|
 |
|
|||||||
|
|||||||||
Diabetes 54:1615-1625, 2005
© 2005 by the American Diabetes Association, Inc.
The Pathobiology of Diabetic Complications
A Unifying Mechanism
From the Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York
Address correspondence and reprint requests to Michael Brownlee, Anita and Jack Saltz Professor of Diabetes Research, Departments of Medicine and Pathology, Albert Einstein College of Medicine, F-531 1300 Morris Park Ave., Bronx, NY 10461-1602. E-mail: brownlee@aecom.yu.edu
Abbreviations:
AGE, advanced glycation end product; eNOS, endothelial nitric oxide synthase; FFA, free fatty acid; GAPDH, glyceraldehyde-3 phosphate dehydrogenase; MnSOD, manganese superoxide dismutase; NF
B, nuclear factor B; PARP, poly(ADP-ribose) polymerase; PKC, protein kinase C; ROS, reactive oxygen species; SOD, superoxide dismutase; TCA, tricarboxylic acid; UCP, uncoupling protein
| The first 300 words of the full text of this article appear below. |
It’s a great honor to join the exceptional club of Banting Award winners, many of whom were my role models and mentors. In addition, giving the Banting Lecture also has a very personal meaning to me, because without Frederick Banting, I would have died from type 1 diabetes when I was 8 years old. However, it was already apparent at the time I was diagnosed that for too many people like me, Banting’s discovery of insulin only allowed them to live just long enough to develop blindness, renal failure, and coronary disease. For example, when I started college, the American Diabetes Association’s Diabetes Textbook had this to say to my parents: "The person with type 1 diabetes can be reassured that it is highly likely that he will live at least into his 30s." Not surprisingly, my parents did not find this particularly reassuring.
At the same time we were reading this in 1967, however, the first basic research discovery about the pathobiology of diabetic complications had just been published in Science the previous year. In my Banting Lecture today, I am thus going to tell you a scientific story that is also profoundly personal.
I’ve divided my talk into three parts. The first part is called "pieces of the puzzle," and in it I describe what was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s. In the second part, I present a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle. Finally, in the third part, I focus on three examples of novel therapeutic approaches for the prevention and treatment of diabetic complications, which are all based on the new paradigm of a unifying mechanism for the pathogenesis of diabetic complications.
 |
PIECES OF THE PUZZLE |
|---|
Increased flux through the polyol pathway.
Intracellular production of AGE precursors.
PKC activation.
Increased hexosamine pathway activity.
|
A UNIFIED MECHANISM |
|---|
How does hyperglycemia increase superoxide production by the mitochondria?
Hyperglycemia-induced mitochondrial superoxide production activates the four damaging pathways by inhibiting GAPDH.
Hyperglycemia-induced mitochondrial superoxide production inhibits GAPDH by activating poly(ADP-ribose) polymerase.
How does the unifying mechanism explain diabetic macrovascular disease?
|
NOVEL THERAPEUTIC APPROACHES |
|---|
Transketolase activators.
PARP inhibitors.
Catalytic antioxidants.
