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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 15
| Issue : 3 | Page : 177-185 |
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Practical use of insulin in diabetes mellitus
Sahana Shetty, Ruth Daniel, Nihal Thomas
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| Date of Web Publication | 7-Aug-2017 |
Correspondence Address:
Sahana Shetty
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_47_17
Insulin therapy is the cornerstone of treatment in patients with type 1 diabetes mellitus (DM) and advanced type 2 DM. Over the years, insulin treatment has advanced from animal insulin to recombinant insulin with more efficiency and fewer side effects and from short-acting conventional insulin to ultrashort and long-acting insulin analogs to mimic various phases of physiological insulin secretion. Various insulin delivery systems from conventional subcutaneous insulin injection using insulin syringe to pen device, subcutaneous insulin infusion pumps, and inhaled insulin to artificial pancreas are now available. Proper insulin injecting techniques and patient education on self-monitoring of blood glucose and insulin dose titration are of utmost importance for effective insulin therapy.
Keywords: Blood glucose, diabetes mellitus, insulin therapy
How to cite this article:
Shetty S, Daniel R, Thomas N. Practical use of insulin in diabetes mellitus. Curr Med Issues 2017;15:177-85 |
| Introduction | |  |
Discovery of insulin for the treatment of diabetes mellitus (DM) was a major milestone in the field of medicine in the 20th century. The physiological insulin replacement is the mainstay of management of type 1 DM and advanced type 2 DM.
DM is a major cause of morbidity and mortality worldwide. The latter is attributed to the significant microvascular and macrovascular complications of the DM. Several epidemiologic studies and clinical trials, including the landmark studies Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study showed that the risk of diabetes complications can be substantially reduced with intensive glycemic control.[1],[2]
The pathophysiology of type 1 DM involves absent insulin secretion due to β-cell destruction, whereas in type 2 DM, the phase 1 insulin response is absent and phase 2 release is delayed and insufficient. With the advancement of type 2 DM, β-cells are exhausted, and insulin secretion is decreased. Insulin therapy provides the most superior glucose reductions as compared to other therapies and can be delivered in regimens mimicking physiologic insulin secretion. The aim of insulin therapy is to approximate the physiologic insulin profile through insulin replacement; however, this is limited by peripheral hyperinsulinemia and portal hypoinsulinemia in peripherally administered insulin as compared to physiological endogenous insulin secretion directly into portal circulation, variable subcutaneous insulin absorption, and the risk of hypoglycemia.
| Classification of Insulin | | |
Insulin formulations are classified as rapid, short, intermediate, or long-acting insulins based on their pharmacokinetic properties, including onset, peak, and duration of action, summarized in [Table 1]. The unique pharmacokinetic parameters of individual insulin products depend primarily on the rate and extent of absorption into the systemic circulation following subcutaneous injection.
| Classification of Insulin | | |
Short-acting regular insulins
Regular human insulin was the first insulin product generated using recombinant DNA technology. The peptide sequence and tertiary structure of regular recombinant human insulin are identical to that of its endogenous counterpart, however, its pharmacokinetic profile is different.[3],[4] Recombinant regular insulin has a delayed onset of action (30–60 min), relatively late peak effect (2–4 h), and a longer duration of action (6–8 h) when compared with endogenous insulin. This is because regular recombinant human insulin tends to self-aggregate into dimers and hexamers in solutions of higher concentration containing zinc ions. This delays the absorption of regular human insulin, which must first dissociate into dimers and monomers in the subcutaneous space to effectively diffuse into the general circulation and exert its glucodynamic action. Given its delayed onset of action, regular insulin should be administered 30 min before meals.[5]
Intermediate-acting human insulin (isophane [neutral protamine Hagedorn] insulin)
Neutral protamine Hagedorn (NPH) is composed of recombinant insulin suspended in a neutral pH solution of protamine and zinc. This unique suspension allows for a significant delay in the absorption of insulin from the subcutaneous tissue, resulting in an onset of action 1.5–4 h after injection, a pronounced peak 4–10 h after administration, and duration of up to 12–20 h.[6]
NPH does not constitute an appropriate surrogate for endogenous basal insulin production in view of its pronounced peak action profile and intermediate duration of action. However, NPH has retained clinical utility as basal insulin when administered twice daily and in a premixed insulin preparation combined with regular human insulin, especially in view of its low cost as compared to long-acting insulin analogs.
