Central and peripheral pathogenetic forms of type 2 diabetes: a proof-of-concept study

HYPOTHESIS: Previous studies provide evidence that glycated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) should not be considered as interchangeable alternatives in the diagnosis of the same type 2 diabetes, but as indicators of its different pathogenetic subtypes. This study was conducted to determine whether a particularly high amount of glucose in either HbA(1c) form or in fasting plasma would be found in diabetic patients genetically predisposed for either intensive cognitive or intensive muscle metabolic activity, respectively. METHODS: HbA(1c) and FPG levels, polymorphisms of genes indicating the predisposition to different cognitive activity (the dopamine D2 receptor (DRD2/ANKK1)), muscle activity (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1A(PPARGC1A))), and vascular regulation of general metabolic activity (the angiotensin 1 converting enzyme (ACE)) were assessed in diabetic patients and nondiabetic controls. RESULTS: DRD2/ANKK1 polymorphism that affects baseline central arousal determined HbA(1c) variations uncorrelated with FPG in total and clinical groups. The mutation of PGC1A mainly affecting peripheral glucose metabolism had an effect on FPG correlated or uncorrelated with HbA(1c) depending on the effect assessment in the total sample or in the nondiabetic group, respectively. ACE insertion/deletion (I/D) gene polymorphism was associated with both HbA(1c) and FPG fluctuations, but only in diabetic patients. CONCLUSION: The findings provide evidence that the HbA(1c) and FPG may predict the risks for different subtypes of type 2 diabetes associated with either brain or muscle metabolic activity in genetically vulnerable people.