Endocrine pathophysiology

Glycolysis

- metabolic pathway within all cells that converts glucose into pyruvate yielding = ATP + NADH as energy sources

Gluconeogenesis

- the process of glycogen synthesis, in which, glucose molecules are polymerized to chains of glycogen for storage of glucose

Glycogenesis

- the process of glycogen synthesis, in which, glucose molecules are polymerized to chains of glycogen for storage of glucose

Glycogenolysis

- the process of breakdown of glycogen to glucose

Lipogenesis

- the process of fat and fatty acid synthesis, in which , acetyl-CoA is converted to fats and FFA, hence storing potential energy

Lipolysis

- the process of breakdown of FFA and TG, releasing this stored energy

What is the pancreas?

- pancreas contains both exocrine and endocrine functions which are critical in both digestion and homeostasis

What are the two main types of tissue in the pancreas?

- acinin
- islets

Acin

- secrete the digestive juices into the duodenum

Islets of Langerhans

- secrete insulin and glucagon directly into the blood

What is the function of digestion in the pancreas?

- the product of the pancreatic exocrine acinar cells is an alkaline fluid risk with digestive enzymes, which is secreted into small intestine to aid in the digestive process
- secretions from acini flow out of the pancreas through a tree like series of ducts

What is the structures and features of Islets of Langerhans ?

- are embedded around the acini in a richly vascularized manner
- each pancreas has 1-2 M IoL
- the Islets contain: alpha cells, beta cells, and delta cells

What are alpha cells?

- 25% of the islets
- secrete glucagon

What are beta cells?

- represent 60% of islets
- secrete insulin and Amylin

What are delta cells?

- represent 10% of islets
- secrete somatostatin

What are epsilon cells?

- represent

What are PP cells?

- a small minority of cells which secrete pancreatic polypeptides

What is the pattern of the cells in the islet?

- the beta cells are located centrally, surrounded by alpha, gamma, nd delta
- the arrangement plays a role in the cell to cell paracrine regulation of hormone release

How much pancreatic mass does the Islets represent?

-2%

How much pancreatic blood flow do the Islets recieve?

- 15%

What is the direction of blood flow in the islet?

- direction of blow flow is from the center of the islet to the periphery: alpha and delta cells are exposed to high concentrations of insulin produced by the beta cells contributing to the inhibition of glucagon release by high local insulin concentrations

What happens when venous blood flow from the pancreas drains into the hepatic portal vein?

- the liver is exposed to the highest concentrations of pancreatic hormones before they reach the systemic circulation

Where does the pancreas receives rich innervation from?

- 10th cranial nerve
- T5-T8 ganglia

What does the 10th cranial nerve do in pancreatic innervation?

- increases secretion of digestive juices as well as all islet hormones

What does the T5-T8 ganglia do in the pancreatic innervation?

- inhibits large levels of basal and glucose stimulated insulin secretion
- stimulates glucagon and low level insulin secretion

What happens to the blood glucose when glucagon is released?

- blood glucose is increased

What inhibits and stimulates glucagon release?

- glucagon release is inhibited by hyperglycemia and stimulated by hypoglycemia
- a meal rich in carbohydrates suppresses glucagon release and stimulates insulin release
- high amino acid levels following protein rich meal stimulates glucagon release
- epinephrine stimulates glucagon through beta 2 mechanism ( while it suppresses insulin from beta cells through an alpha 2 mechanism)
- vagal stimulation increases glucagon release

What is an important role that glucagon plays?

- it is important in the regulation of glucose homeostasis by producing antagonistic effects on insulin action - major effect is raised blood glucose

What are the principal target tissues for glucagon?

- liver
- adipose tissue

How is ketogenesis regulated?

- by the balance between the effects of glucagon and insulin at their target organs

What happens with glucagon in the adipocyte?

- glucagon stimulates activation of HSL resulting in the liberation of FFA into the circulation ( lipolysis
- FFA can be used as fuel by most tissues, predominantly skeletal muscle and liver , as they undergo beta oxidation and conversion into ketone bodies

What are the factors that stimulate glucagon secretion?

- hypoglycemia
- amino acids ( protein rich meals)
- gastrointestinal hormones
- cholecystokinin ( CCK)
- fasting
- exercise
- neural influences ( vagal activity - acetylcholine , sympathetic activity)
- beta adrenergic stimulation ( norepinephrine, epinephrine)

What are the factors that inhibit glucagon secretion?

