Endocrine 1 Exam 1: Witt-Enderby Pathophysiology (p1-11)

Glucose is tightly regulated by what 4 hormones released from the Islets of Langerhan?

glucagon, insulin, amylin, somatostatin

Glucagon ____ glucose through the ___ cells of the Islets of Langerhans

increases, alpha

Insulin and Amylin ____ glucose through the ___ cells of the Islets of Langerhans

decrease, beta

Somatostatin ____ or ____ glucose through the ___ cells of the Islets of Langerhans

increases, decreases, delta

Low blood glucose would ____ the alpha cells and ___ the beta cells (bc we want to increase glucose levels)

stimulate, inhibit

What is the homeostatic glucose level?

80-100 mg/dL

Insulin is released in response to rising glucose levels (> ____ mg/dL)

100

Insulin is released in response to declining glucose levels (<____ mg/dL)

80

to cause insulin release from beta cells of the pancreas and for glucose to result in energy production in tissues, glucose enters via transporters GLUT__-GLUT___

1-5

GLUT2 is found in the __ and ___

liver, pancreas

GLUT4 is found in skeletal ___, ___ tissue, and ___ tissue

muscle, cardiac, adipose

Mechanism of glucose-dependent insulin release

Step 1: glucose enters the beta cell of the pancreas by facilitated transport which is mediated by the ______ (glucose transporter)

GLUT2

Mechanism of glucose-dependent insulin release

Step 2: after entering the beta cell, the glucose is ____ by ____ (a type of hexokinase). The phosphate group is donated from ATP within the cytoplasm to yield ADP.

phosphorylated, glucokinase

Mechanism of glucose-dependent insulin release

Step 3: There is an increase in ___ due to glycolysis of glucose-6-P

ATP

Mechanism of glucose-dependent insulin release

Step 4: Because of the increased ATP, ATP-sensitive ____ ___ will close

K+ channels

Mechanism of glucose-dependent insulin release

Step 5: Because ATP-sensitive K+ channels close, there is an increase in ____ charge in the cell

positive

Mechanism of glucose-dependent insulin release

Step 6: Because of the increase in positive charge, the cell is now ___

depolarized

Mechanism of glucose-dependent insulin release

Step 7: The depolarization of the cell causes voltage gated ____ ____ to open

Ca2+ channels

After the channels open, there is an influx of extracellular Ca2+ into the cell. This causes activation of phospholipase A2 (PLA2) and ____ ____ (PLC)

phospholipase C

Mechanism of glucose-dependent insulin release

Step 8: Phospholipase C produces the secondary messengers ____ and ___

IP3, DAG

Mechanism of glucose-dependent insulin release

Step 9: IP3 binds to IP3 receptors located on the ___ ___

endoplasmic reticulum

Mechanism of glucose-dependent insulin release

Step 10: After IP3 binds its receptor, there is increased release of ____ calcium stores

intracellular

Mechanism of glucose-dependent insulin release

Step 11: The increase in intracellular calcium promotes the release of ___ and ___ from the beta cell

insulin, amylin

Mechanism of GLP1-dependent insulin release

Step 1-3: in response to ____, gut motility increases and releases ___-__

eating, GLP-1

Mechanism of GLP1-dependent insulin release

Step 4: GLP-1 interacts with GLP-1 ___ on the beta cell

receptors

Mechanism of GLP1-dependent insulin release

Step 5: Gs (stimulatory G protein) and adenylyl cyclase increase intracellular ____

cAMP

Mechanism of GLP1-dependent insulin release

Step 6: increased cAMP increases ___

PKA

Mechanism of GLP1-dependent insulin release

Step 7: increased PKA increases ___ and ___ release

insulin, amylin

___ is the enzyme that breaks down GLP-1

DPP4

DPP4 inhibitors inhibit the breakdown of GLP-1 and therefore ___ its half life

increase

Both sulfonylureas and repaglinide work by inhibiting ___-__ __ ___

ATP-sensitive K+ channels

Once insulin is released into the bloodstream, it is transported to various parts of the body and stimulates insulin receptors to promote the uptake of ___ into cells (ie increase its utilization)

glucose

Once insulin is released into the bloodstream, it also promotes energy storage in the form of triglycerides (via increasing ____), glycogen (via increasing ____), and proteins (via increasing ____ ____)

lipogenesis, glycogenesis, protein synthesis

Once insulin is released into the bloodstream, it also promotes energy storage in the form of triglycerides, glycogen, and proteins via activation of various signal transduction cascades (___, __ ___, __ ___)

