Overview of Insulin in the Body

Insulin is a neuroendocrine hormone produced by the beta cells of the pancreas. The primary functions of insulin are to maintain glucose homeostasis and to act as a signaling molecule for virtually all tissues in the body.

Insulin Mechanism of Action

Insulin secretion occurs mainly in response to food (carbohydrate) ingestion, helping to restore blood glucose back to appropriate levels by sending glucose to specific cells to be used and also instructing cells how to use glucose for energy. Insulin receptors are present on most body cells, which help to allow glucose inside the cell to be used for intracellular functions. While other macronutrients can be used for energy, carbohydrates (which are metabolized to glucose) are the primary energy source for the body, especially the brain.

However, when there is insufficient insulin release from the pancreas, or when insulin sensitivity is compromised (called insulin resistance), glucose can’t be effectively metabolized, and blood sugar levels remain elevated. Giving exogenous insulin is required to lower blood sugar in patients with diabetes mellitus when the pancreas fails to produce sufficient insulin to meet body demands.

Pancreatic Insulin Release

In normal physiologic functioning, the pancreas secretes a low level of insulin all the time, referred to as basal insulin release. Beyond basal insulin release, the pancreas also secretes insulin in response to exposures to certain specific factors:

• Glucose
• Carbohydrates
• Leucine
• Certain antidiabetic medications

In addition, other compounds in the body don’t necessarily induce pancreatic insulin release, but instead they potentiate and amplify insulin secretion:

• Fatty acids
• Other amino acids (besides leucine)
• Hormones
• Neurotransmitters

Insulin treatment regimens for clinical diabetes work best when they are designed to mimic physiological secretion of insulin from the pancreas, which often includes both basal insulin and prandial (mealtime) insulin types. Starting insulin treatment requires several considerations: achieving glycemic control, preserving insulin sensitivity, and minimizing side effects, like weight gain and hypoglycemia.

Understanding Basal Insulin

Basal insulin plays a pivotal role in diabetes care of insulin-dependent diabetes mellitus to achieve better glycemic control. Long-acting basal insulins are designed to have lasting, flat, consistent activity without peaks of action. Basal dosing insulin acts to suppress hepatic gluconeogenesis to prevent glucose release in the fasting state (thus preventing hyperglycemia). Various basal dosing insulins are available, which differ in their concentrations, half lives, and duration of activity.

Intermediate-Acting Basal Insulins

Intermediate-acting insulins are on the shorter end of basal insulin duration of action. They generally take effect in about 2 hours, gradually peak within 6-10 hours, and last for about 12-14 hours. Neutral protamine hagedorn (NPH) is the most common intermediate-acting insulin.

In order to be an effective basal insulin, NPH insulin must be dosed more than once daily and/or be combined with prandial insulin. Of the basal insulin forms, intermediate-acting insulins are associated with the highest risks of nocturnal hypoglycemia and daytime hypoglycemic episodes.

Long-Acting Insulins

Long-acting insulin analogues are designed to have longer-lasting activity. Insulin detemir has a half-life of about 12 hours, and it is usually given twice daily. An insulin glargine injection lasts for as long as 24 hours, and insulin glargine is typically dosed once daily. These insulins start to take effect within 1.5 to 2 hours, and they have a flatter and longer plateau. Long-acting insulins have a lower risk of daytime and nocturnal hypoglycemia, as compared with intermediate-acting insulins.

Ultra-Long Acting Insulins

Insulin degludec was developed for longer, more stable blood glucose control. An insulin degludec injection softly peaks at about 25 hours and may last as long as 42 hours. According to many randomized controlled trials, ultra-long acting insulin degludec results in less glucose variation and even lower risks of hypoglycemia than long-acting insulins.

Weekly Basal Insulins

Clinical trials are currently underway for weekly basal insulins. Weekly-dosed basal insulins may potentially provide better glucose control and further reductions in the risk of hypoglycemia. According to a randomized controlled trial in the New England Journal of Medicine (N Engl J Med), once-weekly insulin efstiora is non-inferior to once-daily insulin degludec in reducing glycosylated hemoglobin (HbA1c) levels.

