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128 Cards in this Set
- Front
- Back
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insulin fxn
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storage and anabolic hormone of the body
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islet amyloid polypeptide (IAPP or amylin) fxns
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modulates appetite, gastric emptying, glucagon/insulin secretion
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glucagon fxn
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hyperglycemic factor that mobilizes glycogen stores
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somatostatin fxn
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universal inhibitor of secretory cells
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gastrin fxn
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stimulates gastric acid secretion
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pancreatic peptide fxn
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small protein that facilitates digestive process via unknown mechanism
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four types of diabetes mellitus
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1) insulin dependent 2) non-insulin dependent 3) other 4) gestational diabetes
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what percent of type I diabetic patients have positive family history
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10-15%
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diabetic ketoacidosis
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excess release of fatty acids and subsequent formation of toxic levels of ketoacids
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when does nonketotic hyperosmolar coma occur
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in type II diabetes - uncontrolled, untreated along with dehydration
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frequency of gestational diabetes
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~4% of all pregnancies in the US
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when is gestational diabetes screened in pregnant women
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24th to 28th week if low-risk, immediately if high-risk
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where is proinsulin processed
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in golgi and packaged into granules
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how is insulin stored in B-cells
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crystals consisting of 2 atoms of zinc and 6 molecules of insulin
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how much insulin is stored in the pancreas
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up to 8 mg
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what can stimulate insulin release
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GLUCOSE, other sugars, certain aas, hormones like GLP-1, GIP, glucagon, cholecystokinin, and vagal activity
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what can inhibit insulin release
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somatostatin, leptin, chronically elevated glucose and fatty acid levels
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mechanism of insulin release
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increase intracellular ATP close K+ channels resulting in depolarization and opening of volteage-gated calcium channels
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what drugs take advantage of the insulin release mechanism to increase insulin release
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sulfonylureas, meglitinides, and D-phenylalanine
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how much of insulin is removed by the liver
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~60% due to location; 60% via kidneys with subQ insulin
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basal and peak insulin levels
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basal 5-15 uU/mL; peak 60-90 uU/mL
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clear, soluble long-acting insulins
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insulin glargine and insuin detemir
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rapid acting insulin
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insulin lispro, insulin aspart, and insulin glulisine; action rarely last more than 4-5 hours reducging postmenal hypoglycemia
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lispro difference from endogenous insulin
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aas of position 28 and 29 switched; less likely to self-associate into dimers
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aspart difference from endogenous insulin
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substitution at position 28 with aspartic acid; reduces ProB28 and Gly23 monomer interaction and inhibits self-aggregation
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glulisine difference from endogenous insulin
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substitute position 3 with lysine and position 29 with lysine
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why is the use of regular human insulin declining
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delayed absorption, dose-dependent duration, variability of absorption (causes mismatch of insulin availability with need)
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when is regular human insulin prefered
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IV, dilution causes dissociation into monomers
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NPH (neureal protamine Hagedorn or isophase) insulin
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intermediate acting; onset 2-5 hours duration 4-12 hours
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why is clinical use of NPH insulin declining
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action highly unpredictable - absorption variability, long-acting insulin analogs have more predictable and physiologic action
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glargine
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soluble 'peakless', long-acting; slow onset 1-1.5 hours, activity 11-24 hours
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binding of glargine
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same as native insulin with insulin receptors; 6-7 fold stronger to IGF-1 receptor - clinical significance unclear
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detemir
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long-acting; increased self-aggregation and reversible albumin binding; onset 1-2 hours duration over 24 hours; background insulin level
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what insulins can not be mixed with other insulins
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glargine and detemir must be given separately
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exceptions to intensive glycemic control
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advanced renal disease and elderly - risks of hypoglycemia may outweigh risks
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general total daily insulin requirement
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weight in pounds divided by 4 or 0.55 times weight in kg; half background and half meal/snack
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when are insulin requirements increased
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obesity, adolescence, later trimester of pregnancy, people with type II diabetes
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HbA1c and diabetic complications
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every 1% decrease achieves about 37% risk reduction for microvascular complications, 21% for any diabetes-related enpoint/death, and 14% for MI
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when does ketoacidosis occur
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generally in type I diabetes; only in type II if unusually stressful conditions present like sepsis or pancreatitis or high-dose corticosteroids
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signs and symptoms of ketoacidosis
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nausea, vomiting, abdominal pain, deep slow (Kussmaul) breathing, change in mental status, elevated blood and urinary ketones and glucose, arterial blood pH<7.3, low bicarb
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fundamental treatment for ketoacidosis
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IV hydration, insulin therapy, maintenance of K+ and other electrolytes
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Hyperosmolar, hyperglycemic syndrom (HHS) symptoms
