Diabetes Flashcards
What are the two types of secretory tissue found in the pancreas?
What are the functions of these two tissues?
*Exocrine Glands - Digestive enzymes
*Endocrine Glands - Hormones
What tissue type is located in the endocrine portions of the pancreas that produces secretory hormones? What cells make up this tissue.
Islet of Langerhans
- Alpha cells
- Beta cells
- Delta cells
- G cells
- F cells
What is produced in the Αlpha cells of the Islet of Langherhans?
What about the Βeta cells?
What about the Delta cells?
- α → Glucagon
- β → Insulin & Amylin
- δ → Somatostatin
How does proinsulin become insulin?
- Proinsulin is cleaved into Insulin and C-peptide.
What does Amylin do?
*Amylin is inhibitory to Glucagon (and a little to insulin as well)
What does Somatostatin do?
*Short acting (5min) inhibitory effect on both insulin & glucagon right after eating.
What receptor type are insulin receptors? What do they do when bound with insulin?
*Tyrosine Kinase Receptors
*Phophorylate effector proteins to promote GLUT transporters to bind to the cell surface.
What is the homeostatic level of blood glucose?
90mg/100mL
How quickly is glycogen used up?
Completely used up in 24 hours.
Why type of receptor is a glycogen receptor?
What organ takes in glycogen for energy storage & also breaks it down for use?
*GPCR.
*Liver.
What signs/symptoms are characteristic of diabetes mellitus? (particularly type I)
*Polyuria, Polydipsia, & Polyphagia
What characterizes Type 1 DM?
*Autoimmune destruction of βcells in the pancrease. Insulin dependent.
What characterizes Type 2 DM?
*Usual metabolic syndrome, non-insulin dependent but will convert to Type I if untreated.
What characterizes Type 3 DM?
*Temporary ↑ BG (pancreatitis, drug therapy, etc.)
What characterizes Type 4 DM?
*Gestational
At what level of βcell destruction is a diagnosis of Type I DM official?
What two types of Type 1 DM exist & which is more common?
*80% of βcells destroyed.
1. Immune (more common)
2. Idiopathic (genetic)
Why do Type 1 diabetics often have weight loss?
What might occur if a Type 1 diabetic is not given insulin replacement.
*Due to the inability to process carbohydrates.
*Fatty acid oxidation → ↑ketones → ↓pH
Which Diabetes Mellitus sub-type is characterized by relative deficiency of insulin secretion & tissue insulin resistance?
What occurs at the cellular level with insulin resistance?
What would blood levels of insulin be in a type 2 DM patient?
*Type II DM (the artist formerly known as “adult onset DM”)
*Downregulation of GLUT transporters.
*Initial ↑ insulin level; ↓ insulin level developed over time.
What blood glucose levels would you expect to see with non-ketotic hyperosmolar syndrome?
What symptoms would be associated with this condition?
> 600mg/dL
- Dehydration & eventual coma/death.
What are three clinical manifestations of chronic type 2 DM?
- Recurrent infections
- Vision problems
- Neuropathy
What is nonenzymatic glycosylation?
*The process by which chronically high blood sugars attach to your hemoglobinA1C.
What is a normal Hemoglobin A1C?
What is a very abnormal one?
4-5%
> 7%
Describe the hyperglycemic effect on the polyol pathway.
Where is this effect most prominent?
*Sorbitol & Fructose increase intracellularly = ↑ osmotic pressure = Hypotonicity of the cell & cell rupture.
*Eye lens, nerves (neuropathy), & RBCs (anemia)
What microvascular areas of damage are associated with Type 2 DM?
*Diabetic Retinopathy
*Diabetic Nephropathy
What are the results of gestational diabetes mellitus?
*↑ child birth weight
*↑ risk for 2nd pregnancy
*↑ risk for development of Type 2 DM.
What should a fasting blood glucose be in a healthy individual?
Describe the glucose tolerance test.
*< 100 mg/dL
*A sugary drink is imbibed and blood glucose levels are drawn 1-2 hours post ingestion. More definitive than a fasting level.