|
CONCLUSION: PERSONAL REFLECTIONS |
|---|
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  R. A. Gubitosi-Klug, R. Talahalli, Y. Du, J. L. Nadler, and T. S. Kern 5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy Diabetes, May 1, 2008; 57(5): 1387 - 1393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-Q. Lai, K. L. Tucker, L. D. Parnell, X. Adiconis, B. Garcia-Bailo, J. Griffith, M. Meydani, and J. M. Ordovas PPARGC1A Variation Associated With DNA Damage, Diabetes, and Cardiovascular Diseases: The Boston Puerto Rican Health Study Diabetes, April 1, 2008; 57(4): 809 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Blatnik, N. Frizzell, S. R. Thorpe, and J. W. Baynes Inactivation of Glyceraldehyde-3-Phosphate Dehydrogenase by Fumarate in Diabetes: Formation of S-(2-Succinyl)Cysteine, a Novel Chemical Modification of Protein and Possible Biomarker of Mitochondrial Stress Diabetes, January 1, 2008; 57(1): 41 - 49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Al-Kateb, A. P. Boright, L. Mirea, X. Xie, R. Sutradhar, A. Mowjoodi, B. Bharaj, M. Liu, J. M. Bucksa, V. L. Arends, et al. Multiple Superoxide Dismutase 1/Splicing Factor Serine Alanine 15 Variants Are Associated With the Development and Progression of Diabetic Nephropathy: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics Study Diabetes, January 1, 2008; 57(1): 218 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shi, D. Patschan, T. Epstein, M. S. Goligorsky, and J. Winaver Delayed recovery of renal regional blood flow in diabetic mice subjected to acute ischemic kidney injury Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1512 - F1517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Jiang, X. X. Wang, P. Scherzer, P. Wilson, J. Tallman, H. Takahashi, J. Li, M. Iwahashi, E. Sutherland, L. Arend, et al. Farnesoid X Receptor Modulates Renal Lipid Metabolism, Fibrosis, and Diabetic Nephropathy Diabetes, October 1, 2007; 56(10): 2485 - 2493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Xu, Y. Wu, P. Song, M. Zhang, S. Wang, and M.-H. Zou Proteasome-Dependent Degradation of Guanosine 5'-Triphosphate Cyclohydrolase I Causes Tetrahydrobiopterin Deficiency in Diabetes Mellitus Circulation, August 21, 2007; 116(8): 944 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Newsholme, E. P. Haber, S. M. Hirabara, E. L. O. Rebelato, J. Procopio, D. Morgan, H. C. Oliveira-Emilio, A. R. Carpinelli, and R. Curi Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity J. Physiol., August 15, 2007; 583(1): 9 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kanwar, P.-S. Chan, T. S. Kern, and R. A. Kowluru Oxidative Damage in the Retinal Mitochondria of Diabetic Mice: Possible Protection by Superoxide Dismutase Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3805 - 3811. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-J. Chiu, R. C Milton, G. Gensler, and A. Taylor Association between dietary glycemic index and age-related macular degeneration in nondiabetic participants in the Age-Related Eye Disease Study Am. J. Clinical Nutrition, July 1, 2007; 86(1): 180 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, V. R. Drel, I. G. Obrosova, and P. Pacher Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H610 - H619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Lim, N. G. Morgenthaler, T. Subramaniam, Y. S. Wu, S. K. Goh, and C. F. Sum The Relationship Between Adrenomedullin, Metabolic Factors, and Vascular Function in Individuals With Type 2 Diabetes Diabetes Care, June 1, 2007; 30(6): 1513 - 1519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kitiphongspattana, T. A. Khan, K. Ishii-Schrade, M. W. Roe, L. H. Philipson, and H. R. Gaskins Protective role for nitric oxide during the endoplasmic reticulum stress response in pancreatic beta-cells Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1543 - E1554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Fadini, S. Sartore, C. Agostini, and A. Avogaro Significance of Endothelial Progenitor Cells in Subjects With Diabetes Diabetes Care, May 1, 2007; 30(5): 1305 - 1313. [Full Text] [PDF]
