Insulin and Oral Glycemic Control Agents Flashcards
Where is insulin synthesized? Stored? What is insulin released with? Where is insulin degraded? What is the half life of insulin?
Synthesized in beta cells of the endocrine pancreas (Islets of Langerhans)
Stored in granules in the form of proinsulin (single chain protein containing insulin and connecting peptide [C-peptide]) - neither proinsulin nor C-peptide have any physiological function
Degraded in the liver and kidney by insulinase (an enzyme that hydrolyzes the disulfide bridges between the A and B chains)
Half life of insulin in the blood = 3-5mins
What is amylin?
Beta cells synthesize and release amylin that has short-acting anorexic effects in the feeding center of the brain
amylin regulates the influx of nutrient products of digestion by: reducing food intake, gastric acid secretion and rate of gastric emptying & decreasing pancreatic glucagon and digestive enzyme secretion
Where is glucagon produced? What does it do?
glucagon is a peptide hormone produced by alpha cells that is stimulated during hypoglycemia
acts as a counter-regulatory to insulin that increases plasma glucose through activation of liver gluconeogenesis
Describe the gastrointestinal mechanisms of secretion of insulin.
primary stimulus for insulin release in humans is glucose
GI hormones, such as gastrin inhibitory peptide, cholecystokinin, secretin, gastrin, and glucagon-like peptide (GLP-1; incretin) enhance glucose-induced secretion of insulin
Describe the endocrine mechanisms of secretion of insulin.
hormones secreted by other endocrine cells in the pancreas regulate the secretion of insulin (glucagon secreted by alpha cells stimulates insulin secretion, whereas somatostatin secreted by delta cells inhibits insulin secretion)
Describe the neural mechanisms of secretion of insulin.
pancreatic islets are richly innervated by sympathetic (adrenergic) and parasympathetic (cholinergic) autonomic neurons that regulate the basal rate of insulin secretion
activation of alpha-adrenergic receptors inhibits insulin secretion (exercise, stress)
activation of beta-adrenergic or cholinergic receptors stimulates insulin release (vagal stimulation)
Describe the action of insulin that is dependent on glucose.
Insulin decreases blood glucose levels by stimulating the uptake and utilization of glucose in a wide variety of tissues by a mechanism involving specific cell membrane receptors
Describe the action of insulin that is independent of glucose.
glucose and utilization occurs in some tissues (e.g. brain, liver) by an insulin-independent process, and during exercise glucose uptake can occur in muscle (an insulin-dependent tissue) in the absence of insulin
What are the actions of insulin in the liver?
Stimulates the storage of glucose as glycogen (by inducing the enzymes involved in the synthesis of glycogen)
inhibits the breakdown of glycogen to glucose (by repressing the enzymes involved in glycogenolysis)
stimulates triglyceride and lipoprotein synthesis and inhibits fatty acid catabolism
What are the actions of insulin in muscle?
stimulates the storage of glucose as glycogen
inhibits the breakdown of glycogen to glucose
stimulates protein synthesis
inhibits protein and amino acid catabolism
What are the actions of insulin in adipose tissue?
stimulates triglyceride and lipoprotein synthesis
inhibits fatty acid catabolism
What is diabetes mellitus? Acute insulin deficiency? Chronic insulin deficiency?
Metabolic disorder characterized by elevated blood glucose levels (hyperglycemia) resulting from impaired insulin secretion by pancreatic beta cells or reduced biological efficacy of insulin at target tissues
acute insulin deficiency results in inappropriate catabolism of carbohydrates, lipids, and proteins which is clinically manifested by hyperglycemica, hyperlipemia and ketonemia (and related symptoms such as ketoacidosis, glycosuria, polyuria, dehydration, polydipsia, polyphagia, and fatigue)
chronic insulin deficiency causes patholgoical changes in blood vessel microcirculation which results in gangrene, retinal impairment, myocardial infarction, polyneuropathy, and nephrosis
What is type 1 diabetes mellitus?
