The new insulin formulation begins to take effect almost immediately after the injection


Researchers at Stanford University are developing a new insulin formulation that begins to take effect almost immediately upon injection, potentially working four times as fast as current commercial fast-acting insulin formulations.

The researchers focused on so-called monomeric insulin, which has a molecular structure that, according to theory, should allow it to act faster than other forms of insulin.

The catch is that monomeric insulin is too unstable for practical use. So, in order to realize the ultrafast potential of this insulin, the researchers relied on some materials science magic.

“The insulin molecules themselves are fine, so we wanted to develop a ‘magic fairy dust’ that you add into a vial that would help to fix the stability problem,” said Eric Appel, assistant professor of materials science and engineering at Stanford.

“People often focus on the therapeutic agents in a drug formulation but, by focusing only on the performance additives – parts that were once referred to as ‘inactive ingredients’ – we can achieve really big advancements in the overall efficacy of the drug.”

After screening and testing a large library of additive polymers, the researchers found one that could stabilize monomeric insulin for more than 24 hours in stressed conditions.

(By comparison, commercial fast-acting insulin stays stable for six to ten hours under the same conditions.)

The researchers then confirmed the ultrafast action of their formulation in diabetic pigs. Their results were published July 1 in Science Translational Medicine. Now, the researchers are conducting additional tests in hopes of qualifying for clinical trials in humans.

One step back, two steps forward

Current commercial formulations of insulin contain a mix of three forms: monomers, dimers and hexamers. Scientists have assumed monomers would be the most readily useful in the body but, within vials, the insulin molecules are drawn to the surface of the liquid where they aggregate and become inactive.

(Hexamers are more stable in the vial but take longer to work in the body because they first have to break down into monomers to become active.) This is where the “magic fairy dust” – a custom polymer that is attracted to the air/water interface – comes in.

[Credit: Professor Eric Appel, Assistant Professor of Materials Science & Engineering, Stanford University; Joseph Mann, PhD Candidate in Materials Science & Engineering, Stanford University; Caitlin Maikawa, PhD Candidate in Bioengineering, Stanford University

“We focused on polymers that would preferentially go to that interface and act as a barrier between any of the insulin molecules trying to gather there,” said Joseph Mann, a graduate student in the Appel lab and co-lead author of the paper. Crucially, the polymer can do this without interacting with the insulin molecules themselves, allowing the drug to take effect unimpeded.

Finding just the right polymer with the desired properties was a long process that involved a three-week trip to Australia, where a fast-moving robot created approximately 1500 preliminary candidates.

This was followed by processing and testing individually by hand at Stanford to identify polymers that successfully exhibited the desired barrier behavior. The first 100 candidates didn’t stabilize commercial insulin in tests but the researchers pressed on.

They found their magic polymer only weeks before they were scheduled to run experiments with diabetic pigs.

“It felt like there was nothing happening and then all of the sudden there was this bright moment … and a deadline a couple of months away,” said Mann. “The moment we got an encouraging result, we had to hit the ground running.”

Researchers develop a new ultrafast insulin
The ultrafast-absorbing insulin is based on simpler insulin monomer molecules, which are absorbed far faster than the more complex dimers and hexamers used in commercial rapid-acting insulin analogs. Credit: J.L. Mann et al., Science Translational Medicine (2020)

In commercial insulin – which typically remains stable for about 10 hours in accelerated aging tests – the polymer drastically increased the duration of stability for upwards of a month.

The next step was to see how the polymer affected monomeric insulin, which on its own aggregates in 1-2 hours. It was another welcome victory when the researchers confirmed that their formulation could remain stable for over 24 hours under stress.

“In terms of stability, we took a big step backward by making the insulin monomeric. Then, by adding our polymer, we met more than double the stability of the current commercial standard,” said Caitlin Maikawa, a graduate student in the Appel lab and co-lead author of the paper.

With a seed grant from the Stanford Diabetes Research Center and the Stanford Maternal and Child Health Research Institute, the researchers were able to evaluate their new monomeric insulin formulation in diabetic pigs—the most advanced non-human animal model—and found that their insulin reached 90 percent of its peak activity within five minutes after the insulin injection.

For comparison, the commercial fast-acting insulin began showing significant activity only after 10 minutes. Furthermore, the monomeric insulin activity peaked at about 10 minutes while the commercial insulin required 25 minutes.

In humans, this difference could translate to a four-fold decrease in the time insulin takes to reach peak activity.

“When I ran the blood tests and started plotting the data, I almost couldn’t believe how good it looked,” said Maikawa.

“It’s really unprecedented,” said Appel, who is senior author of the paper. “This has been a major target for many big pharmaceutical companies for decades.”