|
|
|
|
|
|
M. Mudra, N. Ercan-Fang, L. Zhong, J. Furne, and M. Levitt Influence of Mulberry Leaf Extract on the Blood Glucose and Breath Hydrogen Response to Ingestion of 75 g Sucrose by Type 2 Diabetic and Control Subjects Diabetes Care, May 1, 2007; 30(5): 1272 - 1274. [Full Text] [PDF]
|
|
|
|
|
|
D. X. Zhang and D. D. Gutterman Mitochondrial reactive oxygen species-mediated signaling in endothelial cells Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2023 - H2031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Davidson and M. R. Duchen Endothelial Mitochondria: Contributing to Vascular Function and Disease Circ. Res., April 27, 2007; 100(8): 1128 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A Little, J. L Edwards, and E. L Feldman Diabetic neuropathies Practical Neurology, April 1, 2007; 7(2): 82 - 92. [Full Text] [PDF]
|
|
|
|
 |
|
 X. SHEN and K. E. BORNFELDT Mouse Models for Studies of Cardiovascular Complications of Type 1 Diabetes Ann. N.Y. Acad. Sci., April 1, 2007; 1103(1): 202 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Meugnier, M. Faraj, S. Rome, G. Beauregard, A. Michaut, V. Pelloux, J.-L. Chiasson, M. Laville, K. Clement, H. Vidal, et al. Acute Hyperglycemia Induces a Global Downregulation of Gene Expression in Adipose Tissue and Skeletal Muscle of Healthy Subjects Diabetes, April 1, 2007; 56(4): 992 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fauconnier, D. C. Andersson, S.-J. Zhang, J. T. Lanner, R. Wibom, A. Katz, J. D. Bruton, and H. Westerblad Effects of Palmitate on Ca2+ Handling in Adult Control and ob/ob Cardiomyocytes: Impact of Mitochondrial Reactive Oxygen Species Diabetes, April 1, 2007; 56(4): 1136 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H. McNulty Hexosamine biosynthetic pathway flux and cardiomyopathy in type 2 diabetes mellitus. Focus on "Impact of type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart" Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1243 - C1244. [Full Text] [PDF]
|
|
|
|
|
|
S. P. R. Rao, R. Wassell, M. A. Shaw, and K. Sharma Profiling of human mesangial cell subproteomes reveals a role for calmodulin in glucose uptake Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1182 - F1189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Robinson, L. E. Ball, and M. G. Buse Reduction of O-GlcNAc protein modification does not prevent insulin resistance in 3T3-L1 adipocytes Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E884 - E890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Glyn-Jones, S. Song, M. A. Black, A. R. J. Phillips, S. Y. Choong, and G. J. S. Cooper Transcriptomic analysis of the cardiac left ventricle in a rodent model of diabetic cardiomyopathy: molecular snapshot of a severe myocardial disease Physiol Genomics, February 12, 2007; 28(3): 284 - 293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Juutilainen, S. Lehto, T. Ronnemaa, K. Pyorala, and M. Laakso Retinopathy Predicts Cardiovascular Mortality in Type 2 Diabetic Men and Women Diabetes Care, February 1, 2007; 30(2): 292 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Cornblath, A. Vinik, E. Feldman, R. Freeman, and A. J.M. Boulton Surgical Decompression for Diabetic Sensorimotor Polyneuropathy Diabetes Care, February 1, 2007; 30(2): 421 - 422. [Full Text] [PDF]
|
|
|
|
 |
|
 V. Bezaire, E. L. Seifert, and M.-E. Harper Uncoupling protein-3: clues in an ongoing mitochondrial mystery FASEB J, February 1, 2007; 21(2): 312 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Benani, S. Troy, M. C. Carmona, X. Fioramonti, A. Lorsignol, C. Leloup, L. Casteilla, and L. Penicaud Role for Mitochondrial Reactive Oxygen Species in Brain Lipid Sensing: Redox Regulation of Food Intake Diabetes, January 1, 2007; 56(1): 152 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. B. Hirsch and M. Brownlee The Effect of Glucose Variability on the Risk of Microvascular Complications in Type 1 Diabetes: Response to Kilpatrick et al. and Bolli Diabetes Care, January 1, 2007; 30(1): 186 - 187. [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Sasser, J. C. Sullivan, J. L. Hobbs, T. Yamamoto, D. M. Pollock, P. K. Carmines, and