Porcine insulin administration can cause local ______ at the injection site.
atrophy
What are insulin secretagogues?
What non-drug insulin secretagogues should be known?
*Anything that causes insulin release
1. Glucose
2. Amino acids
3. Hormones
4. Fatty acids
5. Incretins
What drugs were noted in lecture to be insulin secretagogues?
*Sulfonylureas
*Isoproterenol
GLUT-4 has an _______ affinity for glucose.
GLUT-2 has a _______ affinity for glucose. What does this mean?
*Intermediate
*Low; this means that high levels of blood glucose are required to stimulate this transporter.
What is the complete process for how insulin is stimulated & released from a cell via extracellular glucose?
- ↑ ECF glucose
- Glucose brought to ICF via GLUT
- Glucose metabolized & ATP created
- ↑ ATP closes K⁺ rectifying channels
- Closed K⁺ channels = depolarization
- Depolarization = ↑ pCa⁺⁺
- ↑ pCa⁺⁺ = VP1 → VP2 & vesicular release of insulin via exocytosis.
What effects are elicited by insulin reacting with the insulin tyrosin kinase receptor?
*↑ uptake of glucose via more GLUT proteins
*↑ glycogen formation
*Activation of more transcription factors.
What GLUT transporters have a very high affinity?
GLUT-3; Brain
What GLUT transporters have a very low affinity?
*GLUT-2; β cells of pancrease, liver, & kidney
What GLUT transporters have an intermediate affinity?
GLUT-4; Muscles & adipose tissue.
What are the 3 endocrine effects of insulin?
1.↓ glycogenolysis = ↓ release of liver glucose.
2.↓ conversion of fatty acids & amino acids to keto acids.
3.↑ glycogen formation/storage.
What non-drug factors inhibit insulin secretion?
Insulin itself, Leptin, SNS activity, chronically high glucose, & amylin
What drugs inhibit insulin secretion?
What type of DM do these then cause?
*Diazoxide, phenytoin, vinblastine, colchicine
*Type III DM
70/30 insulin is a combination of what?
How effective is the combination?
Combo:
- Short acting (regular)
- Intermediate acting (Neutral protamine hagedorn NPH).
The 70/30 combo is decent but not as good as a basal/bolus method with rapid-acting & long-acting
Why is nasal insulin not in more frequent use?
Nasally administered insulin causes bronchoconstriction.
What method is preferable for tight blood glucose level control?
Continuous subcutaneous insulin infusion devices (CSIID)
Basal Bolus method with long acting (next best)
1 unit of rapid-acting insulin “covers” how many carbs that are eaten?
1 unit RA insulin = 12-15g carbs (ex. 75g carb meal requires 5 units RA insulin)
1 unit of rapid-acting insulin drops blood glucose by _____ mg/dL.
50mg/dL
When metabolic rate increases, what occurs with insulin requirements?
Insulin requirement increases as well
At what blood glucose level is one considered hypoglycemic?
< 60mg/dL
What drug class is first-line therapy for DM?
What drug is prototypical of this class and what is its mechanism of action?
What is a normal dose & what is the max dose where one would want adjunct therapy?
Biguanides =Metformin
Reduces hepatic glucose production
Dosing starts at 500mg & maxes out at 2500mg/day
What drug classes are insulin secretagogues? Which of these can have trigger sulfa- allergies?
What is this drug classes MOA?
Sulfonylureas (sulfa)
Meglitinide
Phenylalanine derivatives
MOA: Binds to rectifying K⁺ channel in pancreatic β cell decreasing threshold & causing depolarization. Depolarization causes Ca⁺⁺ influx & vesicular release of insulin.
1st generation sulfonylureas have a ______ dose than 2nd generation sulfonylureas. What does this mean for safety?
higher
1st generation have a higher doses = more side effects. 2nd generation is safer with its lower doses.
Which sulfonylurea is associated with bad outcomes and increased instances of MI?
