WEEK 3 Flashcards
Where is the pancreas located?
beneath liver and tucked into curvature of duodenum
What are the exocrine functions of the pancreas?
- secretes enzymes into duodenum to support digestion of macromolecules
- secretes bicarbonate into duodenum to raise pH of chyme
What are endocrine functions of pancreas
- islet of langerhans include two types of cells that secrete hormones
. alpha cells - secrete glucagon in response to low blood glucose and to activity of sympathetic nervous system
. Beta cells - secrete insulin in response to high blood glucose and to activate of parasympathetic nervous system
what are the islet of langerhans
groups of pancreatic cells secreting insulin and glucagon
what does glucagon do?
raises blood glucose
what does insulin do
lowers blood glucose
Why is glucose important?
it is a preferred source of energy to produce ATP by cells of body
normal range for BG
during fasting - 4-7mmol/L
2 hours after meals - 5-10mmol/L (5-8) if tightly controlled
Why is insulin called a hypoglycemic hormone?
acts to decrease BG levels
difference between glucose and glycogen
glucose - found in blood
glycogen - found in liver and muscle cells and is a collection of many glucose molecules that is stored for future use (like a camel)
How does insulin bring the blood sugar down?
- decreased glycogenolysis - inhibits breakdown of glycogen to glucose
- decreased gluconeogenesis - inhibits making of glucose from non-carbs
- increased glycogenesis - turns glucose into glycogen
How does glucagon increase blood glucose
-increase glycogenolysis - breaks down glycogen to glucose
- increase gluconeogenesis - turns non-carbs into glucose
Why is glucagon a hyperglycemic hormone
Acts to increase BG levels
think of proinsulin as insulin’s dad
How is insulin made?
- Proinsulin is composed of an A peptie chain and a B peptide chain connected by a C peptide chain and 2 disulfide bonds
- C peptide is cleaed by proteolytic enzymes, leaving the bonded A and B peptide chains that become insulin
What is C peptide a measure for in the blood?
indirect measure of serum insulin synthesis
Glucose uptake: How does insulin work?
- Insulin binds with plamsa membrane receptors in cell found throughout the body
- as insulin binds, it sets off a cascade of signals to activate glucose transporters (GLUT) for entry of glucose into cell
Where is GLUT stored?
- stored in cellular vesicles until activated by insulin recpetors
- it is then translocated to cell surface where it facilitates the diffusion of glucose into the cell
- translocation of GLUT4 to cell surface is associated with a 10-21 fold increase in glucose fiddusion into the cell - skletal, cardiac, liver, adipose cells
Fast acting vs slow acting hyperglycemic hormones (AKA counter regulatory/ stress hormones)
FGE (Fast England Girl), SGGC - (Slow Gnome Growth Candy)
fast acting - EG - glucagon and epinephrine
Slow acting - GGC - growth hormone, glucocorticoid hormones, cortisol
effect of counter regulatory hormones - infection, illness, injury, surgery, physical/emotional stress
- causes hyperglycemia
- increases epinephrine, increased GH, increases cortisol and inhibits glucose uptake into cells - increase in BG through glucogenolysis and glycogenolysis- inhibits insulin release
- causes increase in BG and hyperglycemia and ketoacidisos can occur
when ill - effect of counter regulatory hormone
- drug regime may change when client is having surgery or some diagnostic test
- ct. must understand that drugs for diabetes should not be withheld during times of illness because counter regulatory mechanisms often increase BG
- food intake is also important during this time because body requires extra energy
- extra insulin may be necessary to meet demands placed on body and to prevent onset of DKA in ctwith type 1 diabetes
What is diabetes?
