Innovative Models for Investigation of Pathomechanisms Leading to Late Diabetic Complications

Background

Recent studies have indicated that diabetes is a general term comprising several probably distinct disorders of metabolism, a term exceeding more than the difference between type 1 and type 2 diabetes [1]. Therefore it is not surprising that doubt has been raised, whether lowering glucose is the major and the only target goal, and whether glucose is the most important parameter for defining diabetes [1–5]. Recently studies have shown that posttranslational modification of the haemoglobin molecule predicts late complications even in patients with normal oral glucose tolerance, thus a subgroup of diabetics may exist in which diabetes is defined by complications rather than by glucose [6]. In view of several studies proving that normalization of blood pressure and optimal treatment of lipids is more effective than lowering glucose [7–9], it becomes now evident that innovative approaches for understanding late diabetic complications are needed. Furthermore it became obvious that glucose concentrations used in vitro to stimulate cells to mimic in vivo situations, are by far too high and may thus mislead the scientist, since in patients late diabetic complications do not occur primarily with glucose concentrations constantly above 200 mg/dl. Thus the question came up whether there are good animal models to unravel novel pathways and pave the way for treatment options different than lowering glucose, lipids or blood pressure.

• References

• 1 Nawroth PP, Rudofsky G, Humpert P. Have We Understood Diabetes?. New Tasks for Diagnosis and Therapy Exp Clin Endocrinol Diabetes 2010; 118: 1-3
• 2 Currie CJ, Peters JR, Tynan A et al. Survival as a function of HbA_1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481-489
• 3 Riddle MC, Ambrosius WT, Brillon DJ et al. Action to Control Cardiovascular Risk in Diabetes Investigators: Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010; 33: 983-990
• 4 Wilson C. Diabetes: ACCORD: 5-year outcomes of intensive glycemic control. Nat Rev Endocrinol 2011; 7: 314
• 5 Fleming T, Cuny J, Nawroth G et al. Is Diabetes an acquired disorder of reactive glucose metabolites and their intermediates?. Diabetologia Jan 22 2012; [Epub ahead of print]
• 6 Skriver MV, Borch-Johnsen K, Lauritzen T et al. HbA_1c as predictor of all-cause mortality in individuals at high risk of diabetes with normal glucose tolerance, identified by screening: a follow-up study of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION), Denmark. Diabetologia 2010; 53: 2328-2333
• 7 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837-853
• 8 Gale EA. Glucose control in the UKPDS: what did we learn?. Diabet Med 2008; 25 (Suppl. 02) 9-12
• 9 Skyler JS, Bergenstal R, Bonow RO et al. American Diabetes Association; American College of Cardiology Foundation; American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009; 32: 187-192
• 10 Tyedmers J. Yeast as a model to understand mechanisms and consequences of protein modification by metabolism derived toxic products. Exp Clin Endocrinol Diabetes 2012; 120: 179-181
• 11 Teleman AA, Ratzenböck I, Oldham S. Drosphila: A model for understanding obesity and diabetic complications.. Exp Clin Endocrinol Diabetes 2012; 120: 184-185
• 12 Jörgens K, Hillebrands J-L, Hammes H-P et al Zebrafish: a model for understanding diabetic complications. Exp Clin Endocrinol Diabetes 2012; 120: 186-188
• 13 Bierhaus A, Nawroth PP. Critical evaluation of mouse models used to study pain and loss of pain perception in diabetic neuropathy.. Exp Clin Endocrinol Diabetes 2012; 120: 189-191
• 14 Peters V, Schmitt CP.. Murine models of diabetic nephropathy.. Exp Clin Endocrinol Diabetes 2012; 120: 192-194
• 15 Müller OJ, Katus HA, Backs J. Macrovascular disease in diabetes: is the mouse a suitable model?. Exp Clin Endocrinol Diabetes 2012; 120: 195-197
• 16 Feng Y, Busch S, Gretz N et al Crosstalk in the retinal neurovascular unit – lessons for the diabetic retina.. Exp Clin Endocrinol Diabetes 2012; 120: 200-202
• 17 Herzig S. Glucose effects on the peritoneum: what can we learn from rodent models?. Exp Clin Endocrinol Diabetes 2012; 120: 198-199