Tolbutamide
Which class of insulin secretagogues has much less efficacy due their very short T½ & duration of action?
Meglitinides
What is the mechanism of action for Thiazolidinediones (Tzd’s)?
What is the prototypical drug of this class & what is the main risk associated with it?
↓ insulin resistance by ↑ GLUT-4 prevalence.
Rosiglitazone = risk of MI, especially with nitrate & insulin use.
What is the mechanism of action of α-glucosidase inhibitors?
When is this drug beneficial?
What side effects are typical?
Blockade of digestion of complex carbs & thus blocking uptake of glucose.
Drug is beneficial in pre-diabetics & high starch diets. (think Japan)
GI problems (flatulence, diarrhea, etc.)
What is the mechanism of action of bile-acid binding resins?
What side effects are typical?
BABR’s bind to food & prevent absorption of glucose.
GI upset.
How do Amylin Analogs treat DM?
What is this drug’s route of administration?
Where is Amylin naturally produced in the body?
↓ glucose release.
IV/IM (not oral)
Amylin is produced in the βcells of the pancreas.
What drug class treats DM through the usage of GI hormones?
What are these specifically & their MOA’s?
What risk (though small) is conferred by these drugs?
Incretin-based therapies.
GLP-1 (Glucagon-like polypeptide-1) = stimulates insulin release & inhibits glucagon release.
DPP-4 (Dipeptidyl Peptidase-4 Antagonist) = blocks breakdown of GLP-1
Pancreatic cancer.
Gliflozins are also known as ______ ________.
What suffix is denoted by this drug class?
SLGT2 Inhibitors
-flozin
How do Gliflozin’s work?
What is the result of this & what side effects can occur?
Prevention of glucose reabsorption in the PCT
Glycosuria (perineal necrosis, ↓BP, weight loss, & dehydration).
Where do SLGT-2 inhibitors work in the kidneys?
How much glucose is reabsorbed despite administration of these drugs?
S1 segment of the PCT.
20-30% glucose reabsorption in S2 (increased by SLGT-2 inhibition, normally 10% in S2 segment)
Sitagliptin
DDP-4 antagonist (dipeptidyl peptidase-4) which enhances the effects of incretin.
pancreatic cancer risk
semaglutide
Incretin (GI hormones)
- GLP 1 agonist (glucagon-like polypeptide-1)
pancreatic cancer risk
acarbose
oral antidiabetic agents
alpha-glucosidase inhibitor
Insulin - Rapid acting (3)
- Lispro, aspart, glulisine
Insulin - Short acting (Regular) (2)
- Novolin, humulin
Insulin - Intermediate acting (1)
- Neutral protamine Hagedorn
Insulin - Long acting (2)
- Glargine, detemir
The pathway for insulin release from pancreatic beta cells involves a series of tightly regulated steps:
- Glucose Uptake
When blood glucose levels rise glucose enters beta cells via GLUT2 transporters - Increase in ATP/ADP Ratio
Elevated ATP levels lead to the closure of ATP-sensitive potassium (K+ATP) channels on the beta cell membrane. - Membrane Depolarization
The closure of K+ ATP channels causes the beta cell membrane to depolarize (since potassium efflux is reduced).
Membrane depolarization opens voltage-gated calcium channels (VGCCs).
- Calcium Influx
The opening of VGCCs allows an influx of calcium ions (Ca2+) into the cell.
The rise in intracellular calcium concentration is a crucial trigger for insulin release.
- Exocytosis of Insulin
The increased intracellular Ca2+
concentration stimulates the exocytosis of insulin-containing vesicles.
Insulin is released from these vesicles into the bloodstream to exert its effects on target tissues, such as muscle, liver, and adipose tissue.
Additional Modulatory Inputs
Incretins: Hormones like GLP-1 (glucagon-like peptide-1) enhance insulin secretion by increasing cAMP and amplifying the effect of calcium on insulin granule exocytosis.
Autonomic Nervous System: Both the sympathetic and parasympathetic nervous systems can modulate insulin release.
