Post-translational modification of insulin: peripheral the ribosome translates a mRNA sequence into a protein, insulin, and passes the protein through the endoplasmic reticulum, where it is cut, folded and held in shape by disulfide bonds.
Then the protein passes through the golgi apparatus, where it is packaged into a vesicle. In the vesicle, more parts are cut off, and it turns into mature insulin.
One third of patients with diabetes currently use insulin and in 2012 insulin cost the US healthcare system approximately $6 billion.
Regulator of glucose and lipid metabolism that is dependent upon its interaction with the insulin receptor which is expressed primarily in muscle, fat, liver, and brain.
By activation of plasma membrane receptors it stimulates glucose uptake by responsive issue and decreases adding glucose production, thereby being the most potent agent for reducing glycemia.
Insulin secretion, responds to postprandial, increases in the levels of glucose or amino acids, promoting nutrition storage and maintaining normoglycemia.
Physiologic insulin secretion, approximates 0.4 to 1 unit per kilogram of bodyweight per day.
An exogenous insulin requirement greater than two or three units of insulin per kilogram per day is classified as severe insulin resistance.
Intestinal hormonal responses to food intake magnify insulin secretion (the incretin effect) that is mediated by glucagon like peptide one (GLP – 1) and glucose dependent insulinotropic polypeptide (GIP), in modulating satiety, foodintake, and other aspects of prandial metabolism..
The promotion of myocardial glucose uptake by insulin may be unfavorable for the failing heart, especially with aggressive glycemic goals: there is increased mortality in aggressively treated patients with diabetes associated heart failure.
Insulin spike after an oral glucose load is much higher than after an intravenous glucose load.
Action in muscle anger and liver requires relay intracellular signals involving phosphorylation and the dephosphorylation events.
Promotes glucose entry into tissues and decreases hepatic gluconeogenesis.
Insulin lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production.
Insulin inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.
Insulin promotes glucose uptake and use by insulin-dependent tissues stimulates formation of glycogen from glucose in the liver and muscle and suppresses glucagon secretion.
In skeletal muscle insulin binds and activates the insulin receptor tyrosine kinase with subsequent phosphorylation of insulin receptor substrate 1 (IRS-1).
Use does not increase the risk of serious morbididities associated with advanced Type II DM and may even prevent them.
Should be considered as the primary treatment for patients who have significant hyperglycemic symptoms and dramatically elevated plasma glucose concentrations of 300-350 mg/deciliter or hemoglobin A1 C levels of 10-12%.
For patients with limited life expectancy or hypoglycemia unawareness less stringent goals such as less than 8% is appropriate.
Insulin therapy is mandatory in patients with catabolic features or ketonuria suggesting the patient has profound insulin deficiency.
25% of diabetics underuse insulin because of cost.
Signs a patient should be started on insulin include poor glucose control that is manifested as nocturia, vaginitis, fatigue, sudden weight loss, hemoglobin levels 7-10% for at least four months despite oral agents, and frequent hemoglobin A1 C levels above 8%.
Insulin therapy is recommended at or near the end of treatment algorithms for diabetes with previous agents.
An anabolic polypeptide hormone produced by the beta cells of the islet of Langerhans.
The beta cells are located centrally with alpha cells and delta cells around them.
Synthesis related to the insulin gene and is transcribed to produce mRNA.
Produced through recombinant DNA techniques using microorganisms.
Using recombinant insulin has decreased the immunogenicity of insulins.
mRNA translated on rough endoplasmic reticulum bound ribosomes which produce preproinsulin.
Preproinsulin molecules enter the rough endoplasmic reticulum containing an N-terminal signal sequence which is cleaved off in the lumen of the rough endoplasmic reticulum to produce proinsulin.
Proinsulin contains the C peptide region that links the insulin alpha and beta chains and allows the protein to fold properly during its formation.
Contains two polypeptide chins linked together by disulfide bonds.
Erratic absorption and action of subcutaneous insulin leads to unpredictable swings in blood glucose concentrations and are associated with elevated glycated hemogoblinlevels and hypoglycemia.
