Classification of Diabetes Mellitus
Type I-Insulin dependent (deficiency)
Type II-Insulin independent (resistance)
What diabetes can cause
major cause of heart disease and stroke; 7th leading cause of death in United States.
Macrovascular complications of diabetes
Coronary artery disease, cerebral vascular problem, peripheral vascular disease
Microvascular complications of diabetes
Nephropathy, retinopathy and neuropathy
Diagnostic Criteria for Diabetes
- Fasting plasma glucose (FPG)
- HbA1c level (also considering FPG results)
- Glucose level 2 hrs after a 75 g glucose load (less used)
Type I Diabetes
Insulin dependent Juvenile onset 10% Inflammation of islets or antibodies to islet Prone to ketoacidosis HLA association No obesity Vascular complications*
Type II Diabetes
NOT Insulin dependent Maturity onset
90%
Inability of insulin action Not prone
No association with HLA
Obesity is a common risk factor Vascular complications*
Model of insulin action on glucose transport in myocytes & adipocytes
Insulin binds to the α subunits of the insulin receptor and stimulates the tyrosine kinase activity of the β subunits. Glucose transport proteins are then activated and translocated from the cytoplasm to the cell membrane which stimulates glucose entry into the cell.
Long-acting therapy
`Glargine
Short-acting
Aspart/Lispro
Regular
Insulin management schedules:
2 or 3 meals (+/-PM) considerations; single or mixed insulin preps
Insulin Delivery Devices:
Syringes; Refillable/Prefilled Pens; Insulin Pumps
Complications of Insulin
Hypoglycemia: relieved by glucose (food intake; i.v. injection, etc.), ketoacidosis, insulin allergy, or lipodystrophy at injection site.
Pathophysiology of T2D
know how glucagon and insulin work
Sulfonylureas(SFUs):
Glyburide
Glyburide mode of action
Induce insulin release from pancreas (closing ATP-K+ channels)
Reduce serum glucagon levels
Potentiates action of insulin on its target tissues
Adverse drug reactions of glyburide
Severe hypoglycemia; weight gain, nausea, vomiting, hypersensitivity reactions
Indication for glyburide
T2D patients failed to achieve glycemic control with diet & life-style modifications; may be used in patients with kidney disease
Biguanides:
Metformin, generally 1st choice therapy
Metformin Mode of Action
↓ hepatic glucose production (HGP) (activates AMP-kinase)
↑ insulin action on peripheral muscle and fat tissues
Non-insulin-dependent effects, thus no hypoglycemia & no weight gain; No effect on release of growth hormone, glucagon.
Contraindications of Metformin
Contraindicated in patients with renal impairment, hepatic diseases, heart problems, acidosis, blood infection, etc.
Thiazolidinediones(TZDs)
Rosiglitazone and Pioglitazone
Mode of Action of rosiglitazone and pioglitazone
Agonists for nuclear peroxisome proliferator-activated receptor-γ (PPAR γ) & activate insulin responsive genes that regulate carbohydrate and lipid metabolism
Promote glucose uptake to muscles/fat & decrease HGP
Require insulin presence for action
Adverse drug reactions of rosiglitazone and pioglitazone
1st year liver function monitoring
Edema (fluid retention), weight gain
Rosiglitazone (FDA restricted access): risk of heart attack/MI;
Pioglitazone: common usage in the US
Indications and other considerations for rosiglitazone and pioglitazone
Good for overweight/obese patients;
Slow onset: 4-6 wks to affect blood glucose (may even take 3-4mos)
α-GlucosidaseInhibitors
Acarbose
Mode of action of acarbose
Delays carbohydrate digestion and slows glucose absorption in the gut
No effect on insulin release
Adverse drug reaction of acarbose
Dose related malabsorption, flatulence, nausea and diarrhea (No weight gain)
Newer Anti-Diabetics
Two main gut incretins:
GIP and GLP-1 (diminished in T2D post-meal)
Exenatide- IV
DPP-4 inhibitors (oral): sitagliptin
Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
Incretins
are a group of GI hormones that increase insulin release from the beta cells of the islets of Langerhans after eating. Incretin levels become elevated even before blood glucose levels. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. They also inhibit glucagon release from the alpha cells of the Islets.
Glucagon-LikePeptide1(GLP-1)Agonists
Exenatide
Mode of action of exenatide
Induces insulin release (glucose-dependent)
Reduces post-meal glucagon, and hence HGP Slows stomach emptying
Promotes satiety and inhibits appetite
Preserves beta cell mass
Exenatide dosing regimens:
injected twice daily 1hr pre-meal; or ER (Extended Release) for once weekly
Adverse drug reactions to exenatide
Nausea, vomiting, headache. Avoid in patients with severe kidney & GI problems
InhibitorsofDipeptidePeptidase-4(DPP-4)
Sitagliptin
Mode of action of sitagliptin
Inhibits degradation of incretins thus increasing GLP-1
Can be administered orally (once daily)
Adverse reactions of sitagliptin
Headache, risk of infections
Caution in kidney problems and potential contraindications