- glucose
- somatostatin
- insulin ( direct effect)
- glucagon like peptide ( decreased GLP-1)
- free fatty acids
- ketoacids
- neural influences ( alpha adrenergic stimulation)

What is insulin historically associated with ?

- with blood sugar by lower blood glucose
- it increases glucose uptake into muscle ( 80% of insulin dependent glucose uptake), fat and other tissue

True/False: Insulin has strong effects on fat and protein metabolism in addition to carbohydrate metabolism

- true

What are the broad effects of insulin?

- if there is excess carbohydrates:
- insulin promotes carbohydrates storage as glycogen in the liver/muscles
- excess carbs that are not stored as converted by insulin stimulation to fat and stored in adipose tissue
- promotes protein uptake into cells and conversion of amino acids into protein
- major effect is to lower blood glucose by promoting uptake into tissue

What is the chemistry and synthesis of insulin?

- it is a small protein consisting of two amino acid chains connected by disulfide bonds

What happens during insulin secretion?

- insulin has a half life of 5-6 minutes in the plasma
- circulates mainly unbound
- metabolized mainly by hepatic insulinase, some in the kidney and muscles as well
- cleared from circulation fully in 10-15 minutes
- rapid removal from the circulation is important as it is often necessary to rapidly turn off the functions of insulin

How is insulin secreted from the beta cell?

- the beta cell is highly specialized and similar to sensory neurons, quickly senses and responds to external stimuli
- in it resting state ( fasting blood glucose) the cell is hyperpolarized
- insulin secretion is initiated by the beta cells ability to sense extracellular glucose

Which incretin hormones use Gs couple receptors to increase insulin release?

- glucagon
- glucagon like peptide 1 (GLP-1)
- glucose dependent insulinotropic peptide (GIP)

How is glucagon released from the alpha cells?

- GLUT 1 senses low glucose to transport glucose inside the cell and causes glycolysis which makes ATP
- ATP binds to ATP sensitive K+ channels which causes mild depolarization to cause influx of sodium and calcium into the cells. This causes secretion of the glucagon from the pancreatic islet

When glucagon is released from the alpha cells what happens when it gets to the hepatocyctes?

- glucagon binds the glucagon receptor which is Gs coupled receptor to stimulate cAMP- PKA and PKA can phosphorylate glycogen phosphate to cause glycogenolysis and production of glucose
- Also PKA can phosphorylate the lactate, glycerol and amino acids though gluconeogenesis to make glucose

What happens to glucagon in the adipose tissues?

- glucagon binds to glucagon receptors which are Gs coupled receptors to stimulate cAMP- PKA which phosphorylates HSL to transfer triglycerides to free fatty acids.
- the free fatty acids are released and are converted to ketones in the liver

What is the glucagon-glucagon positive feedback mechanism?

- when glucose is low glucagon binds to glucagon receptors that are coupled to Gs receptors which causes more release of glucagon

What inhibits glucagon release in the alpha cells when glucose levels are normal?

- insulin

How is insulin secreted from the beta cell?

- GLUT-2 want bind glucose unless glucose is really high because it has low affinity for glucose but it has a high capacity to transport glucose
- When glucose binds to the GLUT-2 receptor and enters the beta cells and once inside it goes through glycolysis to generate a lot of ATP
- ATP sensitive K+ channel can move potassium in or out of the cell ( this is why the cell is in a hyperpolarized state)
- high level of ATP causes ATP sensitive K+ channel to not be able to stay hyperpolarized which decreases K+ conductance and this causes strong depolarization. This leads to a influx of Ca2+ which stimulates insulin secretion
- Also Gs couple receptors can stimulate insulin release from the beta cells
- Gq coupled receptors can stimulate insulin release

What can inhibit the release of insulin from the beta cells?

- Gi coupled receptors ( a2 receptors, somatostatin)

What is the mechanism of insulin action in the skeletal muscle, liver, and adipocytes?

- insulin binds to insulin receptor ( phosphorylates itself)- IRS, PI3K - Akt/ PKB - to stimulate GLU T( inside the cell)
- translocation of GLUT-4 to the surface of the cells causes glucose to be brought inside the cell
- once inside the it goes through glycolysis to make energy and once their is enough it goes through lipogenesis to store the glucose as fat

How does insulin inhibit glucagon secretion from the alpha cells?