Beta cells stimulated by elevated glucose levels caused calcium to enter the cells and triggers exocytosis of secretory granules containing insulin and C peptide.
As glucose enters the beta islet cells through the GLUT2 transporter, it is then phosphorylated by glycosidase and is trapped in the beta cells, then it is used to form ATP which inhibits ATP-sensitive potassium channels that pump potassium out of the cells, the accumulation of potassium causes the membrane to depolarize, causing an influx of extracellular calcium and that triggers the release of vesicle containing insulin and C-peptide.
Binds to insulin receptor, a tyrosine kinase.
The binding of insulin to tyrosine kinase activates it to phosphorylate insulin receptor substrate proteins, which in turn, activates cellular kinases and phosphatases .
Binds to its receptor and both are taken into cells where insulin is degraded and the receptor may return to the cell membrane.
Oral glucose stimulates 2 to 3 times more insulin release in the same amount of glucose administered intravenously, and this is due to the presence of incretins, gastrointestinal peptides.
Stimulates uptake of potassium by cells and is useful to treat hyperkalemia.
Transports glucose into cells within seconds to minutes, induces changes in enzyme activities within minutes to hours and increased glucokinase, phosphofructokinase and private kinases.
Endogenous release of insulin is greater with oral glucose versus intravenous glucose administration.
Its secretion is stimulated by glucose, amino acids, especially arginine, secretin, and other gastrointestinal hormones, free fatty acids, ketones, sulfonylurea drugs, cholecystokinin, acetylcholine, and glucagon.
Secretion is inhibited by epinephrine, norepinephrine cortisol, and growth hormone.
Serves as an anabolic hormone as it maximizes the body’s storage of dietary glucose in the well fed state.
Its action is to decreases serum glucose levels and its target tissues are those utilized for glucose storage and utilization, they are the liver, muscles and adipose tissue.
Insulin is the principal driver of fuel absorption and storage, with adipose tissue responsible for 5% of insulin mediated glucose uptake and adults who are lean and 20% those who are obese.
In the liver it inhibits gluconeogenesis, breakdown of glycogen and promotes glycogen synthesis.
The above indicates that white adipose tissue is an endocrine organ producing leptin, adiponectin and other adipokines that affect local in distant physiology such as pro-inflammatory tumor necrosis factor, monocyte chemotactic protein 1, and the sex hormone estrogen.
Insulin promotes the release of free fatty acids (FFAs) from adipose tissue into the blood.
Insulin promotes the production of new FFAs in the liver via de novo lipogenesis.
Insulin-in muscle it promotes glycogen synthesis, increases glucose entry into cells, and stimulates the entry of amino acids needed for protein synthesis.In muscle it promotes glycogen synthesis, increases glucose entry into cells, and stimulates the entry of amino acids needed for protein synthesis.
In adipose tissue it increases glucose uptake into cells, increases triacylglycerol synthesis, decreases triacylglycerol degradation, inhibits activity of hormone sensitive lipase and increases lipoprotein lipase activity.
Levels found to be positively associated with breast cancer risk, recurrence and mortality.
Lifesaving for type 1 diabetes and utilized to attain improved control in type 2 diabetes when glycated hemoglobin level is not in the target range despite treatment with oral hypoglycemic agents.
5 million individuals take insulin injections everyday in the U.S.
Significant resistance the use of insulin because of the associated pain, inconvenience, hypoglycemic side effects and weight gain.
Inverse association of magnesium intake and insulin concentrations.
Half life of intravenous insulin is 5-9 minutes.
Insulin is recommended is the second line therapy when non-insulin agents alone or in combination at maximal tolerated doses fail to achieve glucose targets within a 3-6 month.
Presentation of patients with blood sugars greater than 300 mg/dL, hemoglobin A-1 C greater than 10%, ketonuria or in patients who was symptomatic are likely to benefit from the insulin therapy initially to lower their blue blood glucose levels.
The use of oral antidiabetic medications or injectable diabetic medications other than insulin, can reduce hemoglobin A-1 C levels only by 0.5-1%.
In newly diagnosed patients with type 2 diabetes who have initiation of therapy with insulin may have improved beta cell function, over time as glucose control is achieved, and some patients may be able to transition to oral medications.