The monomeric insulin also finished its action sooner. Both beginning and ending activity sooner makes it easier for people to use insulin in coordination with mealtime glucose levels to appropriately manage their blood sugar levels.

A multifaceted success

The researchers plan to apply to the Food and Drug Administration for approval to test their insulin formulation in clinical trials with human participants (although no trials are planned yet and they are not seeking participants at this time).

They are also considering other uses for their polymer, given how significantly it increased stability in commercial insulin.

Because their insulin formulation activates so quickly – and, therefore, more like insulin in a person without diabetes – the researchers are excited by the possibility that it could aid the development of an artificial pancreas device that functions without the need for patient intervention at mealtimes.

Additional Stanford co-authors include former visiting scholar Anton Smith (from Aarhus University in Denmark); graduate students Abigail Grosskopf, Gillie Roth, Catherine Meis, Emily Gale, Celine Liong, Doreen Chan, Lyndsay Stapleton and Anthony Yu; clinical veterinarian Sam Baker; and postdoctoral fellow Santiago Correa. Researchers from CSIRO Manufacturing in Australia are also co-authors. Appel is also a member of Stanford Bio-X, the Cardiovascular Institute, the Stanford Maternal and Child Research Institute and a faculty fellow at Stanford ChEM-H.

The prevalence of type 1 (T1DM) and type 2 diabetes mellitus (T2DM) has been increasing in the United States, with approximately 23.2 million people (7.3% of the US population) in 2016 compared with 21.1 million people (7.0%) in 2010; approximately 5% are estimated to have T1DM (Bullard et al., 2018; Center for Disease Control, 2019). Diabetes contributes to the development and progression of microvascular and macrovascular complications that cause significant morbidity and mortality (Fowler, 2008). Intensive insulin therapy improves glycemic control, which reduces the risk of diabetes-related complications (Nathan et al., 2005; Stratton et al., 2000; The Diabetes Control and Complications Trial Research Group, 1996). Evidence suggests that regimens must lower both fasting and postprandial hyperglycemia to achieve therapeutic goals (Garg, Ellis, & Ulrich, 2005). Thus, guidelines recommend that treatment plans be individualized and aim to achieve near-normalization of plasma glucose levels with target HbA1c values, including target goals for both fasting plasma glucose (FPG) and postprandial glucose (PPG) (American Association of Clinical Endocrinologists and American College of Endocrinology, 2015; American Diabetes Association, 2019; International Diabetes Federation Guideline Development Group, 2014). Despite these treatment targets and the wealth of evidence supporting a glucose-lowering regimen, an analysis of 2007–2010 data from the National Health and Nutrition Examination Surveys showed that almost half of patients with diabetes did not achieve target HbA1c <7.0% (<53 mmol/mol) (Stark Casagrande, Fradkin, Saydah, Rust, & Cowie, 2013); similar results have been reported in other developed countries (de Pablos Velasco et al., 2009; Schmieder et al., 2018; Yokoyama et al., 2016).

In individuals without diabetes, insulin and glucagon are secreted at a near-constant rate during the fasting state. This maintains a stable blood glucose profile at nighttime and before meals. At meal times, elevated blood glucose levels promote secretion of presynthesized insulin from the pancreatic β-cells, followed by a slower secretion of newly synthesized insulin (Rorsman & Renstrom, 2003). Individuals with T1DM have an absolute insulin deficiency in which there is little or no endogenous insulin secretory capacity due to destruction of insulin-producing β cells (Home, 2015). Meanwhile, results from animal models suggest that during the early stages of T2DM, there is loss of the first-phase insulin response (that should occur with onset of ingested calories) as a result of impaired β-cell function, which may occur due to age and/or obesity. Individuals with T2DM may also have overall reduced insulin secretory capacity, insulin resistance, and β-cell fatigue, all of which will eventually affect both fasting and PPG levels (Del Prato & Tiengo, 2001; Rorsman & Renstrom, 2003).

Individuals with T1DM must manage blood glucose with exogenous insulin, with mealtime insulin representing an important approach to maintaining PPG in T1DM. Although there are several therapeutic options available for management of blood glucose levels in individuals with T2DM, the progressive nature of this disease means that many patients may ultimately require bolus insulin injections to control PPG.