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declining mental status, seizures, glucose >600 mg/dL, not acidotic, dehydration
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insulin complications are generally caused by
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hypoglycemic rxns - inadequate carb consumption, unusual physical activity, too large of a dose
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signs of hypoglycemia caused by insulin overdose
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sympathetic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger)
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what occurs to patients frequently exposed to hypoglycemic episodes during tight glycemic control
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warning signs less common or absent
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what can expidite absorption of glucose
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simple sugar or glucose given in liquid form
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secretagogues
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sulfonylureas, meglitinides, and D-phenylalanine derivatives
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secretagogues general fxn
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increase B-cell secretion of insulin
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Biguianide general fxn
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decrease hepatic glucose production
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thiazolidinedione general fxn
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reduce insulin resistance
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alpha-glucosidase inhibitors
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slow digestion and absorption of disaccharides
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amylin analog fxn
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decreases post-meal glucose levels and reduces appetite
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incretin-based therapies
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control post-meal glucose excursions by increasing insulin release and decreasing glucagon secretion
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sulfonylureas mechanism of action
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bind receptor associated with a beta-cell inward rectifier ATP-sensitive potassium channel - inhibits efflux of K+ and results in depolarization
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first generation sulfonylureas
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tolbutamide, chlorpropamide, and talazamide
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tolbutamide
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well absorbed, rapidly metabolized by liver; safest for elderly diabeteic due to short half-life (4-5 hours)
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chlorpropamide
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half life 32 hours, slowly metabolized/excreted
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chlorpropamide contra-indications
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elderly, hepatic/renal insufficiency
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chlorpropamide toxicity
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<1% have hematologic toxicity - transient leukopenia, thrombocytopenia
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tolazamide
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shorter duration, similar potency as chlorpropamide; 7 hour half-life
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second generation sulfonylureas
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glyburide, glipizide, and glimepiride
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whom should second generation sulonylureas be used with caution
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cardiovascular disease, elderly patients
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glyburide metabolism
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in liver into products with little hypoglycemic effects
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glipizide
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half-life 2-4 hours; ingest before meal due to delayed absorption; 90% liver metabolized to inactive products
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glimepiride
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long duration with half-life of 5 hours - once daily dosing; completely metabolized in liver to inactive metabolites
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Meglitinides site of action
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two binding sites in common with sulfonylureas and one unique binding site
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Repaglinide
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very fast action, peak 1 hour duration 5-8 hours; cleared by CYP3A4; used in postprandial glucose excursions
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what meglitinide can be used in type 2 diabetics with sulfur or sulfonylurea allergy
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repaglinide
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D-phenylalanine derivative
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nateglinide
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nateglinide mechanism of action
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stimulates very rapid and transient release of insulin from B-cells through closure of ATP-sensitive K+ channels; improves initial insulin response
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when does nateglinide have minimal effect
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ocernight or fasting glucose levels
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nateglinide speccs
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injested b4 meals; absorbed within 20 minutes, peak <1 hour, half-life 1.5 hours duration <4 hours
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advantages of nateglinide
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diminished effect in presence of normoglycemia, hypoglycemia incidence low, safe in individuals with reduced renal fxn
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biguanides mechanism of action
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reduce hepatic glucose production through activation of AMPK and other possible minor mechanisms
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metformin (biguanide) specs
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half-life 1.5-3 hours; not bound to plasma protein, not metabolized
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complication of metformin along with renal insufficiency
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increase risk of lactic acidosis due to impaired hepatic metabolism of lactic acid
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why is metformin used as first-line therapy in type II diabetes
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insulin-sparing agent and does not increase weight or provoke hypoglycemia
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what additional med is added with metformin of monotherapy inadequate
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inculin secretagogues or thiazolidinediones
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whom can metformin prevent dvlp of diabetes
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middle-aged, obese people with impaired glucose tolerance and fasting hyperglycemia (didn't help older, leaner prediabetics)
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most common toxicity of metformin
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GI (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea) in up to 20%; dose-related, occur at onset of therapy and are transient
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what should be monitered in metformin therapy
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B12 levels, may affect absorption
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thiazolidinedione mechanism of action
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ligands of peroxisome proliferator-activated receptor gamma (PPAR-g) in fat, muslce, and liver; modulate lipid and glucose metabolism, insulin signal transduationl, and adipocyte/other tissue differentiation
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PPAR-g
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part of steroid and thyroid superfamily of nuclear receptors
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what does Tzd action promote in adipocytes
