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Insulin is secreted as a complex of 2 atoms of _________ and 6 molecules of ________.
All Insulin preparations have the same function. What is it?
Bind to and activate insulin receptors
Different preparations of insulin have been bioengineered to have alterations in their amino acid sequence that alter (enhance or inhibit) the insulin's ability to exist as a hexamer with zinc (a protamine) or as a monomer. What form binds the insulin receptor?
This insulin type in characterized as recombinant, with low propensity to form hexamers due to point mutations in the C-terminus of the B-chain, efficacious ~10 min after injection. Used immediately before meals 5-10 minutes. Duration is seldom more than 3-4 hours. The immediate onset and short duration of action enhance glycemic control.
- Ultra-short Acting/ Rapid Acting
- Insulin Lispro & Insulin Aspart
This insulin type is characterized as crystalline zinc insulin, efficacious 30 min after injection, biochemically identical to the insulin made by the pancreas. The biggest “problem” with this preparation is that the patient must eat within 30 minutes or there is a risk of severe hypoglycemia.
NOTE: this is the only form of insulin that can be administered IV and only under the direct supervision of a physician
- Regular Human Insulin
This insulin type is characterized as onset of action is delayed by combining insulin and protamine in a ratio (1:10 – protamine:insulin by weight – 1:6 molar) so that neither is present in an uncomplexed form. The complex slowly dissociates. This preparation allows a circulating concentration of insulin for long periods of time.
- NPH Insulin (Neutral Protamine Hagedon)
This type of insulin is characterized as poorly soluble crystal of zinc insulin with delayed onset of action. The injected insulin is more slowly absorbed into the body.
- Ultralente Insulin
This type of insulin is characterized as bioengineered form of insulin that is soluble at pH 4, but precipitates at physiologic pH (7.4). When the clear solution is injected, it forms microprecipitates in the body, delaying its absorption and prolonging its duration of action. Administered once daily, with no peak of activity.
o Longer acting preparations allow a mechanism of continual glucose uptake.
o Used in combination with shorter acting preparations.
What is an example of a mixture of insulin? These are packaged for convenience since most patients will need a mixture insulin preparations for immediate and long-term glucose uptake. (Note: premixed preparations containing insulin lispro or aspart can be made right before use by the patient, but are not packaged that way because the immediate acting insulins are unstable). Care needs to be taken with combining insulin preparations as excess zinc or protamine may form undesired insulin complexes.
Vials of insulin are available at doses of _____ U/ml and dispensed in ___ ml vials.
These are pen sized injectors with replaceable cartridges. Administers a single dose of insulin, so measuring is not necessary
Portable Pen Injectors
These give continuous subcutaneous insulin infusion. An external manually programmable pump allows for modification of dosing regimen. Allows for both continual and bolus administration of insulin.
What are the four main complications of Insulin Therapy?
- Hypoglycemia: due to poor regulation of food intake and insulin administration
- Lipodystrophy: injection would lead to atrophy of fatty tissue at injection site, but new preparations of more neutral pH’s and variation in injection site has minimized this issue.
- Weight gain: due to increased glucose uptake
- Immunopathology: immune response to insulin.
The average person produces approximately ___ - ____ Units/day of insulin
What is the treatment for Type I Diabetes?
What are the three therapeutic goals for Type II Diabetes?
- Insulin release
- Increased sensitization to insulin
- Decrease Blood Glucose
These insulin secretogogues bind the surfonylurea receptor that associates with a B cell inward rectifier-type ATP sensitive potassium channel. Binding inhibits the efflux of potassium ions through the channel causing depolarization. Depolarization opens the voltage gated calcium channel, increasing cellular calcium and releasing preformed insulin. Additional sulfonylurea binding proteins are localized to intracellular membranes that facilitate exocytosis of insulin granules.(refer to diagram of insulin secretion)
Increased intracellular calcium results in increased insulin secretion. Sulfonylurea hypogycemic drugs block the ATP-dependent ____________ channel, thereby depolarizing the membrane and causing increased insulin release by the same mechanism
Chronic use of sulfonylureas decreases ________ ________ concentrations and is thought to contribute to the hypoglycemic effects of the drug
What are three common first generation Sulfonylureas?
This drug has a t1/2 = 4 -5 hours – rapid onset of action, metabolized by the liver – not for patients with hepatic impairment.
This drug has a t1/2 = 32 hours – metabolized by liver, 20-30% unchanged drug is excreted by kidneys, not for patients with hepatic impairment and renal insufficiency
This drug has a t1/2 = 7 hours – slowly absorbed, shorter duration of action.
What are the three second generation Sulfonylureas?
This drug is contraindicated for patients with hepatic impairment and renal insufficiency
This drug has a t1/2 = 2-4 hours, taken 30 min before breakfast, shorter t1/2 means less propensity for hypoglycemia, contraindicated for patients with hepatic impairment and renal insufficiency
This drug has a t1/2 = 5 hours – allows for once a day administration, completely metabolized by the liver.
What class of drugs makes up the non-sulfonylurea secretagogues? What are the two drugs within this class?
