INSULIN REVIEW
- See insulin chart for a review of available insulins and their properties
- Physiology
- Insulin is a natural hormone secreted by the beta cells (also referred to as "islet cells") of the pancreas
- Insulin is secreted in response to rising blood sugars which typically occur after consuming food
- Insulin acts primarily on the liver, fat tissue, and muscle tissue
- Liver effects
- In the liver, insulin stimulates the formation of glycogen from glucose. Glycogen is comprised of glucose molecules linked together, and it is the primary storage form of glucose.
- Insulin inhibits the breakdown of glycogen into glucose
- Muscle and fat tissue effects
- In muscle and fat tissue, insulin promotes the uptake of glucose from the bloodstream
- Muscles use glucose as an energy source or store it as glycogen. Fatty tissues convert glucose into fatty acids for storage as triglycerides.
- Insulin inhibits the release of amino acids from muscle, and it inhibits the release of free fatty acids from fat tissue [1]
- Overview
- Mild reactions including localized redness, itching, pain, and swelling may occur in up to 3% of patients. These reactions typically begin 8 - 12 hours after injection and peak at 24 - 48 hours before resolving over a few weeks. [5]
- More significant reactions include changes in fat tissue (lipodystrophy) and amyloidosis. Rotating injection sites can help prevent these adverse effects.
- Lipoatrophy
- Lipoatrophy is thinning of fat tissue at the sites of injection
- Lipoatrophy is thought to be caused from an immune reaction
- Lipoatrophy is not common anymore with the introduction of purified,
human insulins (insulin used to come from pig and cow pancreases) [7]
- Lipohypertrophy
- Lipohypertrophy is thickening of the fat tissue at the sites of injection
- Lipohypertrophy is characterized by soft bumps that form underneath the skin
- Sites of lipohypertrophy often lose sensation causing diabetics to prefer these sites which can make the problem worse
- Treatment for lipohypertrophy is to rotate injection sites and hope for regression
- If regression does not occur, liposuction may be necessary to remove cosmetically unacceptable growths [2]
- In some studies, lipohypertrophy occurs in up to 50% of diabetics who inject insulin [3,4]
- Factors associated with the development of lipohypertrophy include:
- Years of insulin use
- Frequency of injection site change
- More daily injections [3,4]
- Localized cutaneous amyloidosis
- Amyloidosis is a term used for diseases where abnormal, insoluble proteins deposit in tissues
- Repeated insulin injections at the same site can induce protein deposition and lead to a rare condition called insulin-derived amyloidosis, or localized cutaneous amyloidosis
- Localized amyloidosis typically presents as hard subcutaneous masses that form at the site of repeated injections. Injection into these sites may inhibit insulin absorption and lead to hyperglycemia. [21]
- Low blood sugar (hypoglycemia)
- Too much insulin can cause hypoglycemia
- See hypoglycemia
- review of hypoglycemia and its treatment
- Low potassium (hypokalemia)
- Insulin causes cells to take up potassium thus lowering blood levels of
potassium
- This is typically only an issue when insulin is given intravenously [6]
- Insulin antibodies
- All exogenous insulins have the potential to induce an immune response that leads to the production of antibodies against the insulin
- This was a larger issue with older insulins (derived from pigs and cows), but it still occurs with modern insulins
- Theoretically, insulin antibodies might decrease insulin effectiveness and increase insulin resistance. Studies evaluating this effect have not found an association between the presence of insulin antibodies and decreased effectiveness. [7]
- Weight gain
- Insulin therapy can induce weight gain in many patients (4 - 9 pounds on average)
- This effect is due to the increased utilization of glucose by the body and the decrease in fluid loss that occurs with hyperglycemia [8]
- Swelling of the feet and legs (edema)
- In rare cases, insulins may cause acute swelling of the feet and legs
- This is more common in poorly-controlled patients who are started on
sudden, intense insulin regimens [5]
- Insulin neuritis
- Long-term, uncontrolled diabetes is associated with the development of
nerve pain or nerve loss (neuropathy)
- Another neuropathy syndrome that is seen less frequently involves the
development of neuropathy after the initiation of insulin therapy
- This syndrome is sometimes called "insulin neuritis" or
"treatment-induced neuropathy"
- The syndrome is typically seen when a person with uncontrolled blood
sugars is treated with insulin, and their blood sugars rapidly come under
control
- Neuropathy typically develops within 6 weeks of rapid control
- Neuropathy may be associated with signs of autonomic dysfunction
including orthostatic hypotension (low blood pressure on standing) and
diabetic gastroparesis (slow stomach emptying)
- Diabetic retinopathy may also worsen (see below)
- The neuropathy typically resolves over a period of months
- The ideal treatment of "treatment-induced neuropathy" has not been
determined
- Medications used in typical, chronic neuropathy may be helpful [9]
- Diabetic retinopathy
- Diabetic retinopathy occurs when diabetes damages the blood vessels that perfuse the retina in the back of the eye. It is the number one cause of blindness.