The aim of insulin therapy was to mimic physiological insulin secretion, thereby controlling FPG and PPG levels, with a long-acting basal insulin injected once or twice daily and a bolus of insulin injected before every meal (Levich, 2011). Basal insulin may be either neutral protamine Hagedorn insulin or a long-acting insulin analogue, whereas prandial (bolus) insulin can either be a regular human insulin (RHI) or a rapid-acting insulin analogue (RAIA) (Home, 2015). Alternatively, insulin pumps can infuse RAIAs as a bolus and continuously in very small amounts to provide basal coverage, obviating the need for a long-acting insulin component. The efficacy of RHI has been established over approximately 35 years of clinical use, but RAIAs offer several clinical advantages over RHI (Home, 2015). The purpose of this review was to summarize the clinical evidence supporting the use of RAIAs as part of a basal–bolus regimen in patients with diabetes, with a focus on new formulations whose pharmacological profiles more closely mimic the endogenous prandial insulin secretion pattern that is seen in individuals without diabetes. Because initiation and intensification of insulin regimens are often delayed in the face of inadequate glycemic control (Khunti et al., 2018), this review also provides a clinical perspective on the use of RAIAs to help guide health care professionals, in particular nurse practitioners (NPs) who have a unique and crucial role in the clinical care paradigm for individuals with diabetes.

Development of conventional and fast-acting insulin analogues
Recombinant engineering of insulin has facilitated the development of RAIAs with faster insulin absorption kinetics compared with RHI. These RAIAs promote earlier and higher insulin levels in peripheral tissues, enhancing peripheral glucose uptake by skeletal muscle and fat. Consequently, there is more immediate suppression of hepatic glucose production and peripheral uptake that, in turn, help to reduce PPG excursions (Basu et al., 2018; Bruttomesso et al., 1999).

Conventional RAIAs include insulin lispro, insulin aspart, and insulin glulisine; these molecules have been engineered with a reduced tendency to aggregate as hexamers, thereby allowing rapid dissociation and absorption after a subcutaneous injection (Pandyarajan & Weiss, 2012). Furthermore, insulin lispro, conventional insulin aspart, and insulin glulisine contain amino acid substitutions that have resulted in faster pharmacokinetics (as discussed in greater detail in the next section) compared with RHI (Sanlioglu, Altunbas, Balci, Griffith, & Sanlioglu, 2013).

The more recently developed fast-acting insulin aspart (faster aspart) is an ultrafast-acting mealtime insulin that comprises conventional insulin aspart in a new formulation with the excipients niacinamide and L-arginine to achieve faster absorption than the conventional insulin aspart molecule (Heise et al., 2015; Home, 2015). Niacinamide promotes a more rapid absorption of faster aspart by accelerating dissociation of insulin aspart hexamers into monomers and, thus, leading to an increased permeation rate of conventional insulin aspart compared with conventional insulin aspart. L-Arginine, a naturally occurring amino acid, acts as a stabilizing agent (Heise, Pieber, Danne, Erichsen, & Haahr, 2017). Other ultrafast-acting injectable formulations (e.g., Biochaperone lispro, treprostinil lispro) currently in development and inhaled formulations (e.g., Afrezza) are not covered in this review.

Pharmacological profile of prandial insulins
Insulin analogues have modified molecular structures that offer several clinical advantages over RHI, based on differences in their pharmacokinetic and pharmacodynamic profiles. Differences between individual insulin formulations may be categorized according to a number of key parameters, including onset of action, peak of action, and duration of action.

Regular human insulin injected subcutaneously shows peak plasma insulin concentration 2–3 hours after injection (Edelman, Dailey, Flood, Kuritzky, & Renda, 2007) (Figure 1). This slow rise to peak insulin concentration does not reflect physiological temporal insulin profiles and may account for postprandial hyperglycemia that is observed in RHI-treated individuals (Zinman, 1989). Because duration of action of RHI is approximately 3–6 hours, there is a risk of late postabsorptive hypoglycemic episodes (Edelman et al., 2007).

Figure 1
Pharmacological properties of RHI and conventional RAIAs (Edelman et al., 2007; Heise et al., 2017; Hirsch, 2005). Some data from the figure have been extracted and adapted from Hirsch, I. B. (2005). Insulin analogues. New England Journal of Medicine, 352, 174–183 (Hirsch, 2005). Table adapted from Edelman, S., Dailey, G., Flood, T., Kuritzky, L., Renda, S. (2007). A practical approach for implementation of a basal-prandial insulin therapy regimen in patients with type 2 diabetes. Osteopathic Medicine and Primary Care, 20, 9, under the terms of the Creative Commons Attribution License (; and Heise, T., Pieber, T.R., Danne, T., Erichsen, L., Haahr, H. (2017). A pooled analysis of clinical pharmacology trials investigating the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in adults with type 1 diabetes. Clinical Pharmacokinetics, 56, 551–559, under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. Faster aspart = fast-acting insulin aspart; RAIAs = rapid-acting insulin analogues; RHI = regular human insulin; T1D = type 1 diabetes.
Role of ultrafast-acting insulin analogues in the management of diabetes
Journal of the American Association of Nurse Practitioners31(9):537-548, September 2019.