Early initiation of insulin therapy may not reduce long-term complications compared to non insulin therapy.
ORIGIN trial showed no difference in cardiovascular or microvascular outcomes after six years of therapy in patients with early diabetes or impaired fasting plasma glucose, when adding daily dose of insulin glarine to achieve normal glycemia compared to standard care.
Insulin therapy associated with more weight gain and hypoglycemic events compared to standard therapy.
The initiation of insulin in patients on non-insulin agents is usually with the long-acting basal insulin like glargine or detemir.
The long lasting basal insulin like drugs are preferred over neutral proteamine Hagedorn, which is associated with increased incidence of hypoglycemia.
Intravenous protocol-utilize 100 U regular insulin in 100 mL of 0.9% normal saline.
-if blood glucose >150 mg/dL give initial bolus determined by dividing blood glucose by 70 and round to the nearest 0.5 U
-after bolus is given an infusion is started at the same hourly rate as the bolus
-if blood glucose is less than 150 mg/dL divide by 70 for initial hourly rate with no bolus treatment, rounding to the nearest 0.5 U.
-with the initiation of insulin treatment hourly blood glucose levels should be done until 3 consecutive levels in range are obtained. With stability can check blood glucose every 2 hours for 12-24 hours until further stability and then every 3-4 hors checks can be done, unless clinical or nutritional changes occur.
-resumption of q 1 hour blood glucose studies if changes are made to the insulin infusion rate, with the initiation or cessation of corticosteroids or vasopressors, significant clinical changes, alterations in in nutritional support or the initiation or discontinuance of dialysis.
Different insulins have variable effects of glucose control, amount of weight gain and risk of causing hypoglycemia.
Prandial insulin replaces endogenous first-phase insulin secretion, and basal insulin decreases levels of fasting hyperglycemia.
In type I diabetes there is loss of pancreatic beta-cells and therefore an absolute insulin deficiency, and because the disease does not affect insulin sensitivity, patients typically require small doses of insulin to maintain glucose control.
In type II diabetes pre-existing insulin resistance and progressive insulin deficiency require higher doses of insulin and gradual upward titration of doses.
Insulin sensitizers may confer protection against diabetic nephropathy.
Treating to Target in Type 2 Diabetes (4-T) study evaluated patients who had suboptimal diabetic control with maximally tolerated doses of metformin and sulfonylurea and randomized biphasic, prandial, or basal insulin during 1 year period: basal or prandial insulin based treatment added to oral therapy had better glycated hemoglobin control than patients who added biphasic insulin based treatment (Holman R).
Sulfonylureas stimulate insulin release by closure of specific potassium channel on beta cells.
Regular insulin, at the time of injection self-associates to form hexamers which are poorly absorbed, delaying activity.
Insulin hexamers gradually dissociate into dimers and monomers, which into the bloodstream more rapidly.
Regular insulin tends to have onset of action 30-60 minutes after injection, a peak effect in 2-3 hours, and the total duration of action of eighth-10 hours.
Regulate insulin has a delayed onset of activity and is typically used 30 minutes before meals.
Insulin analogs can be injected closer to meal times then regular insulin.
Regular insulin’s pharmacokinetic profile does not overlap with the rate of carbohydrate absorption as well as insulin analogs.
In a trial of human insulin versus analog insulin the hemoglobin A-1 C levels increased slightly, 0.14%, but was not clinically meaningful.
Regular insulin can produce postprandial hyperglycemia soon after meals and can be associated with delayed hypoglycemia several hours after meals, and these findings may be more pronounced in patients with type I diabetes because of their relatively high insulin sensitivity.
Regular insulin is bio identical to endogenous insulin and its immunogenicity is very low.
Regular insulin costs about one fourth to one tenth My the price of insulin analogs.
Rapid acting insulin analogs include: lispro, aspart and glulisine.
Rapid acting insulin analogs are modifications to the insulin molecule that causes rapid dissociation of hexamers into dimers and monomers after injection.
Rapid acting insulinS ameliorate. The early postprandial hyperglycemia, followed by hypoglycemia that is often seen with regular insulin.