- affects metabolism of carbs, fat and protein
- characterized by hyperglycemia - resulting from defects in - insulin secretion, insulin action, or both
- categories - type 1, type 2, gestational diabetes, other specific types
Type 1 diabetes: common theory (how it happens)
Autoimmune - genetic and environmental factors, resulting in gradual process of autoimmune destruction in genetically susceptible individuals
Nonautoimmune: Unknown
Type 1 diabetes: presence of antibody
Autoantibodies to insulin and glutamic acid decarboxylase (GAD65)
Type 1 diabetes: Insulin resistance
Insulin resistance at diagnosis is unusual, but may occur as individual ages and gains weight
type 1 diabetes: insulin secretion
Severe insulin deficiency or no insulin secretion at all
Type 1 diabetes: characteistics
- cellular mediated autoimmune destruction of pancreatic beta cells - leads to absolute insulin deficiency
- individual prone to ketoacidosis
- insulin dependant
- 75% of individuals develop before 30 years of age
- usually not obese
Type 1 diabetes: genetic susceptibility
- first degree relative - parent/sibling with type 1 diabetes
- strongest association with major histocompatibility complex - group of genes that code for proteins found on the surfaces of cells that help the immune system recognize foreign substances
Type 1 diabetes: environmental factors
- viral infection
- helicobacter pylori
- exposure to cows milk proteins
- relative lack of vitamin D - also implicated
Type 1 diabetes: pahtophysiology
- immunologically mediated destruction of beta cells
- lymphocyte and macrophage infilterate islets, resulting in inflammation and beta cell death
- autoantibodies are produced against islet cells, insulin, glutamic acid decarboxylasae and other cytoplasmic proteins
- hyperglycemia, glucagon and hyperketonemia
- both alpha and beta cells are abnormal and both lack insulin and amylin and have excess glucagon, contributing to hyperglycemia
Type 1: P3WF = (PoWerPPuff)
Clinical manifestations of type 1 diabetes
- Polydispia
- polyuria
- polyphagia
- weight loss
- fatigue
Type 1 diabetes: treatment
- goal - to restore BG elvels and correct metabolic disorders
- combination of insulin, meal planning, excersise and self monitoring of BG transplant (islet cells and whole pancreas)
Type 2 diabetes or Type 1 diabetes. Which is more common?
- Type 2 diabetes
Risk factors for type 2 diabetes:
- age
- obesity
- HTN
- physical inactivity
- family history
- central/visceral obesity - distrubition of fat is localized around abdomen and upper body (apple shape)
- dyslipidemia - increased triglycerides (fat storage), decreased HDL-C (high density lipoprotein)
- increased BP
- increased FBG - fasting blood glucose
- affects both adults and children
- genetic, epigenetic and environmenttal interactions - msut be genetically predisposed
- ranges from predominantly insulin resistance with relative insulin defiecieny to predominantly an insulin secretory defect with insulin resistance
Type 2 diabetes: etiology
- genetic susceptability combined with environmental determinants- defects in beta cell function combined with insulin resistance - associated with long duration obesity
are antibodies present in type 2 diabetes?
no
Insulin resistance - type 2 diabetes
insulin resistance is virtually universal and multifactoral in origin
Insulin secretion- type 2 diabetes
typically increased at time of dignosis, but progressively declines over course of illness
Type 2 diabetes: characteristics
- usually not insulin dependant but may be insulin requiring
- individual not ketosis prone but may from ketones under stress
- obesity common in abdominal region and also associated with hypertension and dyslipidemia
- generally occurs in those older than 40 years, but frequency is rapidly increasing in children
- strong genetic disposition
Type 2 diabetes- three core mechanisms
A. insulin resistance - response of insulin sesitive tissues (liver, muscle and adipose) to insulin is suboptimal, obesity makes one prone to insulin resistance
B. beta cell dysgunction - beta cell mass is decreased, inflammation and changes occur in adipokines
C. Glucagon - pancreatic alpha cells are less responsive to glucose inhibition - hyperglycemia- abnormally high levels of glucagon increase hepatic production of glucose
what are adipokines
cytokines produced by adipose tissue
what is leptin?
hormone released by adipose tissue that helps maintain normal weight on a long term basis eg - feeling full
what is adiponectin
secreted by adipocytes - factor for regulating glucose levels
what is a free fatty acid?
important energy sources for most body tissues
MA FIH? (means HUHHH in arabic)
How does obesity lead to insulin resistance and type 2 diabetes?
