucose is always needed from induction of secretion, potentisation afterwards

important communication between intestine and endocrine pancreas

oral administration of glucose associated with increased plasma insulin level compared to intravenous administration

Incretin responsible for 50-70% of the total insulin secretion

GLP1 & GIP

GIP = glucose-dependant insulinotropic polypeptide

GLP1 = Glucagon-like peptide 1

secreted by intestine

short half-life: degradation by DPP-4 (Dipeptidyl peptidase 4) by cleavage of 2 AA in Nter

same precursor (proglucagon) as glucagon (produced in the pancreas)

different post-translational modifications in gut/brain lead to GLP1

2 active forms: amidated GLP1 or glycine-extended GLP1

stimulus = nutrients

receptor sense glucose (uptake via SGLT1 together with sodium)

membrane depolarization

opening Ca2+ channels

release GLP-1 in portal vein

via intestinal capillaries to portal circulation (75% lost due to degradation by DPP-IV)

over the liver into systemic circulation and into the pancreas

only 15% reach the pancreas for potentisation, the rest is destroyed by DPP-IV

halflife 2-3 min

GLP-1R

GPCR (7 transmembrane domains)

coupled via stimulative regulative G protein linked to adenylate cyclase

on ß cells

stimulates insulin secretion even at fasting glucose levels in ß-cells (increases cAMP—>PKA activation—>stimulates release of Ca2+ from ER)

inhibitory effect on glucagon secretion in α-cells

inhibition of gastric and pancreatic acid secretion & deceleration of gastric emptying

action on the nervous system: injection in portal veil activates hepatic afferent fibers and increases the activity of pancreatic efferent nerves

increase: proinsulin gene expression & translation, ß-cell proliferation & neogenesis

decrease: ß-cell apoptosis

incretin

1 gene, 1 mRNA, 1 protein

produced in enterocytes (intestine)

GPCR

coupled via stimulative G protein linked to adenylate cyclase

on pancreatic ß cells

stimulation insulin secretion even at fasting glucose level (also release of Ca2+ and potentization of the signal)

no inhibitory effect on glucagon secretion (no effect on α-cells main difference to GLP-1)

hunger hormone, mechanical secretion depending on the size of the stomach

empty: ghrelin secretion —>appetite increases (low CCK, GLP-1& PYY)

full: no ghrelin, no appetite (CCK, GLP-1 & YPP secreted)

begins as soon as blood glucose level increases after a meal (digestion-microbiota)

importance of glucose sensor system (nutrient sensor)

importance of endocrine and nervous communications

essential role of the digestive tract (appetite, hormones)

GLP-1 & GIP are the 2 major incretin hormones (primary action on the pancreas)