Insulin and Oral Glycemic Control Agents

Question 1

Where is insulin synthesized? Stored? What is insulin released with? Where is insulin degraded? What is the half life of insulin?

Answer 1

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

Question 2

What is amylin?

Answer 2

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

Question 3

Where is glucagon produced? What does it do?

Answer 3

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

Question 4

Describe the gastrointestinal mechanisms of secretion of insulin.

Answer 4

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

Question 5

Describe the endocrine mechanisms of secretion of insulin.

Answer 5

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)

Question 6

Describe the neural mechanisms of secretion of insulin.

Answer 6

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)

Question 7

Describe the action of insulin that is dependent on glucose.

Answer 7

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

Question 8

Describe the action of insulin that is independent of glucose.

Answer 8

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

Question 9

What are the actions of insulin in the liver?

Answer 9

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

Question 10

What are the actions of insulin in muscle?

Answer 10

stimulates the storage of glucose as glycogen

inhibits the breakdown of glycogen to glucose

stimulates protein synthesis

inhibits protein and amino acid catabolism

Question 11

What are the actions of insulin in adipose tissue?

Answer 11

stimulates triglyceride and lipoprotein synthesis

inhibits fatty acid catabolism

Question 12

What is diabetes mellitus? Acute insulin deficiency? Chronic insulin deficiency?

Answer 12

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

Question 13

What is type 1 diabetes mellitus?

Answer 13

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

Question 14

What are the species of insulin?

Answer 14

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

Question 15

Why are purity and concentration of insulin important?

Answer 15

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

Question 16

Describe short-acting insulin preparations

Answer 16

‘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

Question 17

Describe intermediate-acting insulin preparations

Answer 17

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

Question 18

what are the pharmacokinetics of insulin?

Answer 18

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)

Question 19

what are the common side effects of insulin?

Answer 19

mild hypoglycemica characterized by functional abnormalities of the CNS (drowsiness, fatigue, headache, mild tremor, and nausea)

local allergic reaction at subcut injection sites

Question 20

what are the adverse reactions of insulin?

Answer 20

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

Question 21

What are the insulin analogs?

Answer 21

‘insulin-like’ molecules with amino acid substitutions which modify the rate of absorption from subcutaneous sites

Question 22

what are the rapid-acting insulin analogs?

Answer 22

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

Question 23

what are the long-acting insulin analogs?

Answer 23

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

Question 24

What is type 2 diabetes mellitus?

Answer 24

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

Question 25

What are sulfonylureas?

Answer 25

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

Question 26

What are the pharmacokinetics of sulfonylureas?

Answer 26

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

Question 27

What are the common side effects of sulfonylureas?

Answer 27

mild hypoglycemia and associated central nervous system abnormalities

occasional GI distress (e.g. anorexia, cramps, nausea, heartburn)

Question 28

What are the adverse reactions of sulfonylureas?

Answer 28

marked hypoglycemia and associated central and autonomic nervous system abnormalities

Question 29

What are the contraindications of sulfonylureas?

Answer 29

treatment of type 1 insulin-dependent diabetes mellitus

pregnancy

Question 30

What are the drug interactions of sulfonylureas?

Answer 30

actions are potentiated by drugs which compete for binding sites on plasma proteins (e.g. oral anticoagulants, anti-inflammatory agents)

Question 31

What are meglitinides?

Answer 31

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

Question 32

What are the pharmacokinetics of the incretin mimetic exenatide?

Answer 32

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

Question 33

What are the adverse effects of the incretin mimetic exenatide​?

Answer 33

nausea, vomiting, and diarrhea

reduced fetal growth, skeletal abnormalities, and teratogenesis in laboratory animals

pregnancy category C - no human studies

Question 34

What are the pharmacokinetics of the incretin mimetic liraglutide​?

Answer 34

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

Question 35

What are the adverse effects of the incretin mimetic exenatide​?

Answer 35

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

Question 36

What are the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitors​?

Answer 36

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)

Question 37

What is insulin resistance?

Answer 37

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)

Question 38

What is metformin?

Answer 38

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

Question 39

What is Pioglitazone?

Answer 39

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

Question 40

What is Acarbose?

Answer 40

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

Question 41

What is the pharmacokinetic of the amylin mimetic Pramlintide?

Answer 41

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

Question 42

What is the mechanism of action of the amylin mimetic Pramlintide?

Answer 42

suppresses postprandial glucagon secretion

slows gastric emptying

suppresses hepatic gluconeogenesis

increases satiety

Question 43

What are the adverse effects of the amylin mimetic Pramlintide?

Answer 43

nausea, vomiting, anorexia, headache

hypoglycemia when used with insulin

Question 44

What is Dapagliflozin?

Answer 44

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