Diabetes and Dyslipidemia Flashcards
Exam 4
What are the 2 major types of secretory tissues of the pancreas?
Exocrine gland (digestive enzymes)
Endocrine gland (Islets of Langerhans)
What are the 5 cell types of islets of Langerhans?
Alpha, beta, delta, G cell, and F cell
What do the alpha Islets of Langerhans cells secrete?
glucagon and proglucagon
What do the beta Islets of Langerhans cells secrete?
insulin, C-peptide, proinsulin, amylin
What is the role of amylin?
suppressed the production of glucagon
_____ is the opposite of insulin
glucagon
What do the delta Islets of Langerhans cells secrete?
somatostatin
_______ blocks the release of glucagon and insulin
somatostatin
What is the main type of cells of the Islets of Langerhans?
Beta cells - 75%
Alpha cells - 20%
Insulin receptors are _____
RTKs - receptor tyrosine kinases
When insulin binds to insulin receptors, what occurs inside the cell?
Glucose transporters migrate to cell surface
What is the normal blood glucose?
90 mg/dL
Describe the homeostatic response to increased blood glucose
Increase in blood glucose → pancreatic beta cells release insulin → body cells take up more glucose and liver takes up glucose and stores it as glycogen → blood glucose levels decline to set point
Describe the homeostatic response to decreased blood glucose
Decrease in blood glucose → pancreatic alpha cells release glucagon → liver breaks down glycogen and releases glucose into the blood → blood glucose levels rises to set point
What are the 4 types of diabetes mellitus?
Type I - Insulin dependent
Type II - Non-insulin dependent
Type III - Other causes elevated blood glucose (pancreatitis, drug therapy, etc.)
Type IV - Gestational
The breakdown of glycogen is also known as _______
glycogenolysis
The creation of glycogen is also known as _______
glycogenesis
What is the most common cause of type 1 DM?
Immune
- idiopathic less common
How high does glucose need to be to be excreted in urine? What is this called?
160 mg/dL
- renal threshold
What are the 3 cardinal signs of all diabetes?
Polyuria, polydipsia, polyphagia
Mellitus means _____
sugar
Type I DM is caused by the destruction of ____, resulting in _____
beta cells
Severe or absolute insulin deficiency
What is the symptom of type 1 DM that differs from type 2?
weight loss
How is type 1 DM treated?
Require insulin replacement
If a patient with type 1 DM doesn’t take insulin, what happens?
Diabetic ketoacidosis (DKA)
Diabetic ketoacidosis causes a patient to have a _____ smelling breath
fruity
What is the patho behind type 2 DM?
Combination of relative deficiency of insulin secretion with tissue insulin resistance
What is the treatment for type 2 DM?
Exercise, treatment of obesity, medication
What are the clinical manifestations of type 2 DM?
- Recurrent infections, vision problems, neuropathy
- Dehydration – nonketotic hyperosmolar coma
What are the 4 chronic complications of type 2 DM?
- Hyperglycemia and nonenzymatic glycosylation - hemoglobin
- Hyperglycemia and the polyol pathway
- Sorbitol and fructose increase intracellular osmotic pressure (attracts water, leading to cell injury)
- Evident in the eye lens, nerves, RBCs
- Protein kinase C - Enzyme inappropriately activated by hyperglycemia
- Microvascular disease - Retinopathy
and Diabetic nephropathy
Prediabetic fasting blood glucose is ____
100-110 mg/dL
What is the normal fasting blood glucose?
70 mg/dL
Gestational DM occurs in __% of US pregnancies
7%
Normal HA1C is __. Target for DM patients is __
4%, 7%
How does gestational DM work?
Hormones block → Insulin resistance
How is DM diagnosed?
- Fasting Blood Glucose
- Glucose Tolerance Test
How is DM monitored?