Rapid acting insulin analogs are administered at the beginning of the meal.
Rapid onset insulin are generally administered 15 to 20 minutes before meals and snacks, and constitute 56% of totally daily dose, with those amounts based on the estimated carbohydrate content and insulin sensitivity.
Rapid acting insulin analogs are available in vial and pen devices.
Insulin lispro and insulin aspart has onset of action in 5-15 minutes, a peak activity in 30-90 minutes, and duration of action for-six hours.
Rapid acting insulins deliver approximately twice the maximal concentration of insulin and take approximately half as much time to reach maximum concentration as regulate insulin injected subcutaneously.
Glulisine a rapid acting insulin has a faster onset then lispro, and may be administered after meals rather than before.
Insulin lispro available in U-100 and U-200 forms and the U-200 contains 600 units per pen instead of the usual 300 units.
Rapid acting insulins are associated with better postprandial glucose control levels and have a lower frequency of postprandial hypoglycemia than regular insulin.
Rapid acting insulins have less variability in insulin levels from injection to injection compared to regular insulin.
Presently there is one intermediate and two long-acting insulins available ( 2010).
Long acting insulin analogues cannot be modulated following injection to provide greater insulin delivery in the pre-breakfast hours, in order to counter the increase in blood glucose levels at that time of day ( dawn phenomenon).
Insulin analogues such as glargine, aspart, and lispro, do not offer a major advantages over human insulin products, such as neutral protamine Hagedorn (NPH) and regular insulin, for patients with type two diabetes.
Insulin analogues does not reduce the rate of severe hypoglycemia nor achieve improved glycemic control.
Insulin analog moderately reduce the rate of nocturnal hypoglycemia, an important outcome for patients with diabetes.
Errors in estimating the size and composition of meals, and the timing and magnitude of preprandial insulin dose may cause excessive hyperglycemia or late hypoglycemia.
NPH insulin (neutral protamine Hagedorn) insulin has a peak onset of action at 2-4 hours, with the peak activity within 4-10 hours and an effective duration of 10-16 hours.
NPH insulin is associated with higher incidence of hypoglycemic episodes than analogs detemir and glarine, which have less peaking actions.
NPH insulin may be used two or three times as a basal insulin or used in the morning to act as a combination of basal and bolus insulin to cover the noon meal.
Lispro and aspart are available as protamine solutions that can prolong their effect and when in such solutions they are long acting component is similar to NPH.
NPH is available without prescription.
NPH Insulin as significant variation in absorption from individual to individual and may cause variation in peak and duration of effect from one injection to another.
NPH insulin is less expensive and readily obtainable, but requires 2 daily injections, whereas one daily injection is usually sufficient when glarine, detemir , or Degludec is used.
Detemir and Degludec are the longest acting preparations with a half-life of approximately 25 hours often and associated with less hypoglycemia.
Adding zinc prolongs the action of insulin and lente and utralente insulins are the result, but they are no longer available in the United States.
Basal insulin secretion is emulated by long acting insulinsglarine and detemir.
Glargine contains amino acids that alter its absorption so that following injection interstitial fluid neutralizes the pH such that it precipitates under the skin and forms a reservoir of insulin producing an extended half-life approaching 24 hours: prolonged action of this insulin reduces peaking effect and lower risk of hypoglycemia then NPH.
Glargine is administered one time daily and may be associated with localized burning sensation.
U-100 gargine has an onset of 2 to 4 hours but only lasts 20 to 24 hours and up to 57% of patients require twice daily administration.
Glargine has not been shown to be more effective in reducing hemoglobin A-1 C compared to NPH.
Basal insulin (Toujeo)) is a concentrated form of glargine insulin.
Toujeo insulin is U-300 glargine with 300 units per mL instead U-100 counterpart such as Lantus which is 100 units per mL.
Toujeo is available in a pen that holds Up to 450 units versus up to 300 units in the traditional pen.
The injections of high doses of insulin require much less volume.
U-300 glargine starts working in 2-4 hours but has no peak onset of action.
U-300 glargine has a median duration of about 30 hours, and makes once daily administration available for many patients.
