Antidiabetic Flashcards
Adrenergic α2
receptor activation decreases insulin release (predominant) by inhibiting β-cell adenylyl cyclase
Adrenergic β2
stimulation increases insulin release (less dominant) by activating β-cell adenylyl cyclase
Vagal stimulation
causes insulin secretion through IP3/DAG- increased intracellular Ca2+ in the β-cell
Insulin receptor
Two α-subunits and two β-subunits. Insulin binds to α-subunit
Activates Tyrosine Kinase → Phosphorylation of tyrosine in β-subunit
Activates insulin receptor substrate (IRS)
Translocation of glucose transporters to cell membrane – increases Glucose uptake into the cells,
Increases glycogen synthesis,
Alters protein and fat metabolism
Actions of Insulin on the liver
Inhibits gluconeogenesis (glucose production from protein, pyruvate, FFA and glycerol) and increases glycolysis
Inhibits glycogenolysis and stimulates glycogen synthesis (glycogenesis)
Increases the synthesis of triglycerides
Increases protein synthesis
Overall effects of insulin
Overall effects of insulin: to favor storage of fuel
Insulin promotes cellular K+ uptake**
Synthesis of proteins and fats (anabolic)
In the absence of insulin, most body cells cannot take up glucose.
Proteins and fats are broken down to provide energy
Actions of Insulin on the muscle
Increases glucose transport and glycolysis
Increases glycogen deposition
Increases protein synthesis
Actions of insulin on adipose tissue
Increases glucose transport
Increases triglyceride synthesis (lipogenesis)
Decreases intracellular lipolysis
Rapid, intermediate & major long term effects
Most of the metabolic actions of insulin are exerted within seconds or minutes (rapid actions)
Others involving DNA mediated protein synthesis have a latency of few hours (intermediate actions)
In addition, insulin exerts major long term effects on multiplication and differentiation of cells
Is insulin orally active
Insulin is orally not active as degraded in the GIT
Insulin is inactivated by insulinase found mainly in kidneys
Sources of insulin
Beef pancreas (bovine insulin): different from human insulin by 3 Amino acids: allergy concerns Associated with a risk of“mad-cow”disease
Pork pancreas (porcine insulin)- differs from human insulin by 1 Amino acids: allergy concerns less than bovine insulin
Human insulin: recombinant DNA technology: Now commonly used
Human insulin differs from bovine insulin by 3 AA and from porcine insulin by 1 AA
How is human insulin produced
Produced by recombinant DNA technology in bacteria (E. coli) and in yeast, or by enzymatic modification of porcine insulin.
Advantages of Human insulin
Diminished antibody (less chance of insulin resistance)
Less allergic reactions
Less lipodystrophy (insulin is lipogenic – could get swelling of subcutaneous fat at the sites of injection)
During surgery or infection
Regular Insulin
(Crystalline Zinc Insulin/Soluble Insulin)
Onset is ≥30 mins, duration of action 6-8 hours;
Regular insulin can be given SC, or IV
intravenous (IV) route (for DKA, during surgery or acute infections)
Need to wait for 30 min to have meals.
Short acting insulin analogues
Insulin Lispro, Insulin Aspart and Insulin Glulisine: Rapid acting
Characteristics of short acting insulin analogues
more rapidly absorbed from subcutaneous sites than regular insulin
Rapid onset within 15 min & duration <3-4 hours;
Meals can be taken within 15 min following injection
more closely mimic normal endogenous prandial insulin secretion than does regular insulin
have the lowest variability of absorption (from s.c. sites) (approx- 5%) of all available commercial insulin
preferred insulin for use in continuous subcutaneous insulin infusion devices
Intermediate acting insulin
NPH (Neutral Protamine Hagedorn, Isophane) and Lente insulin
Duration of action~ 12-24 hours
Long acting insulin
only s.c.