IRS, PI3 kinase, MAP kinase

Once insulin is released into the bloodstream, it also has ____ actions on the body by promoting cellular proliferation (MAPK)

anabolic

Insulin receptors are found on virtually every cell including the __, ___, __, and in minute amounts on blood cells, brain cells, and gonadal cells.

liver, muscle, fat

Insulin receptors are found in every tissue within the body that uses glucose for ___

energy

Even though the __ has its own specialized transport system for the uptake of glucose, insulin has been found there

brain

What are the 3 structural forms of insulin?

monomer, dimer, hexamer

Which structural form of insulin binds to and activates the insulin receptor, and is the most efficacious?

monomer

Which structural form of insulin binds to and activates the insulin receptor, but less effectively than monomers?

dimer

Which structural form of insulin does not have any activity at the insulin receptor, and needs to be broken down into monomers to have efficacy?

hexamer

structural forms of insulin

Monomer: ___-acting insulin

Dimer: ___-acting insulin

Hexamer: ___-acting insulin

regular, medium, long

Insulin receptors are classified as ___ ___ ___

receptor tyrosine kinases

Insulin receptors exist as ____ with alpha and beta subunits

monomers

Insulin receptors

-the alpha subunits are located on the ___ of the cell

-the beta subunits are located _____ the cell

outside, inside

Pathways of Insulin Signaling

Step 1: Insulin activates the insulin receptors

Step 2: The insulin receptors ___, which causes the tyrosine amino acid located on the beta subunit to be exposed and ____ by tyrosine kinases

dimerize, phosphorylated

Pathways of Insulin Signaling

The phosphorylation of tyrosine causes ____ (insulin receptor substrate) and ___ ___ to be activated

IRS, MAP kinase

Pathways of Insulin Signaling

Activation of IRS causes ___-__ to be activated

PI3-kinase

Pathways of Insulin Signaling

When PI3-kinase is activated, this stimulates ___ synthesis, ___ synthesis, and translocation of ____

protein, glycogen, GLUT4

Pathways of Insulin Signaling

Translocation of GLUT4 to the plasma membrane leads to "___ of glucose," which means it is converted into Glucose-6-Phosphate to be used in metabolic pathways for ATP production

utilization

Pathways of Insulin Signaling

When MAP kinase is activated, this stimulates ____ (cell proliferation and tissue growth)

mitogenesis

When the ATP:AMP ratio is high (___:___), the cell has sufficient ATP, so excess glucose is diverted toward storage as glycogen, TGs, or proteins

10:1

What is the significance of stimulating glycogen synthesis (ie stimulating glucose storage)?

-____ blood glucose levels

-___ ATP levels

decrease, decrease

Insulin stores glucose by increasing glycogenesis (glycogen synthesis) through the activation of __ ___

glycogen synthase

When the ATP:AMP ratio is low (1:10), the cell activates ____ (which is drug target activated by metformin) to shift cell to more ATP-producing pathways

AMPK

What is the significance of stimulating protein/cell/tissue synthesis (ie mitogenesis)?

-____ blood glucose levels

-___ ATP levels

-____ anabolic effects in body

decrease, decrease, increase

Since we know insulin is anabolic (builds tissue), it makes sense that gestational diabetes can cause babies to grow excessively, called ____

macrosomia

Since we know insulin is anabolic (builds tissue), it makes sense that we have to ___ injection sites on the abdomen and buttocks because local anabolic actions at the injection site can cause dimpling and poor insulin absorption

rotate

What is the significance of stimulating GLUT4 translocation to the plasma membrane?

-____ glucose levels in blood (because we are ↑glucose levels in cell)

-can increase or decrease ATP levels depending on the ___ of ATP:AMP

decrease, ratio

Insulin will be released from the beta cells of the pancreas if glucose levels rise > ___ mg/dL

100

Insulin is the primary hormone of control for the ___, ___, and __ of cellular nutrients like glucose, amino acids, and fatty acids

uptake, utilization, storage

High insulin promotes the ___ of energy.