- Self: Glucose POC
- Hemoglobin A1C
- Insulin
Insulin is a ____ hormone
peptide
The alpha and beta chains of insulin are held together via ______
disulfide linkages
Insulin is activated in the _____ before being released into the bloodstream
granules
The proform of insulin contains ______ which is _____ before entering the bloodstream
C-peptide
cleaved off
What is the function of C-peptide?
no known function
C-peptide is a measure of how much _____ function a patient has
beta cell
What is an insulin secretagogue? What are the different types?
increases release of insulin
- Glucose
- Amino acids
- Hormones
- Fatty acids
- Incretins
- Drugs – sulfonylureas, isoproterenol
The number one insulin secretagogue is _____
glucose
What are the transporters used to transport glucose into the beta cell?
GLUT2
Describe the effects of inward movement of glucose into pancreatic beta cells via GLUT2 transporters
excess glucose converted into ATP via metabolism → higher level of ATP binds to potassium channel - closing the channel → more positive Vrm → calcium channels open up → calcium enters beta cell → calcium triggers vesicle fusion and insulin exocytosis
How long does insulin last in the blood stream?
6 min
GLUT2 transporters have ____ affinity for glucose, meaning they have a ___ Km
low, high
Describe the pathway of insulin binding to its receptor
dimerization of units → insulin binds to receptor → beta units start internal signaling by becoming phosphorylated → IRS (insulin response substrates) activated → MAP kinase and IP3 pathways activated
Which glucose transporters have a high affinity for glucose?
GLUT1, 3, 5
Where are GLUT1 transporters located?
All tissues, especially RBCs and brain
GLUT4 transporters have a ____ affinity for glucose
medium
Where are GLUT2 transporters located?
Beta cells of pancrease
liver, kidney, gut
Where are GLUT3 transporters located?
Brain, kidney, placenta
Where are GLUT4 transporters located?
muscle and adipose
Where are GLUT5 transporters located?
gut, kidney
What are the main 3 endocrine effects of insulin?
- inhibits glycogenolysis
- inhibits conversion of fatty acids and amino acids to keto acids (prevents DKA)
- Promotes glucose storage as glycogen
What are the 5 inhibitors of insulin secretion?
- Insulin
- Leptin
- SNS (alpha adrenergic)
- Chronically high glucose
- Drugs – diazoxide, phenytoin, vinblastine, colchicine
What are the 4 types of insulin preparations?
- Rapid acting
- Short acting (regular)
- Intermediate acting
- Long acting
What are the 3 rapid-acting insulin preparations?
Lispro, aspart, glulisine
What are the 2 short-acting (regular) insulin preparations?
Novolin, humulin
What is the 1 intermediate-acting insulin preparation?
Neutral protamine Hagedorn
What are the 2 long-acting insulin preparations?
Glargine, detemir
Why are there so many types of insulin preparations?
To mimic normal insulin secretion
What are the different forms of insulin delivery?
- SQ injection – hypodermic needle
- Portable pen injectors
- Continuous Subcutaneous Insulin Infusion Devices (CSIID) - pump
Which type of insulin delivery is best for tight insulin control?
Continuous Subcutaneous Insulin Infusion Devices (CSIID)
How is insulin calculated?
- Basal – 1 injection, long-acting
- Bolus – Carbohydrate coverage
- 1 unit of RA insulin – disposes 12-15g of carbohydrate
- Correction – High glucose
- 1 unit of RA insulin needed to drop 50 mg/dL
Which type of insulin delivery is considered “okay” insulin control?
70:30 premixed
We need ____ insulin when sick. Why?
more - metabolic rate increases
What are the 6 symptoms of hypoglycemia?
Anxiety, blurred vision, palpitations, shakiness, slurred speech, sweating
What is the treatment for hypoglycemia?
- glucose/simple sugars: 3-4 glucose tablets, ½ can of soda
- glucagon injection
What are the 8 types of oral antidiabetic agents?
- Biguanides
- Insulin Secretagogues
- Thiazolidinediones (TZDs)
- α-glucosidase Inhibitors
- Bile Acid Binding Resins (BABR)
- Amylin Analogs
- Incretin-based Therapies
- SGLT2 Inhibitors - Gliflozins
What is the MOA of Biguanides?
Reduction in hepatic glucose production
- gluconeogenesis: making glucose from other things
What is the first-line therapy for type 2 DM or NIDDM?
Biguanides - metformin (Glucophage)
What is the MOA of insulin secretagogues?