Insulin analogs
Insulin analogs are produced through targeted structural manipulation of the human insulin molecule such as amino acid substitutions, inversions, or additions [Figure 1][4] using recombinant technology and protein bioengineering techniques leading to alteration in pharmacodynamic and pharmacokinetic profiles [Figure 2].[4] In general, rapid-acting and long-acting insulin analogs have been modified to possess a weaker or stronger ability to self-associate, and hence a faster or slower diffusion rate following subcutaneous tissue injection, respectively.[4] | Figure 1: The primary structure of human insulin and insulin analogs. (a) Native human insulin; (b) rapid-acting insulin analogs (lispro, aspart, glulisine); (c) long-acting insulin analogs (glargine, detemir, degludec). Modifications of each insulin analog are highlighted in the figure.
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 | Figure 2: Pharmacokinetic profiles of human insulin and insulin analogs.
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Rapid-acting insulin analogs (lispro, aspart, and glulisine)
Insulin lispro is produced by transposition of amino acids proline and lysine at positions B28 and B29 leading to a conformational change. The resulting pharmacokinetics makes them compatible with physiological meal-stimulated insulin release.
The rapid onset of action of insulins, that is, lispro, aspart, and glulisine allows for greater flexibility and convenience in the timing of administration. They can be given either at mealtime or even immediately after a meal with improved normalization of postprandial glucose excursions. However, there is a risk of early postprandial hypoglycemia and preprandial hyperglycemia when compared with regular insulin.[7]
Long-acting insulin analogs (glargine, detemir, and degludec)
Long-acting insulin analogs (in view of their long duration of action without a pronounced peak) can be used as basal component of basal-bolus insulin regimen in insulin replacement therapy or as an augmentation therapy. They may be used in addition to oral glucose lowering agents (OGLAs) in patients who failed to achieve optimum glycemic control with maximum recommended OGLAs.
Glargine
In insulin glargine, replacement of asparagine with glycine at position A21 and the addition of 2 arginine residues at position B30, respectively, results in a molecule that is less soluble at neutral, physiologic pH yet stable in the acidic pH of its storage solution. Thus, when injected into the neutral milieu of the subcutaneous tissue, glargine forms an amorphous precipitate from which insulin molecules are slowly released into the circulation.[8]
Detemir
In insulin detemir, deletion of amino acid threonine at position B30 and acylation of a 14-carbon aliphatic fatty acid (myristoleic acid) to the μ-amino group of lysine at position B29, enhances its affinity for albumin, and forms multimeric complexes within the subcutaneous tissues leading to sustained release postinjection.[9]
Both insulin glargine and detemir have comparable pharmacokinetic profile with the onset of action within 1-3 h of administration and a relatively peakless, dose-dependent, mean duration of action of approximately 24 h representing better surrogates for basal insulin replacement. The principal advantage of insulin glargine and detemir over NPH insulin is a lower frequency of hypoglycemic reactions, longer duration of action, and reduction in glycemic excursion due to dawn phenomenon. The glucose-lowering effect of these basal insulin analogs tend to wax and wane considerably over 24 h with once-daily dosing resulting in hyperglycemia late in the expected action profile (dusk phenomenon), which might necessitate a twice daily administration.
Degludec
Insulin degludec is an ultra-long-acting basal insulin analog produced by the conjugation of hexadecanedioic acid through gamma-L-glutamyl spacer at the amino acid lysine at position B29 leading to formation of multihexamers in subcutaneous tissues. Slow sustained release from subcutaneous tissue leads to the longer duration of action of around 42 h making it once daily basal insulin.[10] In view of lower incidence of hypoglycemia, especially nocturnal hypoglycemia, insulin degludec is recommended in patients with recurrent hypoglycemic events and significant glycemic variability with other long-acting insulin;[11] however, the limiting factors are the higher cost and stacking effect.
