Modifying insulin kinetics - clinical requirements and limitations (Part 1)

Part 1: Long acting insulins

Introduction

Insulin supplementation is a life sustaining requirement for patients with type 1 diabetes mellitus and an increasing number of patients with type 2 diabetes mellitus not anymore controlled with other, non-insulin antidiabetic medications. In a physiological sense, insulin is released from the beta cell in a strictly glucose dependent manner keeping blood glucose concentrations within a narrow range, without causing risk of hyperglycemic or hypoglycemic derangements. The goal of insulin treatment in patients with diabetes mellitus is to mimic insulin physiology and match glucose control as much as possible to non-diabetic subjects.

After the release of insulin from the beta cell in to the portal blood stream, insulin is first delivered to the liver, where it supresses the glucose output from the liver. After passing the liver, insulin is distributed within the peripheral circulation creating a relative ratio of hepatic to peripheral insulin concentration of around 2:1 (figure 1). In healthy individuals, insulin secretion could be divided in basal insulin secretion during fasting conditions, and prandial insulin secretion, which follows the ingestion of carbohydrate containing meals. A low rate of continuous insulin secretion is required to regulate glucose metabolism within the fasting state and especially over the night. Nocturnal insulin requirements on individual level can vary from night to night due to circadian hormonal fluctuations or varying insulin sensitivity.

In patients with diabetes mellitus, insulin deficiency or hepatic insulin resistance lead to an increase in liver gluconeogenesis and glycolysis, causing an increase in fasting and postprandial glucose levels.  With regard to exogenous insulin supplementation, there are a couple of hurdles which, up date, prevent us from mimicking insulin supply in a physiological manner. The major challenge is to approach exogenous insulin into the blood stream. Up to date, the subcutaneous route of insulin application is the standard for insulin treatment in patients with diabetes mellitus. Even though, this technology has been consistently improved over the last decades, it still presents with some major limitations. In contrast to the glucose mediated insulin release from the beta cell, the absorption of insulin from the subcutaneous space is glucose independent and strictly follows the absorption kinetics of the respective insulin formulation. Rarely providing plasma insulin concentrations which reflect current insulin requirements, and to regulate glucose haemostasis in a physiological sense. Absorption of insulin from the subcutaneous tissue underlie a huge inter and intra individual variability from day to day according to anatomical conditions at the injection site, or variations in subcutaneous microcirculation.

In addition, insulin requirements might frequently alternate in an individual subject due to short term changes in insulin sensitivity. In case of some insulin formulations, the pharmacodynamic action profile can vary up to fifty percent from day to day in an individual subject (1). Another limitation of the subcutaneous route of insulin application is an artificial distribution of insulin in the body. As illustrated in figure 1, insulin absorbed from the subcutaneous tissue is provided to peripheral tissues before it reaches the liver, causing a reversal of the physiological hepatic / peripheral insulin ratio and unpredictable glucose shifts within the body.

Figure 1: Schematic presentation of insulin circulation and peripheral / hepatic insulin ratio (A = physiological distribution after insulin release in to the portal blood (PB); B = distribution after subcutaneous insulin injection)  

Long acting, basal insulins

A lot of efforts have been undertaken to modify insulin formulations for subcutaneous use to provide absorption profiles better reflecting physiological insulin concentrations in non-diabetic subjects. For this reason long acting insulins have been developed to mimic basal insulin requirements, and short acting insulins to address the needs for postprandial insulin. There are a number of pharmacokinetic and pharmacodynamic (PK/PD) properties to characterize an ideal basal insulin formulation. Since even modest increases in nocturnal insulin levels might cause a sustained suppression of the endogenous glucose supply from the liver and precipitate nocturnal hypoglycemia, insulin peaks during the night are considered as unfavourable. The PK profile should be flat as possible, without distinct peaks, with duration of action ≥ 24 hours, and a low variability in the PK/PD properties from day to day. An overview of current available insulin formulations is given in table 1.

Table 1: Pharmacokinetic characterisation of current available long acting (basal) insulins

Neutral Protamine Hagedorn (NPH) insulin     

NPH is intermediate acting insulin which was developed in the 1950’s. Initially NPH insulins were from animal sources containing porcine or bovine insulin. Later, recombinant human insulin has replaced the use of animal insulin molecules in the formulation of NPH insulins. To achieve effective insulin levels over twenty four hours, NPH insulin has to be injected twice daily. Since NPH insulin formulations show a peak insulin concentration at around 4.5 hours after the injection, hypoglycemia, especially during the night, remains a problem (2,3). Moreover, the duration of action of NPH insulins can vary substantially, lasting as little as eight hours or as long as twenty-four hours (1). Another disadvantage of NPH insulin is that it requires an extensive mixing before injection. Without carefully mixing, the PK properties of NPH insulin become totally unpredictable (4). Taken together this does not qualify NPH insulins as ideal basal insulin.