Low insulin promotes the ___ of energy

storage, release

to remember pathways

“-_____” = formation

“-____” = breakdown

lysis, genesis

What is the term for formation of TGs?

lipogenesis

What is the term for formation of glycogen?

glycogenesis

What is the term for formation of glucose?

gluconeogenesis

What is the term for breakdown of TGs?

lipolysis

What is the term for breakdown of proteins?

proteolysis

What is the term for breakdown of glycogen?

glycogenolysis

Low insulin (like in T1D patients) means ___ storage and ___ breakdown

low, high

Low insulin means low storage and high breakdown, resulting in ___

hyperglycemia

Low insulin promotes the release of energy by stimulating the breakdown of proteins (___), TGs (___), and glycogen (___).

proteolysis, lipolysis, glycogenolysis

Low insulin stimulates lipolysis (breakdown of TGs), which then provides the substrates needed for _____ (making new glucose)

gluconeogenesis

High insulin (insulinemia) means ___ storage and ___ breakdown

high, low

High insulin promotes the storage of energy by stimulating ___ ____, formation of TGs (___), and formation of glycogen (___)

protein synthesis, lipogenesis, glycogenesis

review

___ insulin promotes: proteolysis, lipolysis, glycogenolysis, gluconeogenesis

____ insulin promotes: protein synthesis, lipogenesis, glycogenesis

low, high

storage of glucose is stimulated by insulin and increased by ___

feeding

breakdown of TGs, glycogen, and protein is inhibited by insulin and increased by ___ and in ____

fasting, diabetes

Glucose is an osmotically active substance, meaning that ___ tends to follow it

water

Too much glucose in the ___ (extracellularly) could pull water out of cells and lead to cellular dehydration (cell shrinks)

blood

If cellular dehydration due to hyperglycemia occurs in brain cells, this can cause a "hyperglycemic hyperosmotic nonketotic ___"

coma

If cellular dehydration due to hyperglycemia occurs in the bladder, this can cause an overall dehydration in the body due to a lack of water reabsorption back into the body via the ___

kidneys

Overall dehydration in the body due to cellular dehydration from hyperglycemia contributes to ___ (↑ urination), ____ (↑ thirst), and ____ (↑eating)

polyuria, polydipsia, polyphagia

Besides dehydration, an increase in glucose in the bladder could result in an increase in bladder ___ (UTIs) due to increased bacterial growth in bladder

infections

At normal glucose levels, glucose will either:

-be converted by ____ to glucose-6-P and then to ATP (major pathway)

-be converted by ___ ___ to sorbitol

hexokinase, aldose reductase

At high glucose levels, hexokinase will become ____, meaning more glucose gets converted into sorbitol (a sugar alcohol)

saturated

An increase in glucose in the body may result in an accumulation of glycosylated products and sugar alcohols in ____ ___ (because hexokinase is saturated so we have more sorbitol)

peripheral tissues

An increase in glucose in the body may result in an accumulation of glycosylated products and sugar alcohols in peripheral tissues, like:

-lens of the ____/the retina

-____ walls

-____ cells of the peripheral nerves

eye, arterial, Schwann

Glycosylated products and sugar alcohols can accumulate in:

-lens of the eye and retina (leading to ___)

-arterial walls (leading to premature ____)

-Schwann cells of the peripheral nerves (leading to peripheral ____)

blindness, atherosclerosis, neuropathy

Another consequence of hyperglycemia is a thickening of the capillary basement membrane and other vascular changes resulting in a ______ (narrowing of the vessel lumina)

microangiopathy

In a normally functioning blood vessel, blood circulates to:

-deliver ___ and ____ to tissues

-remove ___ ___

glucose, oxygen, carbon dioxide

In a narrowed blood vessel due to hyperglycemia, there is no blood flow to tissue, resulting in:

-decreased O2 (____)

-decreased _____

-increased ___ ___ (acid)

-____ (death) of tissues

hypoxia, glucose, carbon dioxide, necrosis

If microangiopathy occurs in the retina (ie retinopathy), this may result in ___, ___, and/or ____

cataracts, glaucoma, blindness

If microangiopathy occurs in the nephron (ie diabetic kidney disease or end stage renal disease), this may result in ___ ___

renal failure

If microangiopathy occurs in the peripheral vasculature (macrovascular disease), this may result in ____ ____ ___

atherosclerotic cardiovascular disease

atherosclerotic cardiovascular disease can cause:

a) ___ ___ disease (like MI, stable angina)

b) ____ disease (like TIA, stroke)

c) ____ ___ disease (like atherosclerosis)

coronary artery, cerebrovascular, peripheral artery

Poor circulation in the extremities can cause necrosis of tissues, resulting in severe ulcerations, gangrene, and amputation. This is why __ exams, ___ exams, and regular health check-ups are essential in DM patients !!

eye, foot

Diabetes Mellitus Type 1 is characterized by a decrease in the utilization of glucose by the cells due to a lack of _____

insulin

in DM Type 1 patients, the beta cell can be genetically predisposed to ____ by a virus from the environment

infection