Using Basal Insulin

Indications for Basal Insulin

According to meta-analyses of years of clinical trials, using basal insulin treatment achieves more consistent glucose control than using rapid-acting insulin analogs as mealtime insulin or correction insulin alone. Using only mealtime or correction insulin regimens without basal insulin doses usually leads to suboptimal glycemic control.

Basal Insulin Dosing

Starting Dose

When starting insulin therapy, the initial basal insulin dose is frequently calculated by weight, using the estimation of 0.1 to 0.2 units per kilogram of body weight per day. Alternatively, basal insulin regimens can start at 10 units per day. For insulin-naive patients, beginning at lower basal doses may improve tolerability.

Dosage Adjustment and Titration

Insulin intensification should involve careful titration to reach a target fasting blood sugar level. Acceptable dosage titration recommendations are to increase the basal insulin dose by 1 unit per day or by 3 units every three days until the fasting blood glucose goal is achieved. During insulin dose titration, patients should monitor blood sugar levels carefully to avoid hypoglycemia.

Glucose Monitoring

Various options are available to monitor glucose levels. Fasting blood glucose levels and postprandial blood glucose levels can be checked with a handheld glucometer. Glucometers are widely available and typically covered by insurance, leaving little out-of-pocket costs for patients. However, this requires multiple fingersticks per day, which is cumbersome and inconvenient for patients.

Continuous glucose monitors (CGMs) are wearable devices that monitor blood glucose continuously, offering real-time, on-demand data, helping to provide intensive glucose control and eliminating the need for fingersticks (aside for calibration when needed). CGMs allow for more precise insulin titration with less glucose variability, especially for patients who use insulin pumps or need tighter glycemic control. However, these devices and their supplies are more expensive, and insurance coverage often varies.

Glycemic Targets

According to the American Diabetes Association, glycemic targets for patients who take insulin therapy are fasting blood glucose levels <140 mg/dL and postprandial blood glucose levels < 180 mg/dL. For long-term control, a hemoglobin A1c (HbA1c) goal of < 7% is appropriate for many patients.

Basal-Bolus Insulin Therapy

Bolus Insulin

In addition to basal insulin therapy, which helps provide steady, continuous coverage, bolus insulin therapy is often given with times of eating to help account for glucose loads within meals. Mimicking the physiologic functions of the pancreas, basal-bolus insulin therapy helps control both fasting and postprandial blood glucose levels, helping to ensure adequate blood glucose control throughout the day.

To use basal and mealtime insulin, a bolus dose of rapid-acting insulin should be given immediately after each meal (called prandial insulin). Bolus insulin is usually given three times daily to account for the rise in blood glucose following each meal. The dosing of bolus insulin should be distributed evenly between meals. It should not be given when meals are skipped.

The best mealtime insulins are usually short-acting (also called rapid-acting) insulins, like insulin aspart or insulin lispro. Rapid-acting insulin usually begins to work within 15 minutes, reaches peak activity within 1 to 2 hours, and remains active for 4 to 6 hours. Each unit of short-acting insulin can be expected to lower blood glucose levels by 34 mg/dL (although this can vary based on many factors).

The 50-50 rule suggests that for basal-bolus therapy, the daily basal insulin dose should equal about 50% of the patient’s total daily insulin dose, and the bolus insulin doses should add up to the remaining 50% of the total daily insulin dose. However, some studies have called this into question for patients with type 2 diabetes mellitus and stable glycemia. Basal insulin needs may vary from as little as 30% to as much as 45-50% of total daily insulin requirements.

Correction Scale Insulin

In addition to a defined basal-bolus insulin regimen, correction insulin provides additional short-acting insulin based on elevated glucose values at mealtimes and other times. The correction scale insulin dose depends upon the carbohydrate ratio. Using correction scale insulin reduces postprandial hyperglycemia and helps patients fine-tune their treatment and optimize glycemic control.

Basal Insulin Delivery Systems

Insulin Vials

The original insulin delivery system has been around for decades, which involves insulin administration from multi-dose vials. Vials of insulin are typically cheaper, but they require patients to draw up the necessary insulin dose based on milliliters of insulin, not units of insulin. This process of insulin administration requires extra needles and syringes, is a complex insulin regimen to follow, and can be cumbersome and inconvenient for many patients.