Detemir is bound to 14- carbon fatty acid increases albumin affinity to albumin which allows it to travel through the bloodstream bound to albumin.
Detemir has an onset of 1-3 hours, peaks in 6-8 hours and lasts 18 to 20 hours, but often requires two injections daily.
Detemir has a duration of effect for 14-21 hours, but the duration is longer at higher doses.
Detemir is approved for once or twice daily usage and has a more predictable glucose lowering effect than NPH.
Detemir has a lower risk of hypoglycemia and NPH, and has not been shown to improve hemoglobin A-1 C compared to NPH.
Insulin degludec (Tresiba) is a U-100 with the flat, stable profile, a half-life of 25 hours, and lasts approximately 42 hours and is given once daily.
Traditionally insulin is utilized as an injection of NPH and regular insulin in the morning and in the evening.
Regular insulin in the morning is intended to control glucose levels after breakfast, and with extended action acts to assist basal insulin requirements.
NPH insulin’s peak action at 4-10 hours serves as a basal insulin and controls blood sugar after the mid-day meal.
Traditionally a second injection of regular and NPH insulin are given at supper time providing glucose control after the evening meal, and the NPH component providing basal insulin overnight.
Regular insulin in addition to above may be used at breakfast and supper for correction of hyperglycemia.
Traditional management can be problematic since the regular insulin and NPH activity can overlap and cause hypoglycemic episodes, and must maintain a relatively inflexible schedule in terms of diet and insulin administration.
Combinations of the newer long acting analogs glargine or detemir that can provide basal insulin coverage with one or two daily insulin injections with rapid acting analogs such as lispro, aspart or glulisine to cover glucose variations are the newest approaches to insulin management: This combination that tends to replicate physiologic insulin secretion, and is associated with greater flexibility in terms of meals and ability to avoid hypoglycemic episodes.
With postprandial glucose elevations, the use of mealtime rapid acting insulin such as aspart, glulisine, or lispro may be beneficial.
The use of rapid acting insulins require glucose checks at each meal.
Insulin is recommended is the second line therapy when non-insulin agents alone or in combination at maximal tolerated doses fail to achieve glucose targets within a 3-6 month.
Presentation of patients with blood sugars greater than 300 mg/dL, hemoglobin A-1 C greater than 10%, ketonuria or in patients who was symptomatic are likely to benefit from the insulin therapy initially to lower their blue blood glucose levels.
The use of oral antidiabetic medications or injectable diabetic medications other than insulin, can reduce hemoglobin A-1 C levels only by 0.5-1%.
In newly diagnosed patients with type 2 diabetes who have initiation of therapy with insulin may have improved beta cell function, over time as glucose control is achieved, and some patients may be able to transition to oral medications.
Early initiation of insulin therapy may not reduce long-term complications compared to non insulin therapy.
ORIGIN trial showed no difference in cardiovascular or microvascular outcomes after six years of therapy in patients with early diabetes or impaired fasting plasma glucose, when adding daily dose of insulin glarine to achieve normal glycemia compared to standard care.
Insulin therapy associated with more weight gain and hypoglycemic events compared to standard therapy.
Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria.
The initiation of insulin in patients on non-insulin agents is usually with the long-acting basal insulin like glargine or detemir.
The long lasting basal insulin like drugs are preferred over neutral proteamine Hagedorn, which is associated with increased incidence of hypoglycemia.
Indications for the use of insulin therapy in type II diabetes include hemoglobin A-1 C level greater than 7% despite the use of metformin and lifestyle changes: And its use may be delayed after the addition of other oral agents such as sulfonylurea, or thiazolidinedione agents.
The initial insulin doses in the form of basal insulin added to existing oral agents is 0.2 units per kilogram of body weight per day and increased every five days until fasting glucose is less than 100 mcg per deciliter.
The presence of renal or hepatic dysfunction is associated with higher likelihood of hypoglycemic episodes.
The liver and kidneys are primarily responsible for gluconeogenesis and glycogenolysis, and also for insulin degradation: dysfunction of these organs will therefore provide less endogenous glucose production, alone were insulin half-life and a higher risk for hypoglycemia.
