How Does Triple Therapy Improve Glucose Metabolism

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First of all, insulin aspart given at the initiation of the meal was in fact able to reconstruct the necessary fast and high insulin peaks compared with non-diabetic subjects (Fig. 3). This seems to be important since the insulin concentration obtained (24-h area under the curve) is much lower in triple therapy despite much lower blood glucose values. This indicates that the insulin profile is more important than the absolute amount of insulin given. We were able to measure insulin aspart with a specific antibody and thereby, for the first time in insulin-treated subjects, measure the amount of endogenous insulin produced together with exogenous insulin. Endogenous insulin secretion is still seen to continue with relatively low peaks at meals and with an overnight concentration of about 50 pmol/L, which is interestingly close to the values seen in non-diabetic controls (Fig. 3). However, the exogenous insulin aspart gives rise to significant peaks after meals, with a steep rise just after injection and an appropriately declining rate following the peak. Interestingly, all exogenous insulin was metabolised around midnight and therefore the T2D subjects rely on endogenous insulin only during the night. To our knowledge this is very important since it protects against nightly hypoglycaemia, as a fall in blood glucose during the night will immediately result in reduced insulin secretion. This can explain why no hypoglycaemic attacks were seen in the triple-therapy group during the night, and this is one of the greatest fortunes when using this new approach.

Blood glucose values increased during the night in the triple-therapy group despite "normal" seruminsulin values. The reason for this must of course be that both the liver and peripheral tissue are insulin resistant. However, during home blood glucose measurements, the mean value reached in the morning was between 7 and 8 mmol/L (based on measurements every morning during 6 months), which is an acceptable value.

As seen in Fig. 3, blood glucose values during triple therapy were not completely normalised during the 24-h period. This may be explained by insulin resistance, since our euglycaemic hyperin-sulinaemic clamp studies showed an improvement only in peripheral insulin sensitivity of about 60%. Therefore, to completely normalise blood glucose values, a more potent insulin synthesizer than rosiglitazone is needed.

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