Insulin Pens

Basal insulin is also available in easier-to-use insulin pens. Insulin pens vary in their concentration and in the number of insulin units they contain. Depending on the concentration and the basal insulin dose, patients usually need several insulin pens to last for one month. Insulin administration from an insulin pen involves using a new needle for each dose. Insulin pens are generally more expensive than insulin vials, but they are much more convenient for most patients.

Insulin Pumps

Insulin pumps are wearable devices that deliver short acting insulin in a manner similar to the action of basal insulin. Insulin pumps also can deliver additional amounts of short acting insulin in response to meals and elevated blood glucose levels. Most often used in patients with type 1 diabetes mellitus, insulin pumps are more expensive and must be used very carefully, as insulin pump malfunctions can lead to dangerous and potentially fatal complications.  They also can be a challenge to manage in the inpatient setting where many clinicians may not be familiar with their operation.

Reducing Side Effects

Hypoglycemia

Hypoglycemia is a common side effect of insulin therapy. Basal insulins are designed to cause a lower risk of hypoglycemia than rapid-acting insulin analogues. However, during times of illness, reduced oral intake, or insulin dose titration, basal insulin therapy can induce hypoglycemia (often to very low blood sugar levels), especially if the dose is not reduced.

Hypoglycemia can lead to falls, organ damage, and even coma. Having glucose tablets or other rapid glucose treatments on hand can help promptly treat hypoglycemia and potentially avoid long-term consequences.

In inpatient settings, a patient-specific insulin dosing software like EndoTool adjusts dosing to reduce the risk of hypoglycemia which may be the result of an excessive basal dose.

Weight Gain

Although insulin therapy improves glycemic control and reduces microvascular complications associated with diabetes, treatment with insulin often causes weight gain, which may increase obesity-associated morbidity and mortality. Insulin-associated weight gain likely occurs for several reasons:

• Insulin effects on appetite, metabolism, and weight regulation
• Increased energy intake out of fear of hypoglycemic episodes
• Increased glucose (energy) storage in adipose tissue
• Less glucose released in the urine

Insulin Resistance

Exposure to excess insulin doses and long term insulin therapy can lead to insulin resistance, where cells become less responsive to insulin, and higher doses of insulin are required to achieve glycemic control. Other conditions, like obesity, non-alcoholic fatty liver disease, polycystic ovary syndrome, metabolic syndrome, and lipodystrophy, are strongly associated with insulin resistance and may lead to additional metabolic complications. Using a lower insulin dose (and combining insulin with other antidiabetic treatments) may help reduce the severity of insulin resistance.

Integrating with Oral Glucose-Lowering Drugs

In patients with type 2 diabetes mellitus, insulin therapy is often used in conjunction with other antidiabetic medications to encourage improved glycemic control. Some oral glucose-lowering medications can cause hypoglycemia by themselves, like sulfonylureas, meglitinides, and thiazolidinediones. When these medications that carry a higher risk of hypoglycemia are used in conjunction with insulin therapy, the risk of hypoglycemia further increases. Appropriate medication dosing, consideration of insulin sensitivity, and careful blood glucose monitoring can help promote optimal glycemic control and patient outcomes.  In the inpatient setting, when oral intake may be decreased, it is recommended to hold these agents when hospitalized.

Given the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists for cardiovascular and kidney health, these medications are often used in combination with basal insulin therapy to provide benefits beyond glycemic control. Considering any existing cardiovascular, digestive, and kidney diseases can help establish an optimal treatment regimen for patients with type 2 diabetes mellitus, while minimizing potential adverse effects.

Key Points

Using basal and mealtime insulin aims to mimic normal pancreatic physiologic insulin release. Basal insulin is important to provide lasting, consistent insulin activity and to reduce the risk of hypoglycemia. However, the dosing of complex insulin regimens must be carefully calculated and implemented to prevent potential treatment complications. Ongoing blood sugar monitoring requires patient and clinician commitment to help achieve optimal glycemic control.

About EndoTool

Made by Monarch Medical Technologies, EndoTool is the only patient-specific insulin dosing system which simplifies the complex task of glycemic management in hospitals environments. The recommended dosing is different for each patient based on multiple clinical characteristics. The FDA-cleared platform is utilized in hundreds of hospitals across the United States and is fully integrated with all major electronic medical records. To see how EndoTool can support your health system, get in touch today.