an enzyme in the GI tract that converts complex starches and oligosaccharides to monosaccharides

inhibited by acarbose and miglitol

insulin lispro

insulin aspart

insulin glulisine

rapid onsets and early peaks of activity = control of postprandial glucose levels

all three have AA sequences that speed their entry into the circulation without affecting their interaction with the insulin receptor

injected immediately before a meal and are the preferred insulin for continuous subcutaneous infusion devices

also used for emergency treatment of uncomplicated DKA

1) perferred insulin for continous subcutaneous infusion devices

2) emergency treatment of uncomplicated DKA

regular insulin

used intravenously in emergencies or administered cubcutaneously in ordinary maintenance preparations

was used for postprandial control before development of rapid insulins - must give 1 hr before meal!!

regular insulin has idential zsequence to human = unmodified

variable absorption rate

only insulin that can be given IV!!!

it is a short-acting insulin - need to give 1 hr before meal

only insulin that can be given IV

has identical sequence to human insulin (unmodified)

Neutral protamine Hagedorn (NPH) insulin

combination of regular insulin and protamine (a highly basic protein used to revers action of unfractionated heparin)

exhibits delayed onset and peak of action

often combined with regular and rapid-acting insulins

insulin glargaline and determir

modified forms of human insulin that provie a peakless basal insulin level lasting more than 20h

helps control BASAL glucose levels without producing hypoglycemia

1.) almost all insulins are sold at the same concentrations (called U100)

2.) administered subcutaneously by injection or pump

3.) Regular can be give IV for emergency, ketoacidosis

4.) inhaled is available but mroe variablity and reports of pulmonary fibrosis (didn't work)

standard = subcutaneous injections with disposable needles and syringes

portable pen-sized injections

programable pumps = continuous basal + adjustments for before meals or while exercising

--> hypoglycemia is most common problem --> Leads to confusion, coma, or seizures - this is most common when one maintains TIGHT CONTROL of blood glucose

1.) Rapid fall in blood glucose detected by hypothalamus and elads to increased epinephrine production which promotes glycogenolysis. Symptoms are increased HR, palpitation, swating, hunger, and weakness (Sympathetic Sx)

2.) Caused by overdose, exercise, skipped meals

'3.) treatment = oral or IV glucose

4.) Repeated hypoglycemic episodes reduces hypoglycemic response and preven patient from recognizing need to treat with oral glucose

--> Lipodystrophy (atrophy of subcut. fat at injection sites) is rare

--> Allergy to insulin is rare

stimulate release of endogenous insulin by promoting closure of K channels in the pancreating B-cell membrane --> depolarizes cells --> triggers insulin release

for T2DM, not for T1DM

includes: sulfonylureas, repaglinide (a meglitinide), and nateglinide (a D-phenylalanine derivative)

rapid onset and short duration of action that make them useful for administration just before a meal to control postprandial glucose levels

can precipateate hypoglycemia, although the risk is less than that associated with insulins

older sulfonylureas are extensively bound to serum proteins --> drugs that compete for protein binding may enhance their hypoglycemia effects

rash or other allergic rxns (rare)

*** weight gain

MOA: close beta cell K channels leading to depolarization and stimulation of more insulin secretion

First generation: tolbutamide, Tolazamide, Chlorpropamide

Second generation: glyburide, glimepiride, glipizide

- more potent than first generation = 1x/day dosing

All are metabolized in liver and are contradindicated with liver failure

Adverse: 1) hypoglycemia can occur and may las several days - hazard increased if hepatic dz present

2) As T2DM progresses, sulfonylureas lose efficacy (loss of beta-cells to respond)

a meglitinide

works on beta-cell K channel --> closure of channel --> cell depolarization --> insulin release

shorter duration of action than sulfonylurea - take before meals (when more insulin release is required)

Risk: hypogylcemia

D-phenylalanine derivative

works on beta-cell K channel --> closure of channel --> cell depolarization --> insulin release

shorter duration of action than sulfonylurea - take before meals (when more insulin release is required)

*** it loses efficacy at low glucose levels, making it safer - hypoglycemia doesn't last as long, so less likely to have an episode of hypoglycemia

biguanide class

MOA/effects:

• increase tissue glucose uptake and reduce hepatic gluconeogenesis, possibly by activation of AMP kinase (incr. AMP = promotes cell to get more energy and promotes glucose uptake)
• Delays or prevents onset of T2D
• reduces postprandial and fasting glucose
• stimulate glucose uptake and glycolysis in peripheral tissues
• slowing of glucose absorption from GI tract
• reduction of plasma glucagon levels
• reduces endogenous insulin production through enhanced insulin sensitivity = does NOT increase weight --> WEIGHT LOSS!!!

