EXAM 4 Diabetes Dr. Roane Flashcards
At what concentration of glucose do we find glucose in the urine?
200 mg/dl
-> saturation of glucose transporter, so it exceeds the maximum transporter (Tm) in the kidneys -> spills in the urine
-in Type 1 and 2:
causes:
Polyuria
Polydipsia (thirsty)
Polyphagia (hunger)
Characteristic Type 1 diabetes
Absence of Insulin
-IDDM (insulin-dependent DM)
-Juvenile onset
-T-cell mediated autoimmune contribution to etiology (may have a viral and genetic component)
Characteristic Type 1 diabetes
-NIDDM (non-insulin-dependent DM)
-adult onset
-obesity-related (55%)
-idiopathic
-significant but diffuse genetic component
-no insulin problem
insulin receptor insensitivity
treated with a variety of drugs + insulin
How do the pancreas and kidney react to high blood glucose?
Pancreas: ß-cells release insulin into the blood
Muscle cells and other cells: use glucose as energy source or convert it into glycogen (storage)
Kidney: converts glucose to glycogen, fats and proteins
How do the pancreas and the kidney react to low blood glucose?
Pancreas: alpha-cells release glucagon into the blood
Kidney: converts glycogen into glucose - GLYCOGENOLYSIS
also Gluconeogenesis: producing glucose form non-carbs
Which organs absorb glucose from the blood?
-Liver
-Muscle and Fat
-Brain
-RBC
-heart
-kidneys etc.
path: glucose gets from the stomach -> arteries -> liver
Which organs absorb glucose in response to insulin (insulin-sensitive)?
Muscle, fat
-Liver
Which organs are not insulin-sensitive in regards to glucose absorption?
-Brain
-RBC
-kidney
-heart
-> they always take up glucose
What is the main effect of insulin?
in general:
insulin binds to insulin receptor -> signal pathway
-> activation of GSV (glut4 storage vesicle containing glucose transporter)
-> Glucose uptake (glucose goes into the cells along the gradient)
different pathways in different tissues
What triggers glucose uptake in skeletal muscles?
-insulin
-exercise
-> muscle contraction triggering GSV production (glut4 transporter)
Overview drugs
-GLP-1: more insulin secretin
-DPP4i, Sulfonylureas, Glitinides: more insulin secretion
-SGLT2i: pee out glucose
TZDs: insulin receptor sensitizers
-metformin: probably involved in hepatic glucose output, also sensitizers
-alpha-glucosidase inhibitors: blocking the absorption of glucose
What is the function of the pancreas
-secretion of insulin and glucagon
-secretion of pancreatic enzymes and pancreatic juice into the intestine
Which cells within the pancreas secrete glucagon and insulin?
Islet cells
alpha cells: secrete glucagon
ß-cells: secrete insulin
How is the active form of insulin formed?
Preproinsulin -> Proinsulin -> Insulin
-one long chain: A and B chain connected by C-chain
-C-chain gets cleaved off -> A and B chain connected by a disulfide bridge
What are the drugs that stimulate insulin secretion?
-Sulfonylureas
-Meglitinides
-GLP-1 agonists
-DPP-4 inhibitors
Pathway of insulin release in ß-cells
Glucose uptake -> metabolized to G6P -> pyruvate
-> ATP in the Krebs cycle
-> ATP binds to K(+) channels and it closes (depolarization causing an action potential -> that opens voltage-gated Ca+ channels -> Ca+ binds to vesicles and causes the fusion with the membrane and insulin release
-also through GLP-1 (released from the intestine) binding to the GLP-1 receptor
-> activates cAMP -> PKA -> causes insulin release
What is the MOA of Sulfonylureas (SU’s)?
-they bind to SU receptors (subunit of ATP-sensitive K(+) channels (K+ channels are also found in multiple organs like the brain, heart, etc - negative effects)
they are closing ATP-sensitivte K(+) channels
-> K+ stays inside -> depolarization -> action potential occurs and activates voltage-gated Ca+ channels -> insulin release
Examples of Sulfonylureas
1st gen (not often used anymore)
-Tolbutamide
-Tolazamide
2nd gen
-Glyburide (Diabeta)
-Glipizide (Glucotrol)
-Glimeparide (Amaryl)
How are 2nd generation Sulfonylureas different from 1st gens?
2nd gens are:
-more potent
-more lipophilic
->better in achieving therapeutic levels
->BUT more likely to cause hypoglycemia
When do Meglitinides most likely work?
at high glucose levels -> closing ATP-sensitive K+ channels
-> therefore less likely to cause hypoglycemia
-> but not often used
Examples of Meglitinides
-Repaglinide (Prandin)
-Nateglinide (Starlix)
MOA of GLP-1 agonists
binds to GLP-1 receptors on ß-cells
-activates signaling pathway: cAMP -> PKA -> stimulates insulin release
-inhibits glucagon release
GLP-1 and GIPs are considered what type of molecules?
Incretins
-> hormones that are released after a meal to stimulate insulin release
What are other helpful effects of GLP-1
-may increase ß-cell mass (pancreas makes more ß-cells, tropic effect)
-Decreases gastric acid secretion and delays
gastric emptying
-decreases appetite (may cause nausea)
-probably decreases
glucose absorption Ra (rate of appearance) and HGO (hepatic glucose output)
Meaning of glucose Ra
glucose rate of appearance - tells how fast glucose enters the bloodstream (from food or the body’s glucose production)
Where is GLP-1 released physiologically?
intestinal L-cells
-> stimulated by carbohydrates, fats, and amino acids in the intestine