- insulin binds the insulin receptors in the alpha cells- PD3 breaks down cAMP so PKA has no activity. This causes glucagon release to be inhibited
- Insulin acting on the delta cells will cause release of somatostatin from the delta cells and binds to the somatostatin receptors on the alpha cells. This is Gi coupled which inhibits stimulation of cAMP which causes no PKA activity and inhibits glucagon secretion

What happens after insulin release in fasting state?

- plasma glucose is 5.6 mM and fatty acids is 400 uM
- glucose is supplies from the liver and fatty acids from the adipose tissue
- plasma insulin levels are low and the plasma glucagon is high which increases glycogenolysis and gluconeogenesis
- low insulin releases adipocytes from normal inhibition allowing increase in lipolysis in the presence of high glucagon
- most tissues will oxidize the fatty acids for use as energy, allowing glucose to be spared for use by the CNS ( the brain does not efficiently utilize fatty acid as an energy source)

What happens after insulin is released after a person eats?

- nutrient absorption presents a challenge to glucose homeostasis, causing great increase in plasma glucose
- under control of insulin , the liver, muscle, and adipose tissue actively take up glucose
- hepatic glucose production and adipocyte lipolysis are inhibited while hepatic glycogenesis and adipocyte lipogenesis are increased ( total body glucose oxidation increases and glucose is used as energy)

What is the role of PNS in glucagon and insulin?

- acetylcholine binds to M3 ( Gq) receptors on the alpha cells to sense low glucose to secrete glucagon
- ACH binds to M3/M5 ( low level) in the beta cells and a low GLU-R to cause a low level of insulin release​

What is the role of the SNS in glucagon and insulin secretion?

- NE/EPI binds to B2( GS coupled receptor) receptors in the alpha cells ​
- NE/EPI binds a2 ( high) receptors on the beta cells which is coupled to Gi to inhibit high levels of insulin rel. NE/EPi binds to B2 ( low) ( Gs) and Glucagon receptor ( low) to cause a low insulin release​

What are incretins?

- GI hormones which are released after meals and stimulate insulin secretion

True/False: Incretins only release insulin when blood glucose is elevated ( want  cause hypoglycemia)

- true

What are the two best known incretins?

- GLP1
- GIP

What are GLP 1 functions in the brain?

- when we eat GLP-1 is release biphasic ( act of eating and when the food gets to the intestines)​

- act of eating sends a signal to the brain and the brain sends a signal through the vagal nerve to intestines to release GLP1​

- the food also causes GLP1 release ​

GLP1 mediated insulin release

GLP1 goes to the pancreatic B cell and it binds to the GLP1 –R ( Gs coupled). This cell has to be undergoing glycolysis . When blood sugar is high this allows for GLP1 to release insulin​

How does GLP1-R agonism inhibits glucagon release from the alpha cell?

GLP1 can shut down glucagon secretion

What is the function of GLP1?

- suppressing glucagon release
- decelerates gastric emptying and reduces food intake
- stimulates satiety and reduces appetite
- leads to weight loss upon chronic exposure
- chronic pancreatic GLP1- R agonism leads to pancreatitis

What is the enzyme responsible for the breakdown of GLP1?

- dipeptidyl peptidase IV

What is the function of dipeptidyl peptidase IV inhibitors?

- stop the breakdown of GLP 1

True/ False: somatostatin inhibits both glucagon and insulin secretion

- true

Glucose reabsorption form the RPT

- low urine glucose because glucose is reabsorbed through the GLUT-2

What happens when their is too much glucose for SGLTs to transport?

- there will be more glucose in the urine ( which is an indicator of a person having diabetes)

Glucose reabsorption from the RPT when it is saturated with glucose

- high urinary glucose level​

- starts making more SGLT2 leading to more glucose reabsorption​

- increased hyperglycemia​

- Tmax is reach and urinary glucose increase​

True/False: GLP1 can not cause hypoglycemia

- true

True/False: you must be hyperglycemic for GLP1 to work

- true

How can we take advantage of GLP1 based therapy?

