Diabetes Insulin Flashcards
What is the relationship between insulin and glucose?
Excursions mirror one another over 24 hours
What unit is insulin given in?
micro-IU/mL or pmol/L
What do some propose is the ideal fasting insulin levels?
8.4 microIU/mL
What does the head and tail of the pancreas connect to?
Head = duodenum
Tail = tapers to left side of abdomen, near spleen
What is the pancreas?
Narrow 6-inch long gland, left side of abdominal cavity
What Type of gland is the pancreas? What secretions does it produce?
Heterocrine glan; Endocrine and exocrine
What cells make up the endocrine portion of the pancreas?
small bundles of Langerhans cells (red stain)
What cells make up the exocrine portion of the pancreas?
Acini (blue stain)
How many islets are found in a healthy, adult pancreas?
1 million
What types of cells are found in the islets?
beta, alpha, delta, PP (or gamma) and epsilon cells
What is found inside islets?
3000-4000 clusters of cells per iselt
Describe the blood and nerve supply to the islets
Highly vascularised; receive 15% of total pancreatic blood supply
Autonomic nerve fibers (terminals with acetylcholine and norepinephrine)
Differentiate between mouse and human lslets of Langerhans
Mouse:
Red: insulin
Green: glucagon
Very organized
β-cells = 80%
Human:
Red: insulin
Green: glucagon
Less organized
β-cells = 50-60%
What do the 5 different pancreatic cell types secrete?
- alpha cells = glucagon
- beta cells = insulin and amylin
- D cells = somatostatin
- Epsilon cells = ghrelin
- PP cells = pancreatic polypeptide
How is insulin biosynthesised?
Describe what occurs in beta cells at rest.
- Low glucose in the blood
- Metabolism slows
- ATP decreases
- kATP channels open
- Cell is at resting potential and no insulin is released
What happens when a beta cell is secreting insulin?
- High glucose levels in blood
- Metabolism increases
- ATP increases
- kATP channels close
- Cell depolarises and calcium channels open
- Ca2+ entry acts as an intracellular signal (ligand)
- Ca2+ signal triggers exocytosis, and insulin is secreted.
What is the biphasic nature of glucose-induced insulin release?
- With each cellular response to glucose, there are 2 phases of insulin release that follow
- First phase = rapid, transient and there is a pronounced increase in insulin levels which quickly declines
- Second phase = Gradual, sustained and less pronounced increase in insulin levels compared to the first phase
Why does the first phase of insulin release take a shorter amount of time than the second?
There is a readily available of pool of insulin-containing vesicles in the cell
What is the impact of GLP1 on glycaemic control?
- GLP-1 has specific effects on glycemic control (how well glucose is cleared from the body)
- All together these affects lead to Glycemic control improvement
- Promotes satiety in brain
- Delays gastric emptying
- stimulates insulin secretion, B-cell proliferation, inhibits B-cell apoptosis and inhibits glucagon secretion
- Overall improves glycaemic control and reduces body weight
Describe the dose-response curve of glucose-induced insulin secretion
- Sigmoidal
- Glucokinase in pancreatic β–cell acts as glucose
sensor & couples insulin secretion to prevailing
glucose levels
*Glucose concentrations below 5 mmol/L do not
affect insulin release, but progressive increase
5-15 mmol/L range
*Potentiators amplify insulin response at stimulatory
concentrations of glucose
The regulation of insulin secretion is affected by many factors. What are these factors and do they positively or negatively control insulin secretion (via islet B-cell stimulation)?
- High BG [ ] is a major control +
- High GI hormones +
- Parasympathetic stimulation +
- Sympathetic stimulation -
- Epinephrine -
What happens metabolically when insulin is secreted (5)?
- Blood glucose lowers
- Blood fatty acids lower
- Blood amino acids lower
- Protein synthesis increases
- Fuel storage increases
What are the effects of insulin on target tissue?
- Insulin = released and transported in circulation
- Effects specific target tissues
- Increased plasma insulin in response to nutrients
- Consider liver: glucose uptake and insulin
facilitates conversion of glucose into glucose 6 phosphate. Insulin facilitates anabolic reactions in storage. Glucose
converted into glycogen or undergoes metabolism forming pyruvate, acetyl-coA and fatty acids - Consider fat cells: insulin directly facilitates
glucose uptake through specific transporters. Lipogenesis occurs in these tissues producing fatty acids. Insulin can also facilitate FA and monoglyceride uptake by affecting transport proteins involved which is stored. - Muscle: AA also taken up under influence of
insulin under transport proteins. Stored in
muscle proteins. Muscle is major site of glucose
uptake and a specific GLUT activated directly by insulin signalling involved in glucose uptake into muscle. Glucose stored as glycogen or used in metabolism. - Red arrows = decreased insulin levels
Describe this important mechanism, which includes muscle glucose uptake.
- Receptor tyrosine kinase (RTK) is found on the sarcolemma cell surface.
- Insulin binds RTK –> Phosphorylation occurs
- Signal cascade is initiated
- IRS1 = recruited to the sarcolemma and phosphorylated by the activated insulin receptor
- IRS1 becomes activated
- Active IRS1 converts PI3 kinase into active form
- *Akt = next kinase in the cascade and is phosphorylated and activated
- Akt activates and facilitates
translocation of GLUT4 containing vesicles - GLUT4 is insulin responsive
transporter - In rested state: GLUT4 = contained within intracellular vesicles
- In activated state: vesicles = stimulated to move to sarcolemma and fuses to sarcolemma
- Glucose = taken up into myocytes
Describe this important mechanism (how the liver indirectly regulated glucose uptake) in the FED STATE
Hepatocytes in fed state:
- Insulin does not directly regulate GLUT2 in the liver
- Liver: GLUT2 always remains on the cell membrane (unlike GLUT4 for muscle)
- Insulin activates hexokinase that catalyzes the conversion: glucose to glucose-6-P
- Thus insulin lowers liver intracellular glucose levels vs. plasma levels
- As a result, there is a concentration gradient that allows glucose diffusion – via GLUT2 - from plasma into liver cells
- If GLUT2 was not present on cell membrane in fasted state, then glucose would be unable to exit liver cells to enter into circulation
Describe this important mechanism (how the liver indirectly regulated glucose uptake) in the FASTED STATE
Hepatocyte in fasted state:
- Glycogenolysis and gluconeogenesis occurs –> liberates glucose and
produces glucose in hepatocyte which is exported. 2. Works via concentration gradient. - Glucose levels = maintained at homeostatic levels during fasting state.
How does insulin promote glucose storage when in a fed/absorptive state?
- Overall, insulin in fed state decreases plasma glucose
How does glucagon respond in the fasted state?
Low plasma glucose stimulates liver cells to secrete glucagon which stimulates glycogenolysis and gluconeogenesis to increase plasma glucose
Which hormone dominates in the fed and fasted state? Note that these hormones are opposing and synergistic.
Fed = Insulin (move glucose out of blood into cells)
Fasted = Glucagon (move glucose out of cells into blood)