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glucose uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins involved in energy regulation; apoptosis and differentiation
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2 available thiazolidinediones
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pioglitazone and rosiglitazone
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pioglitazone
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PPAR-a and PPAR-g activity; greater triglyceride lowering effect; reduces mortality and macrovascular events
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rosiglitazone
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higly protein bound
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onset of Tzds
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slow - weeks or months
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common adverse effect of Tzds
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fluid retention (mild anemia and peripheral edema), dose related weight gain, increased fractures in women, congestive heart failure
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competative inhibitors of intestinal alpha-glucodsidases
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acarbose and miglitol
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what is the net affect of alpha-glucosidase inhibitors
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reduce post-meal glucose excursions by delaying digestion and absorption of starch and disaccharides
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which a-glucosidase inhibitor is six times more potent in inhibiting sucrase
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miglitol
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what are alpha-glucosidases
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sucrase, maltase, glucoamylase, and dextranase
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other effects of miglitol
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isomaltase and on B-glucosidases
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when are acarbose and migitol taken
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just before ingestion the first portion of each meal
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prominent adverse effects of acarbose and migitol
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flatulence, diarrhea, abdominal pain due to undigested food entering colon - decreases with use
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when is hypoglycemia a concern with acarbose and miglitol
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when used with a sulfonylurea treatment
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how are acarbose and migitol excreted/metabolized
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kidneys
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pramlintide
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synthetic analog of amylin; injectable antihyperglycemic agent that modulates postprandial glucose levels
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pramlintide mechanism
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suppresses glucagon via unknown mechanism, delays gastric emptying, and has CNS-mediated anorectic effects
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pramlintide specs
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rapid absorption, peak 20 minutes, duration <150 minutes; renally metabolized/excreted
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when should pramlintide be administered
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immediately before eating
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adverse effects of pramlintide
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hypoglycemia, GI symptoms - cnausea, vomiting, anorexia
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exenatide
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synthetic analog of glucagon-like peptide 1 (GLP-1)
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how is exenatide used
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in conjunction with metformin or metformin plus sulfonylureas
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exenatide effects
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potentiation of glucose-mediated insulin secretion, suppression of postprandial glucagon release, slowed gastric emptying, and central loss of apetite
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exenatide specs
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peak 2 hours, duration up to 10 hours
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major adverse effects of exenatide
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nausea (44% users), vomiting, diarrhea - decrease with ongoing usage; rare necrotizing and hemorrhagic pancreatitis
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sitagliptin
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inhibitor of dipeptidyl peptidase -4 (DPP-4)
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DDP-4 fxn
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degrades incretin and other GLP-1 like molecules
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major action of sitagliptin
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increase circulating levels of GLP-1 and GIP
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sitagliptin specs
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85% oral bioavailability, 12 hour half-life
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adverse effects of sitagliptin
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nasopharyngitis, upper respiratory infections, headaches; rare severe allergic rxn
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what should be done if clinical failure occurs with biguanide
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second agent or insulin added
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what second agent can be added
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insulin secretagogue, Tzd, incretin-based therapy, amylin analog, or glucosidase inhibitor; preference to sulfonylureas or insulin due to cost, adverse effects, and safety concerns
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third-line therapy
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biguanide, multiple other oral meds
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recommended 4th line therapy
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intensified insulin management with or without biguanide or Tzd
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what diabetic drugs are NOT appreoved for type 1?
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insulin secretagogues, Tzds, biguanides, alpha-glucosidase inhibitors, incretin-based agents
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what additional med can be used for control in type 1 diabetes
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pramlintide taken with meals
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precursor intermediate of glucagon
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glicentin
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glucagon half-life in plasma
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3-6 minutes
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enteroglucagons
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family of glucagon-like peptides including glicentin, GLP1, GLP2; secreted by intestinal cells
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GLP-1 fxns (aka insulinotropin)
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potent stimulant of insulin synthesis and release and beta-cell mass; inhibits glucagon secretion, slows gastric emptying, anorectic effect
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why is GLP1 limited clinically
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continuous subQ infusions required to produce sustained lowering of fasting and postpandrial hyperglycemia
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where do the first 6 aas of glucagon bind
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Gs specific protein receptors on liver cells - cAMP mediated
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glucagon on heart
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inotropic an chronotropic effects; similar to B-adrenoceptor agonists without requiring functioning B receptors
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glucagon and smooth muscle
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relaxation - may be due to other mechanisms than adenylyl cyclase
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difference of pramlintide and amylin
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substitution of proline in 3 positions making it soluble and non-self-aggregating
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