Bind to K+ channel
- Rectifier current
- Binding causes depolarization and additional release of insulin
What are the 3 classes of Insulin Secretagogues?
- Sulfonylureas
- Meglitinide
- Phenylalanine derivatives
What is the difference between 1st generation vs 2nd generation sulfonylureas?
1st generation requires higher dose
What is the main contraindication for taking Sulfonylureas?
CV disease - increases risk of CV mortality
What is the MOA Thiazolidinediones (TZDs)?
- Decrease insulin resistance (PPAR mediated)
- Increase insulin signal transduction
Meglitinides are _____ than Sulfonylureas
safer - half-life is shorter
What is the risk of taking Thiazolidinediones (TZDs)?
Risk of MI - Increased with insulin, nitrates
What is the MOA of α-glucosidase Inhibitors? What is the medication called?
Block digestion of complex carbohydrates - more beneficial for people have primary carbohydrate diet
Acarbose
α-glucosidase Inhibitors are more beneficial in _______
Pre-diabetics
What are the main side effects of α-glucosidase Inhibitors?
Prominent GI effects
- Flatulence, Diarrhea, Abdominal pain
What is the MOA of Bile Acid Sequestrant?
Surrounds food, preventing absorption
- Large cation exchange resins – not absorbed
- Bind bile acids – prevent reabsorption
Bile Acid Sequestrant can also be used to treat ______ because it surrounds ______
hyperlipidemia, cholesterol
How must Bile Acid Sequestrants be taken?
with food
What is the MOA of Amylin Analogs?
Suppresses glucagon release, decreases circulating glucose
What is the MOA of Incretin-based Therapies?
Mimicking a substance normally produces by intestines
What is the risk of Incretin-based Therapies?
Pancreatic cancer risk
What are the 2 types of Incretin-based Therapies?
- Glucagon-Like Polypeptide-1 (GLP-1) Agonists - Semaglutide
- Dipeptidyl Peptidase-4 (DPP-4) Antagonists - Sitagliptin
What is the MOA of SGLT2 Inhibitors (Gliflozins)?
Prevents glucose reabsorption in PCT
- specifically inhibits SGLT2
- increased glucosuria
What are the side effects of SGLT2 Inhibitors?
Dehydration and necrosis in the genital region
SGLT2 Inhibitors also acts as a _______
Osmotic diuretic
What is the leading cause of death in the US?
Atherosclerosis
Describe the cycle of atherosclerosis in LDLs
LDL entry and enlargement → foam cell formation → cholesterol crystallization in foam cells → apoptosis of foam cells and extracellular lipid deposit → plaque with lipid-rich necrotic core
What are the 6 major lipids?
- Free Fatty Acids
- Phospholipids
- Cholesterol (Free & Esterified)
- Triglycerides
- Glycolipids
- Prostaglandins
What are the 4 types of molecules that sterols are precursors to?
- Steroid hormones
- Cell membranes
- Vitamin D
- Bile salts
______ is when the liver makes cholesterol from chronically high cholesterol
De novo synthesis
HMG-CoA is converted to ______ via ______
mevalonate
HMG-CoA Reductase
Statins reduce cholesterol by inhibiting ________
HMG-CoA Reductase
What are the 4 types of lipoproteins?
chylomicrons, VLDLs, LDLs, and HDLs
Which type of lipoproteins are formed in the intestine and end up in the liver?
Chylomicrons
Which type of lipoproteins are secreted by the liver and travel to peripheral tissues?
VLDLs
Which type of lipoproteins transport cholesterol from the liver to the cells, resulting in deposition in arteries in excess?
LDLs
Which type of lipoproteins scavenge cholesterol from cells, resulting in decreased levels of atherosclerosis?
HDLs
What does a lipid profile consist of?
- Total and LDL/HDL Ratio
- Triglyceride determination
- Lipoprotein electrophoresis
There is a _________ relationship between HDL cholesterol and coronary risk
inverse
What is the most common disease that causes high cholesterol?
Familial hypercholesterolemia
What are the 6 classes of hyperlipidemia drugs?
- Statins
- Niacin
- Fibrates
- Binding Resins
- Absorption Inhibitors
- Monoclonal Antibodies
What is the MOA of statins?
