Diabetes Flashcards
Primary forms of Diabetes
Type 1
Type 2
Type 1 Diabetes
- selective B-cell destruction, severe or absolute insulin deficiency
- juvenile onset
- – 1A: autoimmune
- – 1B: non-autoimmune
Type 2
- late onset
- tissue resistance to insulin
- usually adult onset
- obesity is common/predisposing factor
Type 3
Other
Type 4
Gestational
- affecting 4% of pregnant women
Glucose concentration cutoff
Above 5.7 => diabetes
Regulation of Blood Glucose Concentration
- negative feedback
- food triggers insulin release
- stimulates absorption of glucose
- decrease in blood [glucose]
- decrease blood [glucose] => decreased insulin levels
Regulation of Blood Glucose Concentration
- liver
- muscle
- adipose
- pancreatic B cells
Insulin Receptor
- glucose transporter translocation to membrane
- glucose uptake increases
- glycogen synthase activity increases (glycogen formation increases)
- increase in lipogenesis and protein synthesis
- enhance DNA synthesis and cell growth and division
Glucose stimulates
insulin secretion
Diabetes Complications
prolonged exposure of tissues to increased concentrations of glucose => development and complications of diabetes
- Glycation of protein
- glycosylated hemoglobin A1c
** formation of sorbitol => increased glucose uptake, aldose reductase converts glucose to sorbitol in neurons, increased osmotic effect, cell death **
Formation of sorbitol
- increased glucose uptake
- aldose reductase converts glucose to sorbitol in neurons
- increased osmotic effect
- cell death
Peripheral nerve complications
diabetes
- selling -> neuropathies
- aldose reductase converts glucose -> sorbitol
- amputation
GI system complications
diabetes
- decreased autonomic nerve activity
- constipation
- gastric stasis
Kidney, capillary membrane complications
diabetes
- thickening, scarring, coarsening
- worsened by hypertension
- accelerates atherosclerosis
- protein glycation and cross-linking => irreversible protein accumulation
RENAL FAILURE
Retina complications
diabetes
- blindness
- protein glycation
- damaged capillary wall -> proliferation new capillaries
- blindness
Skin complications
diabetes
- slowed mucopolysaccharide turnover
- impaired wound healing
heart and cardiovascular system complications
diabetes
death
Controlling blood glucose levels means
delaying complications
Treatment of diabetes
- no cure
- lifetime control
- – blood glucose levels - glycemic control
- prevent or delay development of diabetic complications
Type I Diabetes
- loss of insulin-producing B cells
- DEFICIENCY OF INSULIN
- B cell loss due to autoimmune attack
- juvenile diabetes
Treatment of Type I Diabetes
insulin supplement
Pharmacotherapy with Insulin
- short acting/long acting
- used in combination to achieve insulin levels which mimic physiological fluctuations
Regular Insulin
- short acting
- SC Prep
- IV Prep
S. C. Prep
- effect timing
- peak
- duration
- short acting insulin
- injection
- effects appear within 30 minutes
- peak at 2-3 hours
- lasts 5-8 hours
- ZN2+
I. V. Prep
- diluted
- phosphate buffered
- especially useful for crisis situations
Ultra-short acting (rapid-acting) insulin analogues
- mutated molecule; changes pharmacokinetic properties, but NOT activity
Lispro
- Ultra-short acting (rapid-acting) insulin analogues
- human insulin analog
- biologic effects ~ regular human insulin
- aggregates less
- absorbed more rapidly
- shorter duration
Aspart
- Ultra-short acting (rapid-acting) insulin analogues
- human insulin analog
- properties similar to Lispro
- biologic effects ~ regular human insulin
- aggregates less
- absorbed more rapidly
- shorter duration
Flulisine
- Ultra-short acting (rapid-acting) insulin analogues
- human insulin analog
- similar to others
Basal Insulin Analogues
- long acting
- take very long time to release
- superior to traditional long-lasting insulins; more expensive
Glargine
Basal Insulin Analogues
- human insulin analog
Detemis
Basal Insulin Analogues
- human insulin analog
Human Insulin Analogs
- amino acid sequence changed with altered pharmacokinetic properties
- no change in binding and activating insulin receptor
Insulin Delivery Systems
- syringes/needles
- portable pen-sized injectors
- continuous subcutaneous insulin infusion pumps
Insulin Regimens
- basal insulin + pre-meal short acting insulin
- NPH insulin + regular insulin
- s.c. insulin pump
Type 2 Diabetes
- cause
- intervention
- goal
Cause
- tissue resistance to insulin action
- a RELATIVE deficiency in insulin secretion
- aging and obesity are a predisposing factor
Intervention
- dietary control + weight reduction
- oral or injectable hypoglycemia agents
- insuling
- – right amount of insulin at the right time for the right situation
Goal
- control blood glucose concentration
- delay development of complications
Metformin
- first line TYPE 2 diabetes drug
- decrease liver glucose release
- increase GLP-1 release
- highly effective in reducing A1C, without causing hypoglycemia
- not metabolized by liver; excreted unchanged
- t1/2 1.5-3 hours
__________________________________________
***- target liver - decrease hepatic glucose output
- decrease fasting glucose***
Metformin Mechanism of Action
- main target organ: liver: decrease hepatic glucose output, decrease fasting glucose
- also increase GLP-1 secretion
- anti-hyperglycemia, not hypoglycemic: lowers glucose to “euglycemia” levels
- does not increase body weight and may help obese pts. lose weight!