- can inhibit DPP4 or agonize GLP1

Type 1 diabetes

- autoimmune ( body attacks the beta cells)
- most common in children and teenagers

Type 2 diabetes

- insulin resistance ( not able to take up glucose)
- can lead to loss of insulin secretion
- no insulin secretion or insulin sensitivity

hyperinsulinemia followed by poor insulin secretion

- Insulin resistance: Hyperinsulinemia because there is a high level of insulin. Insulin sensitivity is lost and GLUT-4 translocation does not occur, so no glucose is brought into the cell​
- there is no glucose inside the cells and there is no glycolysis happening to produce energy​
- the cell perceives a lack of energy ( so they think there is no glucose)​
- In type 2 diabetes there is insulin resistance, so insulin is not being secreted so the alpha cells perceives there is low blood sugar and starts making more glucagon​
Adipose: lipolysis happens because the adipose perceives no glucose so it makes free fatty acids​
- decrease AMPK – lipogenesis happens to store the free fatty acids​
- macrophages causes inflammation of the adipose​

Diabetic ketoacidosis

- may be the first symptom of undiagnosed diabetes

Symptoms of diabetic ketoacidosis

- dehydration ( thirsty)
- hyperventilation
- hyperglycemia

What can excessive dehydration and volume depletion lead to in people with diabetic ketoacidosis?

- tachycardia
- hypotension

How is diabetic ketoacidosis diagnosed?

- excessive ketones in blood/urine
- low blood pH (

Which receptors increase intake of food

- a2 agonist
- 5HT-1A agonist
- a1 antagonist
- b2 antagonist
- 5HT-2B or 2C antagonist
- H1 or H3 antagonist
- D1 or D2 antagonsit

What receptors decrease food intake?

- a1 agonist
- b2 agonist
- 5HT-2B or 2C agonist
- H1 OR H3 agonist
- D1 or D2 agonist
- a2 antagonist
- 5HT-1A antagonist

What is basal insulin?

-controls blood sugar between meals and while fasting (covers glucose that the liver makes)​

What is bolus insulin?

- controls blood sugar when you eat

True/False: at even higher concentrations at neutral pH in the presence of ZN insulin hexamerizes

- true

True/False: the hexamer of insulin is slow

- true

True/False : The monomer of insulin is fast

- true

Insulin- Humulin

- inject 30-45 minutes before you eat
- hexamer regular acting insulin with slow duration
- known as Humulin-R
- side effects: hypoglycemia

Afrezza

- inhaled at the beginning of meal
- contraindicated in patents with Asthma , COPD
- people with normal lung function can have decrease lung function over time
- side effect: hypoglycemia

Short acting insulin analogs

- absorbed more rapidly SQ
- inject

Insulin Lispro ( Humalog, Ademlog)

- short acting insulin analog
- can eat at the same time you take medication
- prevalence of hypoglycemia is reduced

Insulin aspart ( Novolog)

- short acting insulin analogs
- replaces proline on the beta chain site 28 with aspartic acid
- hexamer of insulin
- low rates of ight time hypoglycemia as compared to other insulins

Humulin-N

- intermediate acting insulin analogs
- regular insulin in a isophane suspension ( stabilizes multiple forms ( hexamer, monomer, dimers)
- insulin dissolves more gradually when injected SQ

NPH

- intermediate acting insulin analogs
- often 70:30 with regular insulin ( Humulin 70:30)
- insulin dissolves more gradually when injected SQ

Insulin glargine ( Lantus)

- long acting insulin
- 2 arginine added to C terminus of beta chain and asparagine at the alpha 21 spot on the alpha chain is replaced with Glycine
- aggregation of hexamer upon SQ injection
- has a acidic pH so do not mix with shorter acting insulins
- basal because it covers a long period of time
- once daily administration

Insulin determir ( Levemir)

- long acting insulin
- has a fatty acid on the Lysine 29 on the beta chain
- twice daily injection
- binds to albumin due to fatty acid

Insulin degludec- Tresiba, Ryzodeg

- ultra long lasting insulin
- 30-90 minute onset
- glucose lowering duration of action lasts for 42 hours

Which insulins are basal insulins ( long duration of time)?

- NPH( Humulin-N, Novolin-N)
- Glargine ( Lantus/Basglar/Toujeo)
- Determir( Levemir)
- Degludec(Tresiba)

What are the insulins that are bolus insulins ( short acting)?

- Lispro ( Humalog)
- Aspart ( Novolog)
- Glulisine ( Apidra)
- Afrezza
- Humulin-R
- Novolin-R

True/False: diet and exercise influence insulin action

- true

Lipoatrophy

- decrease fat

Lipohypertrophy

- increase fat

What are oral medications that are insulin sensitizers?

- metformin
- thiazolidinediones

What is insulin sensitizers?

- make the patient sensitive to the effects of insulin