- Repaglinide & Nateglinide
This class of drugs modulate insulin release by modulating beta cell insulin though decreasing potassium channel efflux. These overlap with the sulfonylureas in their site of action. There is no direct effect on insulin exocytosis.
These are characterized by a rapid onset of action -- peaks within 1 hour
** Hypoglycemia may be slightly less frequent than with sulfonylureas. These are metabolized by CYP3A4, so inhibitors ( ketoconazole, erythromycin, etc) may increase serum concentrations and induces of CYP3A4 (rifampin, etc) may decrease serum concentrations
Meglitinides (Repaglinide, Nateglinide)
What is the major class of Insulin Secretagogues?
What are the major classes of Insulin Sensitizers?
- Biguanides (Metformin)
- Thiazolidinediones (Pioglitazone, Rosiglitazone)
The molecular mechanism for this drug class is unknown, but it causes a decrease in blood glucose levels independent of a functioning beta-cell. To a lesser extent, these increase peripheral glucose utilization.
Stimulation of glycolysis in tissues, inc removal of blood glucose
Reduced hepatic and renal gluconeogenesis
Slowing of glucose absorption from GI tract
Reduction of plasma glucagon levels
These drugs are "euglycemic" -- decrease hyperglycemia, with little or no incidence of hypoglycemia
They are used for patients with refractory obesity whose hyperglycemia is due to ineffective insulin action
They are used with sulfonylureas when sulfonylureas alone are inadequate
GI side effects: anorexia, nausea, vomiting, abdominal discomfort, diarrhea
Contraindicated in patients with renal disease, alcoholism, hepatic disease, and conditions predisposing to tissue anoxia (heart diseases)
Biguanides (specifically Metformin)
The good news about this drug is that, when used alone, it does not cause hypoglycemia and may produce modest weight loss (2-3 kg). The bad news is that the weight loss is likely due to unpleasant GI distress. This drug causes a metallic taste, nausea, diarrhea, and abdominal pain, but symptoms may be reduced by taking the drug slowly with food. Lactic acidosis is a rare, but potentially fatal side effect.
The mechanism of action of this drug class is not fully understood. They function by enhancing insulin target tissue sensitivity by enhancing activity of the peroxisome prolierator-activated receptor-gamma (PPRAgamma) nuclear receptor. PPRAgamma regulates expression of genes involved in glucose and lipid metabolism -- functions only in adipose, skeletal muscle, and the liver.
These drugs are euglycemic -- increase glucose uptake into muscle and adipose tissue
Therapy causes redistribution of body fat (decreased visceral fat mass, increased peripheral small adipocytes)
Chronic therapy is associated with decreased triglyceride levels
Metabolized by p450s in the liver
Adverse effects are weight gain and fluid retention -- which can lead to congestive heart failure. Both retard fetal development in animals and are not recommended for use during pregnancy.
What is the drug class, and what are the drugs within this class?
- Pioglitazone & Rosiglitazone (avandia -- likely will be off market soon)
What are the two alpha-Glucosidase Inhibitors?
These drugs inhibit the enteric enzymes of the brush border of the intestinal cells. This action prevents the breakdown of complex starches, oligosaccharides, and disaccharides.
The goal is to minimize absorption and digestion of ingested starch and disaccharides, so these drugs are taken with meals.
Adverse effects include GI distress -- severe flatulence, diarrhea, and abdominal pain. Slowly increasing the dosage of these drugs can help alleviate some of these side effects.
These are contraindicated in patients with chronic intestinal disease, inflammatory bowel disease, colonic ulceration, or any degree of intestinal obstruction.
Hypoglycemia may occur with concurrent sulfonylurea therapy and should be treated with dextrose, not sucrose
alpha-Glucosidase Inhibitors (Acarbose, Miglitol)
This molecule is secreted as a prohormone by the alpha cells of the pancreas. It is degraded by the liver, with a t1/2 of 3-6 minutes.
This is a "counter" hormone to insulin, and induces an increase in blood glucose by causing glycogen release.
It signals through the 7 transmembrane spanning G-protein coupled glucagon receptor.
Metabolic: increased cAMP production; facilitates stored glycogen; increases gluconeogenesis and ketogenesis. Its infusion increases blood glucose, and decreases hepatic glycogen
Cardiac: increases in cAMP-mediated beta-adrenergic receptor like effects
Smooth Muscle: profound relaxation of the small intestines
What are the four clinical uses of Glucagon?
- Treatment of Severe Hypoglycemia: converts glycogen to glucose, so can be used to help restore blood glucose levels
- Diagnosis of Endocrine Disorders: treatment with a bolus of glucagon causes the release of beta cell secretory reserves. Measurement of C-peptide levels are used to indicate beta cell function. Often insulin can not be measured because the patient will produce antibodies to insulin which interferes with the assay for insulin levels
- Beta-Blocker Poisoning: Glucagon, like beta-adrenergic receptor agonists, produces cAMP by stimulating adenylyl cyclase. If too much beta-blocker has been administered, cAMP levels can be amplified by the administration of glucagon
- Radiology of the Bowel: Profound relaxation of the small intestines facilitates x-rays
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