• Hyperglycemia/Hypoglycemia
• Diabetes Mellitus

Diabetes has a devastating systemic impact on those who suffer from it, including a 2- to 4-fold increase in cardiovascular events and stroke, nontraumatic lower extremity amputations, end-stage renal disease, and blindness in working age adults. These outcomes underscore the importance of identifying novel pathways that lead to late diabetic complications. Prof. Dr. Angelika Bierhaus, Department of Medicine I and Clinical Chemistry, University Hospital, Heidelberg, Germany, reviewed the latest research and hypotheses on novel pathways.

Risk for complications may be due, in part, to shortcomings in HbA1C. Recent clinical studies show that HbA1C and the duration of disease only explain approximately 11% of the risk of diabetic microvascular complications. The remaining 89% of the risk most likely reflects the fact that HbA1C fails to fully capture the elements of glycemia that determine risk [Lachin JM et al. Diabetes 2008].

According to Dr. Prof. Bierhaus, HbA1C reflects time-averaged mean glucose only—it does not mirror any other elements independently of glycemia that might determine risk. This leads to the Diabetes Paradox—that hyperglycemia is necessary for the development of late diabetic complications—but average blood glucose HbA1C only explains a small percentage of complications.

Skriver et al. [Diabetologia 2010] studied a subtype of patients who were phenotypically at high risk of developing diabetes but currently had normal glucose tolerance (NGT). The primary aim was to assess whether HbA1C added prognostic information in relation to all-cause mortality in people with normal NGT and high risk of type 2 diabetes.

Compared with individuals with NGT and HbA1C <6%, adjusted hazard ratios were 1.21 (95% CI, 0.95 to 1.56) for those with NGT and HbA1C between 6.0% and 6.5%; 2.48 (95% CI, 1.23 to 4.99) for individuals with NGT and HbA1C ≥6.5%; and 1.73 (95% CI, 1.40 to 2.13) for those with type 2 diabetes. The authors concluded that HbA1C levels in patients with NGT and a high risk of diabetes were clearly associated with increased risk of all-cause mortality [Skriver MV et al. Diabetologia 2010].

Prof. Dr. Bierhaus and colleagues have found that a focus not only on hyperglycemia but also on the balance between excess metabolite formation and reduced metabolite detoxification not only lends itself to an explanation of the “diabetic paradox” but also provides new therapeutic approaches to the as-yet unsolved problem of late diabetic complications.

Data indicate that the level of risk for complications is determined by glucose-dependent activation mechanisms and independent inactivation mechanisms. Proposed major independent mechanisms of hyperglycemia-induced tissue damage include increases in polyol pathway flux, hexosamine pathway, and protein kinase C activation, leading to increased formation of advanced glycation endproducts (AGEs) and activation of the AGE/receptor for advanced glycation endproducts (RAGE) axis. Loss of renal function is reduced by blockade/absence of RAGE [Wendt TM et al. Am J Pathol 2003].

Multiple independent inactivation mechanisms could be implicated in late diabetic complications, including a novel pathway in which small reactive molecules directly reduce neuronal blood flow and induce hyperalgesia. This finding might provide a new concept for therapeutic options in treating pain [Bierhaus A et al. In revision].

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