Alternative Assessment of Glycemic Control

Abstract

Diabetes mellitus is a chronic disease associated with development of microvascular and macrovascular complications. Optimal glycemic control, usually measured by HbA1c is the cornerstone for prevention of complications. In this thesis glycemic variability (which resembles actual glucose levels, glucose peaks and nadirs) and advanced glycation end products (AGEs) (a more long-term reflection of hyperglycemia and tissue glycation) are investigated as alternative assessment of glycemic control. In this thesis we suggest the parameter to measure glycemic variability to be standard deviation of blood glucose (SD), because we showed strong correlations with the other parameters of glycemic control. Glycemic variability is higher in type 1 diabetes compared to type 2 diabetes, probably caused by different progression rates of these diseases. In patients with type 2 diabetes glycemic variability increased to levels comparable with type 1 diabetes after approximately 20 years of insulin therapy. This emphasizes that large glycemic variability is not only present in type 1 diabetes, but also an important feature of (longstanding) type 2 diabetes on insulin therapy. Glycemic variability was associated with more diabetes distress, measured by the disease-specific Problem Areas in Diabetes Scale (PAID), especially in the domains of the PAID questionnaire concerned with diabetes-related emotional problems and treatment-related problems. This emphasize glycemic variability as a clinical treatment target. Two theoretical possibilities to reduce glycemic variability are intervention in the incretin pathway and real-time glucose monitoring, which enables patients to react to glucose excursions immediately and thereby reduce glucose excursions. The ability of this device was shown in our review. We investigated intervention in the incretin system in our small randomized study with addition of vildagliptin to start of once-daily insulin therapy. However, due to a small sample size, we could not prove that vildalgiptin reduced glycemic variability by glucose dependent improved beta cell function and alpha cell function. Measurement of accumulation of AGEs can provide information about hyperglycemia for a much longer period of time than HbA1c. AGEs are modified (i.e. glycated) long-lived tissue proteins that accumulate in body tissue during aging and accelerated accumulation is seen in patients with diabetes. AGE-accumulation can easily be assessed non-invasively by the AGE-reader (measured as skin autofluorescence (SAF)). We showed associations of AGE accumulation with all different diabetes complications and with increasing number of these complications. SAF was associated not only with neuropathy and nephropathy, but also linearly with the severity of these complications. SAF was also associated with retinopathy, albeit dependent on the stage of retinopathy (the association was only found for proliferative retinopathy). The use of the AGE-reader was never investigated in gestational diabetes mellitus. We found no difference in SAF in patients diagnosed with gestational diabetes compared to normal pregnancy, therefore the AGE-reader cannot be used to detect gestational diabetes. In contrast we did show that SAF was higher in pregnant patients with pre-existent diabetes. Moreover, it was unexpectedly found in this study that SAF slightly decreased in normal pregnancy in contrast to pregnancy complicated by diabetes.