Login to view PhD Thesis

Enter your username and password here in order to log in on the website:


Forgot your password?

BASAL INSULIN THERAPY IN TYPE 2 DIABETES Clinical pharmacokinetic and pharmacodynamic studies

Tina Parker

Summary

Insulin treatment is required in many patients with type 2 diabetes as beta cell failure progresses. Subcutaneous injections of insulin with intermediate- or long-acting insulin preparations, however, are associated with innate drawbacks. Absorption of insulin from the subcutis takes place with pronounced intra- and inter-individual variations. Moreover, the insulin profiles in plasma displays unphysiological peak concentrations and may not fit 24 hours requirements. The purpose of this thesis was therefore to evaluate the impact of simple standard regimens providing a theoretically optimal constant basal subcutaneous insulin supply. The hypothesis was that basal subcutaneous insulin delivery still could be improved in order to achieve a more optimal glycaemic control in patients with type 2 diabetes co-treated with oral antidiabetic drugs. For this purpose we used insulin pumps with a rapid-acting insulin analogue. To differentiate between endogenous and exogenous insulin levels specific assays were used. 

In study 1, an 8 hours overnight continuous subcutaneous insulin infusion significantly reduced fasting plasma glucose. The most optimal insulin infusion rate was found to be 1.5 or 2.0 IU/h, as this resulted in near normal fasting plasma glucose levels with a low risk of hypoglycaemia. In study 2, a fixed insulin dose of 1.5 IU/h was infused subcutaneously either for 8 hours overnight or for 24 hours. The two regimens significantly reduced fasting plasma glucose and to a similar extent, whereas the effect of 24 hours infusion on 2-hour post-prandial plasma glucose was superior to that obtained with an overnight infusion approach. A fixed overnight infusion approach did not seem to be sufficient. In study 3, an equal 24 hours dose of a continuous subcutaneous infusion of a rapidacting insulin analogue was compared to once daily subcutaneous bedtime injection of a long-acting insulin analogue. The basal insulin infusion produced less between-days intra-subject variability in fasting plasma insulin and fasting plasma glucose values (for glucose non-significant) than the  insulin injection. A more flat insulin profile was seen during the infusion regimen as compared to the injection regimen. Moreover, the constant infusion regimen improved the overall day and night glucose levels by 10 % as compared to the once daily injection regimen. 

The constant insulin supply in study 1-3 was accompanied by suppressed endogenous insulin production. Endogenous insulin seemed to exert “buffer-effect” in these patients, which caused the exogenous basal insulin delivery to be simple and robust. During all tree studies relatively few mild hypoglycaemic episodes and no major hypoglycaemic episodes were recorded and no safety concerns were raised. 

Thus, simple basal standard insulin infusion regimens seem to be favourable in patients with type 2 diabetes who cannot achieve sufficient glycaemic control by treatment with oral anti-diabetic drugs. The changed insulin pharmacokinetics during constant delivery did translate into a more optimised glycaemic control. In practice this may be achieved by the development of new long-acting insulin analogues resembling constant subcutaneous insulin infusion even more. Alternatively, as a simple basic insulin infusion regimen seems to be effective, robust and safe, the development of more convenient insulin pumps, maybe as simple few dose steps insulin patches, could be a future treatment approach.