Pancreoprivic diabetics have greater risk for hypoglycemia episodes since injury or removal of the pancreas decreases both beta cells and alpha cells with secondary glucagon deficiency.
Inadvertent intramuscular injection of insulin can lead to unpredictable, usually faster, absorption of insulin and destabilization of the blood glucose level.
Intramuscular injections occur with increased frequency with longer needles, and slimmer and younger patients, males, and those who use limbs rather than truncal sites for insulin delivery.
It is thought that a reduction in the frequency of basal insulin injections might facilitate treatment acceptance and adherence among patients with type 2 diabetes.
Insulin icodec is a basal insulin analogue designed for once-weekly administration that is in development for the treatment of diabetes.
In a phase 2 trial to investigate the efficacy and safety of once-weekly insulin icodec as compared with once-daily insulin glargine U100 in patients who had not previously received long-term insulin treatment and whose type 2 diabetes was inadequately controlled while taking metformin with or without a dipeptidyl peptidase 4 inhibitor.
Participants were randomly assigned (1:1) to receive icodec or glargine.
The estimated mean change from baseline in the glycated hemoglobin level was −1.33 percentage points in the icodec group and −1.15 percentage points in the glargine group, to estimated means of 6.69% and 6.87%, respectively, at week 26.
Once-weekly treatment with insulin icodec had glucose-lowering efficacy and a safety profile similar to those of once-daily insulin glargine U100 in patients with type 2 diabetes.
Insulin icodec is a basal insulin analogue administered once weekly, with a time to maximum concentration of 16 hours and a half life of approximately one week.
Insulin preparations have distinct, pharmacokinetics, and pharmacodynamics characteristics.
Glarine, determir, and degludec are the most common preparations of basal insulin use the treatment of children and adolescents with type one diabetes.
INSULIN
RAPID-ACTING
Insulin Aspart NovoLog
(Novo Nordisk)
Rx SC CSII IV
Give dose within 5–10mins before a meal.
SC: May mix with NPH insulin. Draw NovoLog into syringe first. Inject immediately after mixing.
CSII: Do not dilute or mix with other insulins.
IV: Do not mix with other insulins.
Insulin Glulisine Apidra
(sanofi-aventis)
Rx SC CSII IV
Give dose within 15mins before a meal or 20mins after starting a meal.
SC: May mix with NPH insulin.
Draw Apidra into syringe first. Inject immediately after mixing.
CSII: Do not dilute or mix with other insulins.
IV: Do not mix with other insulins.
Insulin Lispro Humalog
(Lilly)
Rx SC CSII
Give dose within 15mins before or immediately after a meal.
SC: May mix with Humulin N
CSII: Do not dilute or mix with other insulins.
SHORT-ACTING
Insulin Injection Regular (R) Humulin R U-100 (Lilly)
SC IM IV*
SC: May mix with longer-acting human insulins. Use syringes marked with U-100.
Novolin R (Novo Nordisk)
SC IM IV
Give dose ≥3 times daily within 30mins before a meal.
INTERMEDIATE-ACTING
Insulin Isophane Suspension (NPH) Humulin N
(Lilly)
SC May mix with Humalog or Humulin R. Use syringes marked with U-100.
Novolin N (Novo Nordisk)
SHORT- AND INTERMEDIATE-ACTING MIXTURES
Insulin Aspart Protamine/Insulin Aspart NovoLog Mix 70/30 (Novo Nordisk)
Rx SC
Give dose twice daily within 15mins before a meal.
Insulin Isophane Suspension (NPH)/ Regular Insulin (R) Humulin 70/30
(Lilly)
SC
Novolin 70/30 (Novo Nordisk)
Insulin Lispro Protamine/Insulin Lispro Humalog Mix 50/50 (Lilly)
Rx SC Give dose within 15mins before a meal
Humalog Mix 75/25 (Lilly)
LONG-ACTING
Insulin Detemir Levemir (Novo Nordisk)
Rx SC Give dose once daily (PM) or twice daily, 12 hrs apart.
Insulin Glargine Lantus (sanofi-aventis)
Rx SC
Give dose once daily at the same time every day.