insulin signaling pathways

Type 1 diabetes

generally an autoimmune mediated process

often occurs early in children

REQUIRES exogenous insulin

prone to kiabetic ketoacidosis DKA with hyperglycemia

type 2 diabetes

generally consequense of metabolic disease

usually after 40 yrs old

may or may not req exogenous insulin

less likely to develop DKA

hypoglycemia

abnormally low blood sugar

glucose <70mg/dL

hyperglycemia

condition of high blood sugar

insulin

enters cell via insulin receptor

polypeptide hormone produced by alpha cells of pancreas which stimulates uptake of glucose by cells(fed state), storage of energy (stimulates glycogen and lipid biosynthesis)

glucagon

polypeptide hormone hormone produced by the alpha-cells of the pancreas which raises the blood glucose level in blood (opposite of insulin)

glucose transporters

glucose enters cells via glucose channel

transmembrane proteins which facilitate the transport of glucose through the plasma membrane of cells

• Glut4 or SLC2A

insulin receptor

a tyrosine kinase transmembrane receptor activated insulin IGF-I and IGF-II

incretins

group of hormones that are release after eating and stimulate the release of insulin among other hormonal activities

dipeptidyl peptidase-4 (DDP-4)

released form endothelial cells of blood vessels

inactivates both GIP and GLP-1

how much glucose does the brain use

~20% of all glucose derived energy

glucose is the primary/major source of energy

how is glucose derived and ingested in the diet

Carbohydrates exist in nature as …

• polysacchairdes(starch, glycogen) - starch represents most of western diet

• disaccharides(sucrose, maltose, lactose)

• monosaccharides(galactose, glucose, fructose)

carbs are broken down in to hexoses in the gut, the cannot pass freely through the cell membrane so they are absorbed via glucose transporters (ex. GLUT4)

differ between the fasting state and prandial state

Fasting: fatty acids are mainly used from adipose to the liver, small amounts of insulin secreted from pancreas

Prandial: less fatty acids are used, carbs are made into glucose and sent to the liver, brain and skeletal muscle, therefore more insulin will be sent to liver, skeletal muscle, and adipose cells

glycogen synthase vs glycogen phosphorylase

synthase: glycogen storage (insulin enters to turn to protein phosphatase moved thro with protein kinase A)

phosphorylase: glucose production - same just uses phosphorylase kinase

insulin biosynthesis

starts as proinsulin turns to prophormone convertase 2 and 3 and into carboxypeptidase and they cleave into insulin and C-peptide

C-peptide

by product of insulin biosynthesis

those who can make insulin have C peptide those who don’t produce C-peptide do not produce insulin

insulin receptor mediated signaling

Insulin receptor: transmembrane receptor composed of alpha and beta chain thats activated by IGF-I, IGF-II, and insulin

• binding of the ligand (IGF-II or insulin) binding to the alpha change induces structural change in the receptor leading to autophosphorylation of tyrosine within the domain of the beta chain

• once this happens the facilitates specific changes in glucose in. homeostasis such as glycogen synthesis, ect…

(signaling for insulin is very complex)

what general mechanism does glucose use to uptake into cells

facilitated (passive diffusion) - transport down concentration

Glut 1

brain, eythrocytes, placenta, fetal tissue

glut 2

liver, kidney, intestine, pancreatic Beta cell

glut 3

brain

glut 4

muscle and adipose tissue

also target for obesity research

glut 5

jejunum

what are the sodium - glucose co transporters

SGLT1 : mediates intestinal absorption of glucose from diet on luminal side of intestinal enterocyte (also important to the glucose mediated secretion of incretin hormone of GIP and GLP-1)

GLUT2: important in the basolateral efflux of glucose into the blood stream

2 types of major incretin hormone

GLP-1 (glucagon like peptide)

GIP (gastic inhibitory peptide)

where else does GLP-1 incretin hormones take place

brain, pancreas, kidney, muscle, bone, heart, GI tract, liver

What pathways is insulin associated with

the fed state and the insulin increases the rate of storage pathways:

lipogenesis and glycogen synthesis (insulin=anabolic hormone)

How does insulin stimulate lipogenesis

by acting on two targets: pyruvate dehydrogenase that forms acetyl CoA and acetyl CoA carboxylase(ACC)

acetyl CoA forms malonyl CoA - two major control points

lipogenesis

insulin raises pyruvate dehydrogenase(PD) phasphatase activity removing the phosohate from PD converting pyruvate into acetyl CoA

• inc levels of acetyl CoA increases the flux through not only the fat synthesis pathway but also the TCA

• Malonyl CoA inhibits fatty acid transp. and oxidation by mitochondria

• Glucagon increase phosphorylation deactivating , thereby inhibiting ACC and slowing fatty acid synthesis

how does insulin activate glycogen synthesis

by changing the phosphorylation states of glycogen synthase and glycogen phosphorylase

• insulin activates protein phosphates, removes phosphate from glycogen synthase(enzyme activation) and removes phosphate from glycogen phosphorylase(enzyme deactivation)

how are insuling, glycerol and glucose related

higher insulin concentration = less glycerol and more glucose

lower insulin concentration = more glycerol and less glucose

why does the brain depend on glucose for an energy source

because other pathways cause small amounts of toxic build up which over time can be deathly to humans

what is increased by insuling

1. fatty acid synthesis

2. glycogen synth

3. protein synthesis

4. fatty acid synthesis

5. glucose uptake

what is decreased by insulin

1. ketogenesis

2. gluconeogenesis

3. lipolysis

what is increased by glucagon

1. glycogenolysis

2. gluconeogenesis

3. ketogensis

4. lipolysis