Premixed insulin preparations
Premixes of conventional insulin products and fixed-ratio mixes of insulin analogs are available in different ratios as shown in [Table 1]. Premixed insulin represents a convenient alternative to basal-bolus insulin therapy, with a decreased number of daily injections, in patients requiring insulin therapy other than type 1 DM.
Indications for insulin therapy
The indications for using insulin in therapy are summarized in [Table 2].
| Insulin Therapy Initiation, Titration, and Follow-up | | |
Insulin therapy may be used either as augmentation therapy or as replacement therapy.
Augmentation therapy
In this case, basal insulin is added to OGLAs in patients with partial beta-cell failure. The goal of basal insulin is to suppress hepatic glucose production and improve fasting hyperglycemia.
Replacement therapy
Basal-bolus insulin regimen, premixed insulin, or insulin pump is recommended as replacement therapy for those where endogenous insulin production is minimal or absent. Insulin replacement therapy aims to replicate endogenous stimulated, and basal insulin release by the healthy pancreas such that postmeal blood glucose (BG) excursions are minimal and hepatic glucose production between meals is appropriately suppressed, respectively.
When using replacement therapy, approximately 50% of the total daily insulin dose is given as basal and 50% as bolus, divided up before breakfast, lunch, and dinner. The rapid and short-acting insulin formulations are used as the bolus component of insulin therapy, whereas intermediate-acting and long-acting preparations are used as basal insulin to replace endogenous basal insulin secretion. The different Insulin regimens used in various clinical settings are summarized in [Table 3].
Dose adjustment
Once an insulin regimen is initiated, it is important to titrate the dose. Adjustments are made in both mealtime and basal insulin based on the prevailing BG levels and the pharmacodynamics of the insulin formulation being used. Fasting glucose readings are used to titrate basal insulin, whereas both preprandial and postprandial glucose readings are used to titrate mealtime insulin. Providing patients with a guideline or algorithm on how to titrate the dose based on self-monitoring of blood glucose (SMBG) will help in better glycemic control. Physicians must avoid the temptation to label insulin use as the result of treatment failure or as a punishment.
| Insulin Therapy in Type 2 Diabetes Mellitus | | |
Basal insulin along with metformin and other noninsulin agents is the most convenient initial insulin regimen. If basal insulin has been titrated to an acceptable fasting BG level, but A1C remains above target, consider combination injectables to cover postprandial glucose excursions. This may be in the form of twice daily premixed insulin injections or basal-bolus injection regimen [Figure 3]. | Figure 3: Approach to insulin initiation and titration of insulin in patients with diabetes mellitus. Adapted from Diabetes Care 2016;39 Suppl 1:S3.
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| Insulin Therapy in Type 1 Diabetes Mellitus | | |
The DCCT clearly showed that intensive insulin therapy (three or more injections per day of insulin) or continuous subcutaneous insulin infusion (CSII) (insulin pump therapy) was a key part of improved glycemia and better outcomes in type 1 DM. In view of absent insulin secretion in type 1 diabetes, the insulin therapy required is a replacement therapy using basal-bolus insulin regimen or CSII which closely mimics physiological insulin secretion.
Most newly diagnosed patients with type 1 diabetes require a starting insulin dose ranging from 0.5–1 U/kg/day depending on whether the patient is symptomatic or has presented with diabetic ketoacidosis (DKA). This can be subsequently adjusted with the reduction in glucotoxicity. Basal-bolus insulin regimen can be started with approximately 40%–50% of the total daily insulin dose given as basal and remaining as boluses, divided up before breakfast, lunch, and dinner.
