Table 3.

Factors related to the injection site/patient that influence insulin pharmacokinetics.

Factor	Effect on insulin pharmacokinetics
Subcutaneous blood flow (SBF) at injection site	Increased SBF accelerates insulin absorption [113, 114]. SBF is influenced by several factors. Increasing temperatures [113] and exercise [128] increase SBF, whereas obesity [114, 127, 135, 136] and smoking [119] decrease SBF. SBF is also increased in the abdomen and arm/deltoid compared to the thigh and buttocks [114] and during a supine compared to sitting position [121]
Lipohypertrophy	Lipohypertrophy delays absorption, and injection into these areas increases within-subject pharmacokinetic and pharmacodynamic variability between injections [137–140] and should be avoided [141]
Skin temperature	Increasing skin temperatures accelerate insulin absorption [99, 113, 115, 117, 120]
Local degradation	Affects the bioavailability of insulin, which is lower for insulin suspensions and biphasic insulin mixtures compared to soluble insulin [111, 142–148]
Local massage	Massage of the injection site accelerates insulin absorption [115, 116, 134], likely due to an increased insulin depot surface-to-volume ratio and not increased SBF [134]
Injection site (i) Abdomen, arm/deltoid, thigh, or buttocks	Insulin is more readily absorbed from the abdomen and deltoid region compared to thigh and buttocks [111, 115, 118, 122–125, 130]. The pharmacokinetic profile of long-acting insulin preparations has been reported to be less susceptible to changes in absorption rate associated with injection site rotation [84, 133].
Administration route (i) Subcutaneous versus intramuscular	Insulin is absorbed faster after intramuscular compared to SC injections [126, 149]. Intramuscular injections should be avoided as they increase the risk of hypoglycaemia [141] but may be taken into use under certain rare circumstances (e.g., in case of ketoacidosis or dehydration) [86]
Blood glucose levels	Hypoglycaemia has been reported to have no influence [150, 151] or decrease [152] the absorption of insulin in healthy [151, 152] and diabetic subjects [150].
Diabetes related comorbidities and complications	For example, oedema has been reported to delay SC absorption [153]
Obesity	Obesity gives rise to a decreased insulin absorption rate [99, 114, 129, 135]. High variation in skinfold thickness between patients may contribute to the high pharmacokinetic variability between people with diabetes [135]
Exercise and activity level	Exercise accelerates insulin absorption [118, 126], and therefore, the insulin dose should be adjusted accordingly to reduce the risk of iatrogenic hypoglycaemia [154]
Smoking	Causes peripheral vasoconstriction and delays insulin absorption [119]
Body position	Compared to a supine position, a sitting position is associated with reduced SBF and delayed insulin absorption [121]