Insulin Glargine U 100

Insulin Glargine U 100 was the first long acting insulin analogue to be approved by the EMA and the FDA. In the insulin glargine molecule, asparagine is substituted with glycine in position A21 of the A chain, and by adding two arginine amino acids on position B31an B32 in the B chain of the human insulin molecule (5). These modifications lead to a shift in the isoelectric point from pH 5.4 to 6.7, making insulin glargine soluble at a slightly acid pH and less soluble at physiological pH levels. Compared with NPH insulin, insulin glargine U100 has a longer duration of action, a flatter action profile and less absorption variability (1,6-8).  In a huge number of studies, insulin glargine U 100 compared to NPH Insulin was shown to better reduce fasting glucose levels, improve glycemic control, reduce the risk of hypoglycemia, and to induce lower weight gain in type 1 and type 2 diabetic patients (9-22).

Insulin detemir

Insulin detemir is a long acting insulin analogue characterised by a covalent binding of a C14 fatty acid to lysine in position B29 and removal of the terminal threonine in position B30 of human insulin. This modification increases the self-association and allows reversible binding of the insulin molecule to albumin (23,24). Insulin detemir provides a duration of action of about to 24 hours with a relative flat profile compared with NPH insulin (7). Compared to NPH insulin, insulin detemir reduces the risk of hypoglycemia, reduces within subject pharmacodynamic variability, and to induces less weight gain in type 1 and type 2 diabetic subjects (7,16,25-31). In comparison to insulin glargine U 100, insulin detemir was shown to provide comparable pharmacodynamic activity in the first 12 hours, but evolve less glucose lowering activity during 12 -24 hours (6). This pharmacodynamic observation is in agreement with studies showing that in most diabetic patients insulin detemir need to be injected twice daily to achieve optimal blood glucose control (32,33).

Insulin glargine U 300       

Insulin glargine U 300 was developed to create a basal insulin formulation with extended PK/PD properties compared with insulin glargine U 100. Insulin glargine U 300 is a high concentrated insulin formulation that delivers the same number of insulin units as insulin glargine U 100, but in a third of the volume. After precipitation in the subcutaneous tissue, the reduced volume renders a smaller surface area and an extended release of insulin. This modification in the formulation of insulin glargine translates into a more constant PK/PD profile with a prolonged duration of action (34,35). In a couple of clinical studies comparing insulin glargine U 300 with insulin glargine U 100, insulin glargine U 300 was found to be comparable with regard to HbA1c reduction, but with a reduced frequency of hypoglycemia and less weight gain (36-40).

Insulin degludec

The insulin degludec molecule retains the human insulin amino acid sequence with a modification for a deletion of threonine at position B30 and the connection of a 16-carbon-fatty-di-acid chain to position B29. After subcutaneous injection, insulin degludec forms a soluble multi-hexameric chain providing a slow and stable absorption of insulin monomers from subcutaneous tissue (41). Like insulin detemir, insulin degludec reversibly binds to albumin. The mean terminal half-life of insulin degludec was found to be twice that of insulin glargine U 100. The increased half-life of insulin degludec is associated with a marked reduction of the PK/PD variability of this new insulin molecule (42). In a couple of clinical studies, similar HbA1c reductions with significant lower rates of nocturnal hypoglycemic events have been observed with insulin degludec compared with insulin glargine U 100 in patients with T1DM and T2DM (43-46). Moreover, the extended duration of action with insulin degludec allows for more flexibility with regard to the dosing intervals (45).          

Future developments

There is still ongoing research to develop new insulin molecules or formulations which will allow an even closer imitation of physiological insulin kinetics and distribution. Hepato-preferential insulins might be able to restore the hepato-peripheral insulin ratio (47). This might help to better synchronise hepatic glucose output and peripheral glucose uptake.

Smart insulins are under development, which promise to allow a glucose responsive absorption of insulin from the subcutaneous tissue (48,49). As schematically illustrated in figure 2, the underlying technology is based on insulin modifications that self-regulate their absorption and bioactivity in response to the ambient glucose level. Thereby acting as a chemical closed loop system with a glucose dependent activation of subcutaneous applied insulin. As shown in table 2, several technologies appear conceivable to realize such kind of insulin supply. Even if these technologies are still in an early development process, they might revolutionize subcutaneous insulin treatment in a way to achieve a much more physiological and glucose regulated insulin supply.

Table 2: Technologies in the development of glucose responsive insulin (smart insulin) (modified according to (48)).

Figure 2: Schematic illustration of the technology for glucose responsive insulin (smart insulin)  

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