More important in these patients is to regularize their meal pattern and physical activity in addition to insulin dose titration based on SMBG. CSII is another form of intensive insulin therapy which has shown lowering of hypoglycemic events, reduction in total insulin dose, and better patient satisfaction as compared to multiple daily injections.[12]
Insulin therapy for management of hyperglycemia in hospitalized patients
The AACE/ADA Task Force recommends targeting BG level between 140 and 180 mg/dL for the majority of Intensive Care Unit (ICU) patients and lower glucose targets between 110 and 140 mg/dL in selected ICU patients. NICE sugar study involving 6000 participants showed increased mortality at 90 days (24.9% vs. 27.5%, P< 0.02) and higher incidence of hypoglycemia (6.8% vs. 0.5%, P< 0.001) with intensive glycemic control in ICU setting.[13] Continuous insulin infusion with dose titration based on frequent glucose monitoring (two to three hourly) is the preferred form of therapy in ICU settings as it allows rapid correction and titration of insulin doses with change in clinical state.
In non-ICU settings, the premeal glucose level <140 mg/dL, and a random BG level <180 mg/dL is recommended for the majority of noncritically ill patients treated with insulin. Subcutaneous insulin therapy with basal or intermediate-acting insulin given once or twice a day in combination with short-acting or rapid-acting insulin administered before meals with frequent glucose monitoring is preferred as an effective and safe strategy for glycemic management in noncritically ill patients.
| Practical Aspects of Using Insulin | | |
Insulin injection technique
Insulin is effective only if correct injecting technique and storage are followed, which are often underemphasized in clinical practice.
Patient education guide on steps of subcutaneous insulin administration using insulin syringe:
- Wash hands
- Inspect the bottle for the type of insulin, absence of precipitates, clumping, frosting, or change in clarity or color
- Gently roll the insulin in the palm of your hands to mix the insulin
- Remove the needle cover and pull back the plunger to draw air into the syringe which is equal to the amount of insulin dose
- Push the needle through the rubber stopper and inject the air into the insulin
- Turn the bottle upside down, now the tip of the needle should be in insulin, and draw insulin into the syringe
- Select a site within your injection area that has not been used for the previous injection
- Clean the skin with an alcohol swab. Lightly grasp an area of the skin and insert the needle at a 90° angle.[Figure 4]
- Push the plunger all the way down to push insulin into the tissue and then release the skin. Hold the needle in place for 10 s to prevent insulin leakage
- Pull the needle straight out. Do not rub the place where you gave the shot
- Avoid reuse of the needle as far as is possible.[Figure 5]
- Appropriately dispose of the syringe and needle.
Injection sites
Injections may be given in the abdomen or outer thigh. Anterior abdominal wall is the preferred site of insulin administration in view of its rapid and consistent absorption and ease of administration. Rotation of injection sites is important [Figure 6] to prevent lipohypertrophy (i.e., scar tissue from repeated injections in the same area) which may lead to poor insulin absorption and depot formation, which may randomly release insulin, causing early postprandial hyperglycemia and/or delayed hypoglycemia.