Rapid-acting insulin analogues (e.g., insulin lispro, insulin aspart, and insulin glulisine) display a lower tendency toward self-association than RHI whose molecules associate into hexamers that diffuse slowly into the circulation. This ability of RAIAs to dissociate into monomers in the subcutaneous depot results in a quicker absorption and shorter time to peak plasma concentrations (Hirsch, 2005). Peak plasma concentration is approximately twice as high and is achieved within approximately half the time compared with RHI (Figure 1). Additionally, the RAIAs have a more rapid tailing-off activity compared with RHI (Howey, Bowsher, Brunelle, & Woodworth, 1994; Kang et al., 1991).

In clinical outcomes, RAIAs are more effective in lowering PPG levels and have improved tolerability profiles because of a lower risk of late postprandial hypoglycemia (Rossetti et al., 2008). Rapid-acting insulin analogues also require less restrictive mealtime planning compared with RHI. Although RHI should be administered at least 30 minutes before meals, insulin aspart may be injected within 5–10 minutes before a meal (NovoLog prescribing information), insulin lispro within 15 minutes before a meal or immediately after a meal {Humalog (insulin lispro injection USP [rDNA origin], 2017) prescribing information}, insulin glulisine within 15 minutes before a meal or within 20 minutes after starting a meal {APIDRA (insulin glulisine [rDNA origin] injection} prescribing information), and faster aspart may be administered at the start of a meal or within 20 minutes after starting a meal (Fiasp [faster aspart] prescribing information, 2018). The advantages offered by RAIAs have a positive impact on patient satisfaction, which may in turn help to promote treatment adherence; reasons for improved patient satisfaction include greater meal flexibility (analogue may be injected immediately before/after food intake), decreased frequency of preprandial and nocturnal hypoglycemia, and more flexibility to schedule injections according to lifestyle (Hartman, 2008). However, conventional RAIAs still have shortcomings in their time-onset profile, which do not yet mimic that of physiological prandial insulin secretion.

Compared with conventional RAIAs, faster aspart has a pharmacological profile that more closely mimics the endogenous prandial insulin secretion pattern observed in individuals without diabetes according to results of a pooled analysis of six clinical studies using subcutaneous injection in adults with T1DM (Heise et al., 2017). In this analysis, the pharmacokinetic and pharmacodynamic profiles were left-shifted for faster aspart compared with insulin aspart (Figure 2). The left-shift in mean concentration–time profiles for serum insulin aspart indicates a more rapid onset and greater early insulin exposure with faster aspart than with conventional insulin aspart (Figure 2A, B). Meanwhile, the left-shift in the mean glucose infusion rate profiles, as measured using a euglycemic clamp, also indicates a quicker onset and greater early glucose-lowering effect with faster aspart than insulin aspart (Figure 2C, D). The differences between the pharmacokinetic and pharmacodynamic profiles of faster aspart and conventional insulin aspart translated into an approximately 5-minute earlier onset of appearance. Furthermore, within the first 30 minutes, a two-fold higher early insulin exposure and a 74% greater glucose-lowering effect was observed with faster aspart compared with insulin aspart. The offset of exposure and glucose-lowering effect occurred 12–14 minutes earlier with faster aspart than with insulin aspart. As a result, greater early insulin exposure and early glucose-lowering effect were consistently observed with faster aspart versus insulin aspart across individual trials comparing them both (Heise et al., 2017). The findings in children and adolescents also demonstrated that the onset of appearance occurred approximately twice as fast (5–7 minutes earlier), and early exposure (0–30 minutes) was statistically significantly greater by 78–98% for faster aspart compared with insulin aspart (p < .05 for both children and adolescents) (Fath et al., 2017). The profile of faster aspart better mimics the physiological first-phase insulin response to ingested calories and improves control over postprandial glycemic excursions.

Figure 2
Key pharmacokinetic and pharmacodynamic properties of faster aspart. Mean concentration–time profiles for faster aspart and insulin aspart from a) 0–300 minutes and b) 0–120 minutes (early phase). Glucose-lowering effect (raw mean glucose infusion rate profiles) of faster aspart and insulin aspart from c) 0–300 minutes and d) 0–120 minutes (early phase). Adapted from Heise, T., Pieber, T.R., Danne, T., Erichsen, L., Haahr, H. (2017). A pooled analysis of clinical pharmacology trials investigating the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in adults with type 1 diabetes. Clinical Pharmacokinetics, 56, 551–559, under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( Shaded bands indicate standard error of the mean.
Role of ultrafast-acting insulin analogues in the management of diabetes
Journal of the American Association of Nurse Practitioners31(9):537-548, September 2019.

More information: J.L. Mann el al., “An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients,” Science Translational Medicine (2020). … scitranslmed.aba6676


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