M- mitochondrial dysfunction - decreased insulin induced mitochondrial activity leads to insulin resistance
A - Adipokines - increased serum levels of leptin and decreased levels of adiponectin result in inflammation and decreased insulin sensitivity
F- Free fatty acids - Increased FFA, along with intracellular deposits of triglycerides and cholesterol, lead to decreased tissue responses to insulin
I - inflammation - Adipocyte- associated proinflammatory macrophages and inflammaory cytokines released from adipocytes induce insulin resistance and are cytotoxic to beta cells
H- Hyperinsulinemia - obesity is correlated with hyperinsulinemia and decreased insulin receptor density
Clinical manifestations of type 2 diabetes
Nonspecific - fatigue, pruritus, recurrent infections, visual changes, symptoms of neuropathy - paresthesia and weakness
Often overweight
dyslipidemic
hypertensive
Type 2 diabetes: treatment
Prevention of type 2 diabetes, especially in those individuals with prediabetes, hinges on diet and excersise
As with type 1 diabetes - goals is to restore near BG levels and correct metabolic related disorders
Diagnostic criteria for prediabetes
FPG - 6.1-6.9 -IFG
- 2hPG in a 75g OGTT - 7.8-11.0 - IGT
- A1C (%) - 6.0-6.4 - Prediabetes
How can you diagnose/find out someone has diabetes
- Glycosylated hemoglobin levels - Permanent attatchment of glucose to Hb molecules - reflects avergae exposure over life of a RBC
- FPG levels
- two hour plasma glucose during oral glucose tolerance testing (OGTT) using a 75g oral glucose load
- random glucose levels in an individual with symptoms
Diagnosic criteria for diabetes
FPG greater than or equal to 7.0 mmol/L (fasting = no caloric intake for atleast 8 hours)
A1C greater or equal to 6.5%
2hPG in a 75 g OGTT greater than or equal to 11.1 mmol/L
Random PG greater than 11.1 mmol/L (random=any time of the day, without regard to interval since last meal)
What is obesity?
relapsing chronic disease characterized by excessive/abnormal body fat
How does excessive adiposity lead to type 2 diabetes or CV
- excessive adiposity is a source of adipokines and infammatory mediators that alter glucose and fat metabolism leading to that risk
Does obesity affect insulin resistance?
yes the degree of obesity affects the degree of insulin resistance
How is adipose tissue classified?
Imagine a big old white person and an energetic brown girl that has iron defiency
WAT - Most adipose tissue, stores excess fat, excess WAT contributes to obesity, visceral and subcutaneous stores, contains macrophages, mast cell, fibroblasts, endothelial cells, blood vessles, nerves and precursor adipocytes, estrogen and estrogen recpetors help metabolize fat
BAT - rich in mitochondria, iron, exposure to cold, activation of SNS, cathecholamines and activation of triiodothyronine stimulate BAT to rapidly generate heat through activation of uncoupling protien 1
Visceral WAT and what it leads to
Adipose tissue localized around abdomen and upper body
* central or visceral obesity
* results in apple shape
* excess causes adipocyte dysfunction and dysregulation of adipokines
Increase in adipocyte size
* exceeds supporting vascular supply resulting in
hypoxia and inflamed and fibrotic adipose tissues
* leads to dysregulation of adipokines, macrophage
infiltration, insulin resistance, chronic proinflammatory state, and altered lipid metabolism.
Excess lipolysis leads to increased release of free
fatty acids (FFAs) into circulation
* excess FFAs are distributed to non-adipose cells, and
when their utilization capacity is exceeded, cellular dysfunction or death occurs (lipotoxicity)
PLush
What happens to the FFA that go into non-adipose tissue?
Pancreatic beta cells - FFAs cause beta cell dysfunction - lipotoxicity
Liver - Increased FFAs and Increased triglycerides - decreased hepatic insulin sensitivity and increase in glucose production - hyperglycemia. Uptake of FFAs from portal circulation leads to hepatic triglyceride accumulation and leads to non-alcohol fatty liver disease
Skeletal muscle - FFAs cause insulin resistance and decrease glucose use in peripheral tissues
Heart - CAD
What is an adipocyte?
- Adipocytes are the cellular basis of obesity and most are white
- They store triglyceride and secrete adipokines
- They regulate food intake, energy metabolism and other hormonal functions
- Adipokines increase or decrease in the blood circulation in relation to the body fat mass
- Contribute to insulin resistance → increased BG levels
- Adipokines primarily from WAT are:
- Leptin
- Adiponectin
leptin
Expressed primarily by adipocytes
* Regulates hepatic gluconeogenesis, insulin sensitivity, and glucose and lipid metabolism in liver, muscle, and adipose tissue
* Leptin levels INCREASE as number of adipocytes increase
* but…increased levels cause body to not respond to leptin
the way is it supposed to!
* leads to dysregulation and leptin resistance
* Leptin resistance results in
* insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia
* stimulates macrophages and endothelial cells to produce proinflammatory mediators
Adiponectin
- primarily produced by visceral adipose tissue
-. insulin sensitizing
anti - inflammatory
antiatherogenic - plasma levels decrease with visceral obesity - contributes to insulin resistance