Insulin-dependent (juvenile)
onset most commonly occurs in individuals prior to 30yrs of age
may result from an infectious or toxic environmental insult to beta cells or a destructive autoimmune response against beta cells in certain genetically-predisposed individuals
circulating insulin is virtually absent and beta cells fail to respond to stimuli for insulin secretion
insulin is required to reverse the catabolic state, prevent ketosis and reduce elevated blood glucose levels
What are the species of insulin?
most commonly in the past = 70% beef and 30% pork insulin
advances in mass production of human insulin by recombinant DNA techniques have supplanted animal-sources of human insulin
Why are purity and concentration of insulin important?
improvements in purification techniques have greatly reduced the content of contaminating in insulin preparations
most commercial preps are available in concentrations of 100 units/mL and are dispensed in 10mL vials
Describe short-acting insulin preparations
‘regular’ crystalline zinc-insulin complex provided in a soluble form and dispensed as a clear solution at a neutral pH
onset of action = 30min after subcut injection, duration of action = 5-7hrs
may be injected by IV for acute management of diabetic ketoacidosis
suspension of the crystalline zinc-insulin complex in acetate buffer produces an amorphous precipitate with a longerd uration of action (12-16hr) following subcut injection
Describe intermediate-acting insulin preparations
commercial insulin preps have been modified to provide a prolonged duration of action and are dispensed as suspensions at neutral pH with either protamine in phosphate buffer or varying concentrations of zinc ions in acetate buffer
NPH isophane insulin preparations have a delayed onset (8-12hr) and prolonged duration of action (18-24hr)
usually used in combo with shorter-acting insulin preps
what are the pharmacokinetics of insulin?
rapidly inactivated in GI tract when taken orally
absorbed well following subcut injection and circulates in the blood as a free hormone
4-6min half life
metabolized in the liver and kidney and excreted in the feces and urine (insulin bound to cell membrane receptors is internalized and destroyed intracellularly by target tissues)
what are the common side effects of insulin?
mild hypoglycemica characterized by functional abnormalities of the CNS (drowsiness, fatigue, headache, mild tremor, and nausea)
local allergic reaction at subcut injection sites
what are the adverse reactions of insulin?
marked hypoglycemica characterized by more pronounced abnormalities of the CNS (e.g. mental confusion, bizarre behavior, coma) and hyperactivity of the sympathetic (e.g. tachycardia, palpitations, sweating) and parasympathetic (e.g. nausea, hunger) autonomic nervous system
systemic allergic reactions (anaphylaxis) and insulin resistance
What are the insulin analogs?
‘insulin-like’ molecules with amino acid substitutions which modify the rate of absorption from subcutaneous sites
what are the rapid-acting insulin analogs?
Insulin Lispro; Insulin Aspart; Insulin Glulisine
insulin analogs have amino acid substitutions which cause less ‘self-association’ of insulin molecules into hexamers which accelerates absorption
can be injected immediately before a meal for better glycemic control
what are the long-acting insulin analogs?
Insulin Glargine has amino acid substitutions which cause delayed absorption
- improved postprandial glycemic control; maintain basal insulin levels
Insulin Detemir
- engineered to add a fatty acyl chain on to the lysine residue of the B-chain, so as to increase binding to albumin
- duration of action is extended due to continued release of insulin that has been bound to circulating albumin
What is type 2 diabetes mellitus?
non-insulin dependent - maturity onset
onset most commonly occurs in individuals after 40yrs of age
obesity is a common risk factor and most patients with type 2 diabetes are obese
milder form of diabetes caused by impaired beta cell response to glucose and target tissue insensitivity to insulin (circulating endogenous insulin levels are sufficient to prevent ketoacidosis but are often subnormal or inadequate to prevent hyperglycemia)
when dietary restrictions and attempts at weight reduction of obesity fail to correct hyperglycemia, insulin, or oral hypoglycemic drug therapy is prescribed
What are sulfonylureas?
2nd generation drugs differ in potency and duration of action: Glyburide, Glipizide
stimulate the release of endogenous insulin from functional beta cells and increase the number of insulin receptors on target tissues
What are the pharmacokinetics of sulfonylureas?
well-absorbed orally
circulate in the blood bound to plasma proteins
metabolized in the liver and excreted in the feces and urine
half-lives vary betwen drugs in direct proportion to their duration of action
What are the common side effects of sulfonylureas?
mild hypoglycemia and associated central nervous system abnormalities
occasional GI distress (e.g. anorexia, cramps, nausea, heartburn)
What are the adverse reactions of sulfonylureas?
marked hypoglycemia and associated central and autonomic nervous system abnormalities
What are the contraindications of sulfonylureas?
treatment of type 1 insulin-dependent diabetes mellitus
pregnancy
What are the drug interactions of sulfonylureas?
actions are potentiated by drugs which compete for binding sites on plasma proteins (e.g. oral anticoagulants, anti-inflammatory agents)
What are meglitinides?