Ultralente, Insulin glargine, Insulin detemir, Protamine-zinc insulin, Insulin degludec
Duration of action ~ 30 hours, Insulin degludec -40 h
Split-mixed regimen
Calculated daily dose of insulin is split in 2 or 3 doses; and insulin preparations used are of mixed types (short-acting+ intermediate acting (30:70, 50:50 etc) or short-acting+ longer-acting, etc)
Frequently used
Insulin dosing for standard treatment
injection of both short and intermediate acting insulin twice a day
Insulin dosing - Intensive treatment
Intensive treatment methods are employed which involve multiple injections:
Multiple regular + intermediate acting insulin injections (in response to monitoring blood glucose levels)
Intensive therapy is not recommended in pts with advanced age and those with hypoglycemic unawareness
Theraputic uses of insulin
Diabetes mellitus (Type 1)**** Diabetes mellitus: Type 2: Sometimes, if not well-controlled. Most type 2 diabetics are treated with dietary changes, reduction in body weight, appropriate exercises and oral antidiabetic agents Diabetic Ketoacidosis (Diabetic coma)**** Hyperosmolar (nonketotic hyperglycemic) coma***
Gestational diabetes**
DKA clinical features
- Nausea and vomiting,
- Abdominal pain
- Dehydration
- Tachycardia
- Hyperventilation – from acidosis
- Hypotension
6 steps to DKA management
- Insulin: Regular insulin IV (bolus + infusion)
After patient becomes fully conscious, maintenance with s.c. inj - IV fluids***: to correct dehydration- Normal saline (0.9% NaCl)
After blood glucose has reached 300 mg/dl, 5% glucose in ½ N saline is the most appropriate solution
glucose is needed to restore the depleted hepatic glycogen
- KCl
Acidosis causes loss of K+ in urine
Additionally, when insulin therapy is instituted K+ is driven intracellularly- leading to severe hypokalemia - NaHCO3
Not routinely needed, because acidosis subsides as ketosis is controlled - Phosphate: (routine use controversial)
- Antibiotics: if required; respiratory infections reported in patients developing ketoacidosis
Hyperosmolae nonketoic hyperglycemic coma
- Usually occurs in elderly type 2 diabetes
- General principle of treatment are same as for DKA, except that faster fluid replacement is to be instituted and NaHCO3 is usually not required.
- Patients are prone to thrombosis (due to hyperviscosity and sluggish circulation), prophylactic heparin therapy is recommended (along with insulin)
ADR of Isulin
Hypoglycemia**
symptoms: sweating, anxiety, palpitation, tremor, dizziness, headache, behavioral changes, visual disturbances, fatigue, weakness, muscular in-coordination, etc → ultimately coma
Most frequent and the most serious reaction
Can occur in any diabetic pt.
Following inadvertent large doses of insulin injection, or by missing a meal or by performing a vigorous exercise
generally, the reflex sympathetic symptoms occur before the neuroglucopenic symptoms
diabetic neuropathy can abolish the autonomic symptoms***
when blood glucose falls further (< 40 mg/dl) mental confusion, seizures and coma occur
S/S of hypoglycemia are related to
counter regulatory sympathetic stimulation- sweating, anxiety, palpitation, tremors neuroglucopenic symptoms (due to deprivation of brain of its essential nutrient- glucose)- dizziness, headache, behavioral changes, visual disturbances, fatigue, weakness, muscular incoordination, etc → convulsion and ultimately coma
Hypoglycemia treatment
Glucose (sugar candy, sugar syrup etc) must be given orally or IV (10% dextrose for severe cases); reverse the symptoms rapidly
Somogyi effect
Blood glucose level drops too low in the midnight hours (Very early morning) due to usage of too much long acting or medium acting insulin at the night before or not eating a snack before bed time.
Released hormones (growth hormone, cortisol, and catecholamines) help to reverse the low blood glucose level but higher than normal in the morning.
Other insulin ADR
sensation: Lipodystrophy (lipoatrophy or lipohypertrophy) of subcutaneous fat at the injection site (less seen with new preparations)
Allergic reactions (Anaphylactoid reactions): due to contaminating proteins added to insulin in its formulation (protamine, etc) (very rare with human/highly purified insulins)
Weight gain (insulin is anabolic)
Hypokalemia (uptake of K+ into cells)
How do beta blockers prolong hypoglycemia
hypoglycemia by inhibiting compensatory mechanisms operating through β2 receptors (β1 selective are less liable).
Additionally, warning signs of hypoglycemia like palpitation, sweating, tremors and anxiety are masked
How does alcohol affect hypoglycemia
can precipitate hypoglycemia by inhibiting gluconeogenesis