Metformin Metabolism & Excretion
- t1/2 1.5-3 hours
- is NOT metabolized by liver
- excreted unchanged
Insulin Secretogogues
- sulfonylureas
- sensitize B cells
- target ATP-sensitive K+ channel action depends on a functional B-cell
- binds K & lower threshold => less ATP needed to release insulin
- increase ATP in cell -> close K+ channel (depolarization) -> Ca2+ floods in -> insulin release
The Sulfonylureas
- 2nd generation agents
- increased potency (100X)
- less required
- less adverse effects
glyburide
sulfonylurea
glipizide
sulfonylurea
glimepiride
sulfonylurea
Sulfonylurea mechanism
- stimulation of insulin release from B cells
- high affinity binding to a B-cell receptor associated with an ATP-sensitive, inward rectifier K+ channel
Thiazolidinediones
“glitazones”
- takes a couple months to see effect
acarbose
a-flucosidase inhibitors
a-flucosidase inhibitors
- competitive inhibitors of intestinal a-glucosidases, enzymes that digest dietary complex starches, oligosaccharides, and disaccharides to absorbable monosaccharides
- upper intestinal digestion of starch + disaccharides decrease
- decrease in digestion
Incretin GLP-1-based therapies
stimulate insulin secretion after a meal
GLP-1
- an incretin
- stimulates glucose-dependent insulin secretion
- inhibits glucagon release
- delays gastric emptying
- reduces food intake
- normalizes fasting and postprandial insulin secretion
incretin
GI hormone that is released after meals and stimulate insulin secretion
GLP-1 rapidly inactivated by
- DPP-4
GLP-1 t1/2
very short
DPP-4
Dipeptidyl peptidase IV
- cleaves GLP1
- – why GLP1 has such a short t1/2
2 types GLP-1 based therapeutics
- injectable DPP-4 resistant peptide agonists of the GLP-1 receptor
- small molecule inhibitors of DPP-4
Exenatide
DPP-4 resistant peptide agonist of GLP-1 receptor
Sitagliptin
- small molecule inhibitors of DPP-4
- prolong GLP1 t1/2
- increase GLP => increase insulin
Kidney SGLT2
- ONLY type 2
- inhibit gliflozins
Major Therapeutic Categories
Oral
- Metformin
- Insulin Secretogogues
- Kidney SGLT2 inhibitors
- DPP-4 inhibitors
- Thiazolidinesdiones
- a-glucosidase inhibitors
Metformin
- major target liver, decreasing hepatic glucose output and lower fasting blood glucose levels
- a biguanide
Insulin Secretogogues
- target pancreatic B-cells, potentiating insulin secretion
- sulfonylureas and meglitinides
Gliflozins
Kidney SGLT2
DPP-4 inhibitors
increase GLP-1 and GIP
Thiazolidinediones
- target adipose, as well as muscle and liver, increasing peripheral insulin sensitivity
a-glucosidase inhibitors
target intestinal a-glucosidases, reducing glucose absorption
Major Therapeutic Categories
Injectables
- GLP-1 agonists
- Amylin agonists
- Insulin
GLP-1 Agonists
- potentiate insulin secretion
- suppress glucagon secretion
- slow gastric motility
Amylin agonists
- slow gastric emptying
- inhibit glucagon productions