1) used to restore fertility in anovulatory women with polycystic ovary diseas (PCOD) and evidence of insulin resistance

2) New data shows anti-cancer benefits

DOES NOT cause hypoglycemia

most common tox.:

1) Gi distress at start of therapy

2) can promote lactic acidosis (esp. in patient with renal or liver dz, alcoholism, or conditions that predispose to tissue anoxia and lactic acid production --> chronic cardiopulmonary dysfunction)

rosiglitazone and pigolitazone

MOA: reduced insulin resistance - acts through PPARγ which alters gene expression --> promotes genes involved in lipid storage, reducing circulating lipid that promote insulin resistance

- reduces expression of cytokines that promote insulin resistance (for example, TNFα) and increases expression of cytokines that increase insulin sensitivity (adiponectin) --> CUT down on INFLAMM.

*** reduce both fasting and postprandial hyperglycemia

- used as monotherapy or in combination with insulin or other oral antidiabetic drugs

- reduce risk of diabetes in high-risk patients

hypoglycemia is rare

weight gain, fluid retention that can promote CHF and rare hepatotoxicity

Rosiglitazone increases heart failure and increased risk of MI

Contraindicated in pregnancy, hepatic failure, and heart failure

may delay type 2 diabetes

Drug: induce CYP P450 activity and can reduce the serum cocentrations of drugs that are metabolized by these enzymes (ex: oral contraceptives, cyclosporine)

acarbose and miglitol

carbohydrate analogs that act within the intestine to inhibit alpha-glucosidase, an enzyme necessary for the conversion of complex starches to monosaccharides that can be transported out of the intestinal lumen and into the bloodstream

- for postprandial hyperglycemia (reduces this) = take just before a meal

monotherapy or in combination with other drugs

prevent T2D in prediabetic persons

tox: moderate GI problems - glatulence, diarrhea, abdominal pain. If get hypoglycemia, tx with oral glucsoe (dextrose) and not sucrose

injectable analogue of amylin (beta cell product secreted with insulin)

reduces postprandial glucose in type 1 and type 2 diabetics

slows GI absorption, reduces appetite, and reduces glucagon secretion

hypoglycemia is the major adverse effect; also GI distrubances

amylin is cosecreted by pancreatic B cells

contributes to glycemic control by activating high-affinity receptors that are a complex of the calcitionin receptor and a recptor activity modifying receptor (RANK)

Pramlintide suppresses glucagon release, slows gastric emptying, works in CNS to reduce appetite.

After subcutaneous injection, it is rapidly absorbed and has short duration of action

INCRETIN

Glucagon-like peptide-1 = GLP-1 = member of incretin family of peptide hormones (released from endocrine cells in the epithelium of the bowel in response to food)

augment glucose-stimulated insulin release from pancreatic B cells, slow gastric emptying, inhibit glucagon secretion, and produce feeling of satiety

GLP-1 receptor is coupled to a G-protein == incr. cAMP and increases free intracellular concentration of calcium

long-acting injectable peptide analog of GLP-1 - - isolated from saliva of Gila monster

must be injected subcutaneously

used in combination with metformin or a sulfonylurea for tx of T2DM

major adverse effects are GI disturbances (esp. nausea during initial therapy and hypoglycemia when combined with sulfonylurea)

has also caused serious and sometimes fatal acute pancreatitis

(from notes 572: in animal models of autoimmune type 1 diabetes, exenatide can reverse diabetes if immune response is suppressed)

• increased insulin secretion
• increased beta cell growth
• reduced glucagon secretion
• slower gastric emptying
• reduced appetite

sitagliptin

• block GLP-1 degradation
• oral agen that has benefits of injectable exentatide
• recently entered market

 use in T2D = monotherapy or in combination with metformin or a thiazolidinedione

PROMOTES insulin release, inhibits glucagon secretion, delays gastric emptying, and has an anorexic effect

ADVERSE: headache, nasopharyngitis, upper respiratory tract infection

dipeptidyl peptidase-4 (DPP-4)

enzyme that degrades GLP-1 and other incretins

- sitagliptin is inhibitor of this enzyme -

GLP-1 analog

has a longer duration of action due to binding to albumin

Dapagliflozin

decreases blood glucose

inhibits SGLT2 tubular glucose transporter and lowers blood glucose

may help reduce weight

increases urine volume and urinary tract infections

combine more than one agent with different mechanisms often provides the greatest benefit

weight loss is almost always beneficial as is exercise