- In some studies, initiation of insulin along with rapid improvement in blood sugar control has been shown to worsen diabetic retinopathy over the short term (up to 18 months) [10,11]
- Vision changes
- For diabetics with uncontrolled blood sugars, treatment changes (ex.
starting insulin or other meds) that bring blood sugars rapidly under
control can cause changes in the lens of the eye
- These lens changes can cause temporary farsightedness (hyperopia) and
blurred vision
- In one review of 14 patients affected by the condition, the following characteristics were seen
- Visual changes started 1 - 7 days (average 3.4 days) after new therapy
was initiated
- Maximum visual change occurred at 10 days on average
- Vision returned to normal at an average of 44.7 days (range 14 - 84
days) after therapy was started [12]
- Injectable insulin
- Known hypersensitivity
- During episodes of hypoglycemia
- Inhaled insulin
- Kidney disease
- In some patients, worsening kidney function can increase the levels and
subsequent effects of insulin (hypoglycemia)
- This is typically seen at the very end stage of kidney disease
- Patients with significant kidney disease should monitor blood sugars
closely and be aware that dose adjustments may be necessary
- Liver disease
- In some patients, worsening liver function can increase the levels and
subsequent effects of insulin (hypoglycemia)
- This is typically seen at the very end stage of liver disease
- Patients with significant liver disease should monitor blood sugars
closely and be aware that dose adjustments may be necessary
- Overview
- Insulin-like growth factor 1 (IGF-1) is a peptide that stimulates cells to divide when it binds to receptors on the surface of cell membranes. Insulin has a similar structure to IGF-1, and it also binds and activates IGF-1 receptors, but to a much lesser degree. Insulin glargine has a higher affinity for IGF-1 receptors than endogenous insulin. It has been hypothesized that insulin glargine may stimulate cancer cells to divide more rapidly through enhanced IGF-1 receptor stimulation thus increasing the risk for cancer.
- In July of 2009, the FDA issued a warning to healthcare providers that
three recently published studies had shown a possible increase in cancer
risk among patients using Lantus®. The FDA last addressed the issue in 2011 in a statement that said based on their findings, they could not attribute an increased risk of cancer to Lantus, but they are "continuing to work with the manufacturer of Lantus and the U.S. Department of Veterans Affairs (VA) to further evaluate the long-term risk, if any, for cancer associated with the use of Lantus."
- A review of studies that have looked at the risk of cancer with Lantus and other long-acting insulins is presented below
STUDY
Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies, Diabetes Care (2016) [PubMed abstract]
- A review in Diabetes Care looked at 16 cohort studies and 3 case-control studies that compared the risk of cancer between users of long-acting insulins (insulin glargine and detemir) and other insulins
- All of the studies included insulin glargine and 4 also looked at insulin detemir. Follow-up ranged from 0.9 to 7 years, and 16 of the studies had follow-up that was less than 5 years.
- The review found the following:
- In studies that reported any cancer, colorectal cancer, and/or prostate cancer, 13 of 15 found no association between insulin glargine and cancer
- In studies that reported breast cancer, 4 of 13 reported an increased risk of breast cancer with insulin glargine
- Findings: The observational studies examining the risk of cancer associated with long-acting
insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer
risk.
- Summary
- It's unclear if Lantus or other long-acting insulins increase the risk of cancer. Randomized controlled trials are too short and do not have enough power to look at this issue, and observational studies have many weaknesses. In the review above, the average follow-up was less than 5 years in most of the studies.
- The FDA has not addressed the issue since 2011, and it's unclear if they ever will
- If Lantus and other long-acting insulins increase the risk of cancer, the effect is likely very small
- Overview
- Synthetic insulins are made from genetically-modified bacteria and yeast. Structurally, Novolin R, Humulin R, Novolin N, and Humulin N are identical to human insulin. Other insulins have been modified slightly to change their pharmacokinetic properties.