Structural analogs of HMG-CoA- decrease cellular cholesterol synthesis by inhibiting HMG-CoA reductase
What are the effects of statins?
- Mostly reduce LDL
- Increase LDLR
- Modest decrease of triglycerides
- Small increase in HDL
What is the toxicity of statins?
- Elevated liver enzymes - Increased with liver damage, patients of Asian descent
- CK elevations - Muscle pain or weakness
Cholesterol is synthesized at ______ and is enhanced by ______
night, food
When do you want to avoid statins?
- Avoid in pregnant and lactating women
- Restricted use in children
The main reason patients stop taking statins is due to _______
muscle pain
What are the effects of niacin?
- Decreases VLDL, LDL - Reduces VLDL secretion from liver
- Increases HDL
What is the toxicity of niacin?
1 - Cutaneous vasodilation (flushing)
- Pruritis, dry skin, rash
- N, abdominal discomfort (rare)
- Elevation of liver enzymes
What is the name of the medication that is a fibrate?
Gemfibrozil (Lopid)
What are the effects of fibrates?
- Decrease VLDL
- Modest decrease in LDL
- Increase lipolysis in liver - PPAR
What are the 2 drugs that are bile acid binding resins?
Colestipol, cholestyramine
How do bile acid binding resins work to reduce cholesterol?
- Large cation exchange resins – not absorbed
- Bind bile acids – prevent reabsorption
- May increase VLDL
- Must be taken with meals
What are the side effects of bile acid binding resins?
- Constipation, bloating
- Steatorrhea (lipid in stool)
What is the medication considered an intestinal sterol absorption inhibitor?
Ezetimibe (Zetia)
What is the MOA of Ezetimibe?
Blocks the NPC1L1 transporter that transports cholesterol transport from the lumen into the enterocyte
What are the effects of Ezetimibe found in the ENHANCE trial?
ENHANCE trial
- Reduced LDL
- PROMOTED arterial wall thickening?
Monoclonal antibodies used to treat hyperlipidemia are called ___________
PCSK9 Inhibitors
PCSK9 Inhibitors are usually given with ______ to lower ______
statins, LDLs
What is the PCSK9 inhibitor medication called?
Evolocumab (Repatha)
How do PCSK9 inhibitors combined with statins lower LDLs? By how much?
Statin therapy upregulates PCSK9
PCSK9 inhibitors allow receptor recycling
65%
What amount of LDL is considered too low aka hypocholesterolemia?
LDL <25 mg/dL
What are the risks associated with hypocholesterolemia?
- Cancer
- Hemorrhagic stroke
- Depression
- Anxiety
- Preterm birth and low birth weight
Diagram a treatment algorithm for patients with Type II diabetes.
1st line - metformin
2nd line - sulfonylurea
3rd line - insulin or Thiazolidinediones (TZDs) or α-glucosidase Inhibitors or DPP-4 inhibitor
4th line - insulin
Calculate coronary artery disease risk using the LDL/HDL ratio.
- First Calculate LDL:
- VLDL= Triglycerides/5
- LDL = total cholesterol-VLDL-HDL
- Figure LDL/HDL Ratio
List target levels of total cholesterol, HDL, LDL, and triglycerides.
Total cholesterol < 200
HDL > 40 (men) and 50 (women)
LDL < 130
Triglycerides < 120
Differentiate between primary hypercholesterolemias and secondary causes.
Primary - familial
Secondary - DM, estrogens, alcohol, nephrosis, cholestasis, corticosteroid excess
Explain why dietary control of lipid intake may not be sufficient to lower cholesterol, and some dietary strategies.
Cholesterol is largely genetic, although some dietary changes can help
What are the 2 sources of cholesterol?
the liver and the foods you eat
Differentiate free and esterified cholesterol.
Free cholesterol is biologically active and found in the surface layer of lipoprotein particles, while esterified cholesterol is a protective form of cholesterol stored in cells and transported in plasma
Describe the difference between triglycerides and cholesterol.
Triglycerides form adipose tissue and are the main storage form of fats in the human body
Cholesterol helps build cells, produce hormones, and digest food; produced in the liver
