Patho Lecture 9: Diabetes Mellitus + DKA

Pancreas and Liver General functions in insulin system

Pancreas Produces insulin

Liver Responds by storing glucose as glycogen + stopping sugar production

What does insulin reception allow for?

allows glucose to enter cells, inside cells glucose is used for energy, growth and storage, helps glucose be stored in health destinations

Describe how insulin helps glucose move into fat/muscle cells

insulin attaches to an insulin receptor which signals GSV vesicles to go to the surface and takeup glucose in GLUT 4 mediated glucose uptake (GLUT 4- relatively high affinity)

What is the primary pathology in Type 2 Diabetes?

vessicles for GLUT mediated glucose uptake don’t move to the surface of cells in peripheral tissues

Pancreatic Cell Role in Insulin Cycle

GLUT 2 receptors (lower affinity) detect high blood glucose (take in glucose) causing ATP inc, opening of potassium channels causing an inc in calcium, this neural signal causes insulin vesicles to rise to the surface and release insulin to the bloodstream

the vessicles moving to the surface is affected in T2DB

Liver Cell and insulin

GLUT 2 receptors (lower affinity), insulin attachment to insulin receptors triggers GSVs to bringg glucose in where the liver stores it as glycogen or promotes lipogenesis in cases of excess glucose

What happens when there’s more glucose than can be used for energy or stored as glycogen?

in liver cells (GLUT 2 receptors) insulin promotes lipogenesis and decreases gluconeogenesis, lipogenesis- conversion of excess glucose to fatty acids which are packed as triglycerides in VLD lipoproteins which are transported through the blood to fat cells

Describe lipogenesis: why it occurs and the cells involved

lipogenesis (the conversion of excess glucose to fatty acids) occurs when there is more glucose in thhe blood than can be stored as glycogen or used for hepatocyte metabolism, insulin receptors on liver cells promote conversion of glucose to fatty acids which are packed as triglycerides in VLDL and transported thru the blood to fat cells where lipoprotein lipase splits the triglycerides back into free fatty acids lets them into the cell and then rebuilds the triglycerides for storage within adipose tissue

Adipose tissue and insulin

in high blood sugar: stores triglycerides liver made from excess glucose (breaks them with lipoprotein lipase then uses alpha-glycerophosphate from glucose to rebuild them in the cell), inhibiting hormone-sensitive lipase decreases lipolysis

What happens in adipose tissue if there is an increase in glucose and insulin?

1) inc triglyceride storage (lipoprotein lipase) 2) inhibit triglyceride breakdown (lipolysis) preventing release of fatty acids 3) inc lipogenesis (glusoce used to make alpha-glycerophosphate) glycerol combines fatty acids to triglycerides

What type of gglucose receptor do muscle, liver, adipose, and pancreatic cells have?

GLUT 4 muscle/adipose, GLUT 2 pancreas/liver, GLUT 2/3 all peripheral tissues

GLUT 2 + GLUT 3

found in all periphery tissues, hhigh affinity, insulin upregulates their intake to make up for glucose that was used up in these cells

(striated) Muscle cell and insulin

insulin attaches to insulin receptors causing GSV vesicles to rise to the surface for GLUT 4 mediated glucose uptake, if you exercise after the meal glucose is used for energy, if you dont exercise then insulin receptors trigger glycogen synthase and glucose is storred as glycogen (glycogen synthesis)

What happens in muscle cells not exercised after a meal?

insulin reception activates glycogen synthase and glucose is stored as glycogen through glycogen synthesis

What are the 4 types of glucose receptors discussed in class in increasing affinity order

GLUT 2 receptors in pancreas and liver (lower affinity) feedback receptor

GLUT 4 receptors in muscle/adipose (relatively high affinity)

GLUT 1+3 receptors in all body tissues (high affinity)

affinity affects how easily glucose can enter the cell

What is a normal blood sugar range?

70-100 mg/dL

Diabetes is a group of _______ _______ associated with ____

metabolic disorders, hyperglycemia

What percent of all cases are type 1 vs type 2 diabetes?

type 1 (5-10%), type 2 (90-95%)

simple sentence definition of Type 1 Diabetes

absolute insulin deficiency cause by pancreatic B-cell destruction usually from autoimmune attack

simple sentence definition of Type 2 Diabetes

peripheral insulin resistence, inadequate compensatory release from B cells, relative insulin deficiency

in type ___ diabetes insulin release begins to drop off at ___ years, but glucose remains relatively normal until ___years when it becomes overt diabetes

1, 10, 20

T1D is affected by ___ genetic loci, the most important of which is the ___ locus which contributes ___% succeptability

multiple, HLA, 50

What are 3 mechanisms that can lead to T1D?

bystander damage, molecular mimicry, viral deja vu

Bystander damage

mechanism for T1D, viral infections cause islet injury/inflammation that releases B-cells and antigens that activate autoreactive T cells

Molecular mimicry

mechanism for T1D, viruses produce proteins that mimic B cell antigens and the immune response reacts wit self tissue

viral deja vu

mechanism for T1D, viral proteins from previous infection reinfect islet cells

all type 1 diabetes mechanisms lead to ______

B cell destruction

Type 1 diabetes starts ___ before the disease is evident. Classical manifestations occur after __% of __cells are destroyed

year, 90, B

to differentiate the type of diabetes you check for _____ level which marks ______ and is _____ in T1D

c-peptide, endogenous insulin release, very low

T1D mechanisms are related to ___cell destruction and a failure of _____ ______ to ___cells

B, self tolerance, T

monogenetic forms of diabetes

primary defect in B-cell function or insulin receptor signaling

Other causes of diabetes

pancreatic defect, gestational diabetes (inc risk for mom and baby), drug induced

B-Cells

beta cells, responsible for insulin secretion in pancreas

main effects of glucagon vs insulin

glucagon: released by A cells (raise BS) cause hepatocytes glycogenolysis and gluconeogenesis, insulin: released by b cells (lower BS) inc glucose absorption, glyconeogenesis, lipogenesis

A cells

pancreatic a cells have channels that generate action potentials in abscence/low levels of glucose triggering Ca signals and glucagon secretion

insulin partially inhibits _____ released by _ cells

glucagon, a cells

The mechanisms that have been proposed to explain the development of Type 1 Diabetes by autoimmune response all involve______

infections by a virus

Differentiating Type 1 vs. Type 2 Diabetes in an individual with hyperglycemia for whom we don't have any previous history or labwork involves testing for:

C-peptide (low in T11, normal/high in T2)

The initial response of the pancreas to the hyperglycemia seen in early Type II diabetes is to

increase insulin release

Ketogenesis is a ___ process in a healthy patient; In a diabetic patient, ketogenesis can cause _____

normal, DKA

Of the following states, which is NOT considered a DANGEROUS effect of suffering from DKA?

peripheral edema

Hypokalemia

Hyponatremia

Dehydration

Acidosis

peripheral edema