- Admelog® (Insulin lispro)
- Synthesized from genetically-altered E. Coli bacteria
- Admelog® is identical to human insulin except that 2 amino acids have been reversed
- Apidra® (Insulin glulisine)
- Synthesized from genetically-altered E. Coli bacteria
- Apidra® is identical to human insulin except that 2 amino acids have
been altered
- Basaglar® (Insulin glargine)
- Synthesized from genetically-altered E. Coli bacteria
- Basaglar® is identical to human insulin except that 1 amino acid has
been changed and 2 have been added
- Fiasp® (Insulin aspart)
- Synthesized from genetically-altered Saccharomyces cerevisiae
(baker's yeast)
- Fiasp® is identical to human insulin except that 1 amino acid has
been changed
- Humalog® (Insulin lispro)
- Synthesized from genetically-altered E. Coli bacteria
- Humalog® is identical to human insulin except that 2 amino acids
have been reversed
- Insulin lispro protamine is a combination of insulin lispro with
protamine
- Insulin lispro protamine is absorbed more slowly and acts longer
- Humulin® N (NPH)
- Synthesized from genetically-altered E Coli bacteria
- Humulin® N is identical to human insulin
- Humulin® N is combined with protamine and zinc so that it is
absorbed more slowly and acts longer
- Humulin® R (Regular)
- Synthesized from genetically-altered E Coli bacteria
- Humulin® R is identical to human insulin
- Lyumjev® (insulin lispro-aabc)
- Synthesized from genetically-altered E Coli bacteria
- Lyumjev® is identical to human insulin except that 2 amino acids
have been reversed
- Novolog® (Insulin aspart)
- Synthesized from genetically-altered Saccharomyces cerevisiae
(baker's yeast)
- Novolog® is identical to human insulin except that 1 amino acid has
been changed
- Insulin aspart protamine is a combination of insulin aspart with
protamine
- Insulin aspart protamine is absorbed more slowly and acts longer
- Lantus® (Insulin glargine)
- Synthesized from genetically-altered E. Coli bacteria
- Lantus® is identical to human insulin except that 1 amino acid has
been changed and 2 have been added
- Levemir® (Insulin detemir)
- Synthesized from genetically-altered Saccharomyces cerevisiae
(baker's yeast)
- Levemir® is identical to human insulin except that 1 amino acid has
been omitted and a fatty acid chain has been attached
- Novolin® N (NPH)
- Synthesized from genetically-altered Saccharomyces cerevisiae
(baker's yeast)
- Novolin® N is identical to human insulin
- Novolin® N is combined with isophane so that it is absorbed more
slowly and acts longer
- Novolin® R (Regular)
- Synthesized from genetically-altered Saccharomyces cerevisiae
(baker's yeast)
- Novolin® R is identical to human insulin
- Semglee® (Insulin glargine)
- Synthesized from genetically-altered Pichia pastoris yeast
- Semglee® is identical to human insulin except that 1 amino acid has
been changed and 2 have been added
- Toujeo® (Insulin glargine)
- Synthesized from genetically-altered E. Coli bacteria
- Toujeo® is identical to human insulin except that 1 amino acid has
been changed and 2 have been added
- Tresiba® (Insulin degludec)
- Synthesized from genetically-altered Saccharomyces cerevisiae (baker's yeast)
- Tresiba® is identical to human insulin except that amino acid threonine in position B30 has been omitted and
a side-chain consisting of glutamic acid and a C16 fatty acid has been attached [20]
- NOTE: Drug
interactions presented here are NOT all-inclusive. Other interactions may
exist. The interactions presented here are meant to encompass commonly
prescribed medications and/or interactions that are well-documented. Always
consult your physician or pharmacist before taking medications concurrently.
CLICK HERE for more information on drug interactions.
- All insulins
- Glitazones (Actos®, Avandia®) in patients with heart failure
- Glitazones may cause fluid retention which can worsen congestive heart
failure
- This effect appears to be more severe when glitazones are used with
insulin
- Patients with congestive heart failure who require insulin should not
take glitazones
- Drugs that may potentiate the effects of insulin
- Drugs that may decrease the effects of insulin
- Drugs that may decrease or increase the effects of insulin
- Drugs that may blunt symptoms of hypoglycemia
- Metabolism and clearance
- Insulin is metabolized by Insulin-Degrading Enzyme (IDE), also called "insulysin" and "insulinase"
- IDE is present in a number of tissues
- An insulin pump is a device that attaches to a patient's abdomen
- It has a needle that is inserted into the subcutaneous space under the
skin (the same space an insulin injection is given)
- The pump delivers a continuous flow of insulin to the patient at a rate
that is adjustable
- The pump can also be instructed to give larger, one-time doses of
insulin if needed (a bolus)
- There are now pumps that can communicate with continuous glucose monitoring systems and automatically adjust insulin doses without patient input.
- Insulin pumps require a high degree of maintenance and attention, and
thus are typically reserved for very motivated patients
- They are mostly used in Type 1 diabetics, and less often in Type 2
diabetics
- They are filled with either rapid or short-acting insulin
- In many U.S. states, insulin can be bought over-the-counter (without a prescription) at pharmacies
- Over-the-counter insulin is typically limited to Regular, NPH, and the 70/30 mixes of NPH and regular
- The availability of over-the-counter insulin is intended to help diabetics in a bind or emergency
- A simple way to find out if a state allows over-the-counter insulin is to call a pharmacy in that state
- 1 - PMID 20821847
- 2 - PMID 14507228
- 3 - PMID 17303282
- 4 - PMID 11874968
- 5 - Lantus PI
- 6 - Novolog PI
- 7 - PMID 17785428
- 8 - PMID 18945920
- 9 - PMID 20437589
- 10 - PMID 15309288
- 11 - PMID 7826293
- 12 - PMID 11004091
- 13 - PMID 19572116
- 14 - PMID 19565214
- 15 - PMID 19603149
- 16 - PMID 19588120
- 17 - PMID 16847295
- 18 - PMID 15855574
- 19 - Humalog PI
- 20 - Tresiba PI
- 21 - PMID 25593849 - Insulin-derived Amyloidosis, Indian J Endocrinol Metab (2015)