Repaglinide (Prandin)
acts via a similar mechanism to sulfonylureas to increase insulin secretion from beta cells
ineffective in the absence of glucose
short half-life, administered before each meal, lower incidence of hypoglycemia
What are the pharmacokinetics of the incretin mimetic exenatide?
glucagon-like peptide-1 (GLP-1; incretin) agonist that acts within the pancreas to increase insulin secretion and inhibit postprandial glucagons secretion
also acts to slow gastric emptying and increase satiety
injected subcutaneously, short half life (2.5hr)
indicated for patients with type 2 diabetes who have not achieved glycemic control on metformin on sulfonylurea, or both
What are the adverse effects of the incretin mimetic exenatide?
nausea, vomiting, and diarrhea
reduced fetal growth, skeletal abnormalities, and teratogenesis in laboratory animals
pregnancy category C - no human studies
What are the pharmacokinetics of the incretin mimetic liraglutide?
soluble fatty acid avcylated GLP-1
C16 acyl chain allows for non-covalent binding to albumin and hinders metabolism by DPP-4 resulting in a prolonged half-life (12hr) and duration of action
What are the adverse effects of the incretin mimetic exenatide?
the most frequent side effects are nausea, vomiting, and increased incidence of diarrhea
stimulates C-cell neoplasia and causes medullary thyroid carcinoma in rats, but human C-cells express very few GLP-1 receptors so relevance to human therapy is unclear
should not be used in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia (MEN) syndrome type 2
What are the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitors?
Sitagliptin, Linagliptin
blocks the catabolism of the endogenous incretins glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)
increase insulin synthesis and release
blocks hepatic gluconeogenesis
indicated in type 2 diabetes
orally active tablets used as monotherapy or in combo with anti-hyperglycemics (metformin and thiazolidinediones)
What is insulin resistance?
syndrome characterized by hyperglycemica and hyperinsulinemia
mechanisms include: alterations in either insulin, insulin receptors, and/or target ecll post-receptor intraellualr mechanisms
implicated in the development of type 2 non-insulin dependent diabetes mellitus
pharmacological strategies in the treatment of insulin resistance include the 2nd generation sulfonylureas (Glyburide, Glipizide), biguanides (metformin), and thiazolindinediones (pioglitazone)
What is metformin?
antihyperglycemic, rather than hypoglycemic
reduces hepatic glucose output by blocking gluconeogenesis
orally active, absorbed in small intestine, does not bind to plasma proteins, and is excreted unchanged in the urine (half life = 1.5-4.5hrs)
acute side effects: diarrhea, abdominal discomfort, nausea, metallic taste, anorexia
lactic acidosis is a possible adverse effect with chronic treatment
What is Pioglitazone?
antihyperglycemic
no effect on insulin secretion from beta cells per se, but potentiates insulin-induced translocation of the glucose transporter resulting in an increased glucose uptake in muscle and adipocytes
What is Acarbose?
intestinal brush border alpha-glucosidase inhibitor
reduces intestinal absorption of carbohydrates
reduces postprandial plasma glucose levels in patients with type 1 and type 2 diabetes
orally active
side effects = malabsorption, flatulence, and abdominal bloating
What is the pharmacokinetic of the amylin mimetic Pramlintide?
synthetic analog of human amylin
injected subcutaneously
short half life 50min
approved for adjunctive tx of patients with type 1 and type 2 diabetes who inject insulin at mealtimes but fail to achieve glucose control
limits the amount of short acting insulin analog required
What is the mechanism of action of the amylin mimetic Pramlintide?
suppresses postprandial glucagon secretion
slows gastric emptying
suppresses hepatic gluconeogenesis
increases satiety
What are the adverse effects of the amylin mimetic Pramlintide?
nausea, vomiting, anorexia, headache
hypoglycemia when used with insulin
What is Dapagliflozin?
inhibits subtaype 2 sodium glucose transport proteins (SGLT2) thereby blocking reabsorption of filtered glucose
orally active, indicated for type 2 diabetes
adverse effects: glycosuria, osmotic diuresis, hypotension, rapid weight loss, fatigue, UTIs
Empagliflozin indicated for use in type 2 diabetes patients with high cardiovascular risk since it has been shown to slower progression of kidney disease and lower rate of cardiovascular morbidity/mortality