Insulin delivery devices
Insulin delivery devices include insulin syringes, pen devices, and insulin infusion pumps. Insulin is available in strengths of U-40 and U-100 in India. Insulin syringes matching the concentration of U-40 and U-100 insulin must be used. Use of appropriate syringe is important as each division is equivalent to 1 unit of insulin in U-40 syringe and 2 units of insulin in U-100 syringe.[14]
Insulin pens
Insulin pens carry insulin in a self-contained cartridge [Figure 7]. Pen devices are available as disposable and reusable insulin pens. Pen device is easy to use, especially for patients with visual or dexterity problems, less painful, and more accurate as compared to syringes. Patients with visual difficulties may listen to the “clicks” of the insulin pen to count the number of units. Patients should be instructed to prime the insulin pen before every use. Priming comprises drawing up 1 or 2 units of insulin and injecting into the air to allow the insulin to fill the needle and then inject.[15]
Continuous insulin infusion
CSII through insulin pumps [Figure 8] provides continuous delivery of insulin with facility for fine titration of insulin doses and mimics physiological insulin secretion with reduced incidence of hypoglycemia. The disadvantages of insulin pump are the cost of the device and its accessories, risk of DKA in case of pump malfunction, and need for patient motivation. Sensor-augmented pump with low-glucose suspend or threshold suspend pump is a more advanced version which combines CSII, continuous glucose monitoring system, and threshold suspend system to reduce the incidence of hypoglycemia by transiently suspending insulin secretion on recording lower threshold glucose levels. Alternate noninvasive routes of insulin administration which are being studied includes nasal, buccal, oral, intraperitoneal, and transdermal routes.[16]
Insulin storage
Insulin vials, cartridges, and prefilled insulin pens should be stored between 2°C and 8°C (36°F and 46°F) as extreme temperatures may lead to clumping, frosting, precipitation, and loss of potency. Insulin pens and vials should be refrigerated, but not frozen. Injecting cold insulin may lead to pain and irritation at injection site, thus it is recommended to keep the insulin for 30 min at room temperature and roll the vial or pen between the palms before injection. If refrigerator is not available, it is advisable to place the insulin vial in a plastic bag, tied with a rubber band, and store in a wide-mouthed bottle or earthen pitcher filled with water. (the insulin is kept in a smaller earthen pot with the larger pot/pitcher; never keep insulin directly inside water to avoid contamination). While traveling, insulin should be stored in a flask with ice or proper container with ice packs/coolant gels. [Figure 9].[17]
Side effects of insulin therapy
Pain at injection sites, hypoglycemia, weight gain, lipohypertrophy, and lipodystrophy. [Figure 10] are some of the common side effects of insulin therapy. Hypoglycemia is the biggest obstacle for intensive glycemic control.[18]
| Conclusion | | |
Insulin therapy has undergone significant advancement over the years. Insulin replacement and supplementation strategies aim to replicate physiologic insulin secretion to optimize glycemic control in patients with type 1 or 2 diabetes and thus prevent the development and progression of long-term complications. Patient education on correct insulin injections techniques and SMBG are of utmost importance to overcome barriers to initiating insulin therapy and facilitate the self-management of diabetes. Novel insulins, routes of administration, and administration devices are under continuous research to ease the administration techniques and improve glycemic status with minimum side effects.
Financial support and sponsorship
Nil.
Conflicts of interets
There are no conflicts of interest.
| References | | |
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| 2. | Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK prospective diabetes study (UKPDS) group. Lancet 1998;352:837-53. |
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| 6. | Starke AA, Heinemann L, Hohmann A, Berger M. The action profiles of human NPH insulin preparations. Diabet Med 1989;6:239-44. |
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| 10. | Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet 2014;53:787-800. |
| 11. | Bode BW, Buse JB, Fisher M, Garg SK, Marre M, Merker L, et al. Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN(®) basal-bolus type 1): 2-year results of a randomized clinical trial. Diabet Med 2013;30:1293-7. |
| 12. | Tamborlane WV, Sikes KA. Insulin therapy in children and adolescents. Endocrinol Metab Clin North Am 2012;41:145-60. |
| 13. | NICE-SUGAR Study Investigators. Finfer S, Chittock DR, Su SY, Blair D, Foster D, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-97. |
| 14. | Down S, Kirkland F. Injection technique in insulin therapy. Nurs Times 2012;108:18, 20-1. |
| 15. | Cuddihy RM, Borgman SK. Considerations for diabetes: Treatment with insulin pen devices. Am J Ther 2013;20:694-702. |
| 16. | Yaturu S. Insulin therapies: Current and future trends at dawn. World J Diabetes 2013;4:1-7. |
| 17. | Tandon N, Kalra S, Balhara YP, Baruah MP, Chadha M, Chandalia HB, et al. Forum for injection technique (FIT), India: The Indian recommendations 2.0, for best practice in insulin injection technique, 2015. Indian J Endocrinol Metab 2015;19:317-31. |
| 18. | McCall AL. Insulin therapy and hypoglycemia. Endocrinol Metab Clin North Am 2012;41:57-87. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
[Table 1], [Table 2], [Table 3]
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