J. S. Pollock Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism J. Am. Soc. Nephrol., January 1, 2007; 18(1): 143 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Elrod, J. J. M. Greer, and D. J. Lefer Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H342 - H347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. A. Jenkins, C. W. C. Kendall, A. R. Josse, S. Salvatore, F. Brighenti, L. S. A. Augustin, P. R. Ellis, E. Vidgen, and A. V. Rao Almonds Decrease Postprandial Glycemia, Insulinemia, and Oxidative Damage in Healthy Individuals J. Nutr., December 1, 2006; 136(12): 2987 - 2992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Caramori, Y. Kim, P. Fioretto, C. Huang, S. S. Rich, M. E. Miller, G. B. Russell, and M. Mauer Cellular basis of diabetic nephropathy: IV Antioxidant enzyme mRNA expression levels in skin fibroblasts of type 1 diabetic sibling pairs Nephrol. Dial. Transplant., November 1, 2006; 21(11): 3122 - 3126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Willsky, L.-H. Chi, Y. Liang, D. P. Gaile, Z. Hu, and D. C. Crans Diabetes-altered gene expression in rat skeletal muscle corrected by oral administration of vanadyl sulfate Physiol Genomics, September 14, 2006; 26(3): 192 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M Marshall and A. Flyvbjerg Prevention and early detection of vascular complications of diabetes. BMJ, September 2, 2006; 333(7566): 475 - 480. [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Schramm, T. Dinh, and A. Veves Microvascular changes in the diabetic foot. International Journal of Lower Extremity Wounds, September 1, 2006; 5(3): 149 - 159. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Puricelli, E. Iori, R. Millioni, G. Arrigoni, P. James, M. Vedovato, and P. Tessari Proteome Analysis of Cultured Fibroblasts from Type 1 Diabetic Patients and Normal Subjects J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3507 - 3514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Proctor, T. Jiang, M. Iwahashi, Z. Wang, J. Li, and M. Levi Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes Diabetes, September 1, 2006; 55(9): 2502 - 2509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Marchetti, R. Menghini, S. Rizza, A. Vivanti, T. Feccia, D. Lauro, A. Fukamizu, R. Lauro, and M. Federici Benfotiamine Counteracts Glucose Toxicity Effects on Endothelial Progenitor Cell Differentiation via Akt/FoxO Signaling. Diabetes, August 1, 2006; 55(8): 2231 - 2237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Yi and N. Maeda {alpha}-Lipoic Acid Prevents the Increase in Atherosclerosis Induced by Diabetes in Apolipoprotein E-Deficient Mice Fed High-Fat/Low-Cholesterol Diet. Diabetes, August 1, 2006; 55(8): 2238 - 2244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Musso, E. Javor, E. Cochran, J. E Balow, and P. Gorden Spectrum of Renal Diseases Associated with Extreme Forms of Insulin Resistance Clin. J. Am. Soc. Nephrol., July 1, 2006; 1(4): 616 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. K. Campbell and D. Baker Getting Past the Sticker Shock of Drugs DOC News, June 1, 2006; 3(6): 4 - 4. [Full Text] [PDF]
|
|
|
|
|
|
C. Huang, Y. Kim, M. L. Caramori, J. H. Moore, S. S. Rich, J. C. Mychaleckyj, P. C. Walker, and M. Mauer Diabetic Nephropathy Is Associated With Gene Expression Levels of Oxidative Phosphorylation and Related Pathways Diabetes, June 1, 2006; 55(6): 1826 - 1831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ouedraogo, X. Wu, S.-Q. Xu, L. Fuchsel, H. Motoshima, K. Mahadev, K. Hough, R. Scalia, and B. J. Goldstein Adiponectin Suppression of High-Glucose-Induced Reactive Oxygen Species in Vascular Endothelial Cells: Evidence for Involvement of a cAMP Signaling Pathway Diabetes, June 1, 2006; 55(6): 1840 - 1846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Yang, A. D. Hodgkinson, P. J. Oates, H. M. Kwon, B. A. Millward, and A. G. Demaine Elevated activity of transcription factor nuclear factor of activated T-cells 5 (NFAT5) and diabetic nephropathy. Diabetes, May 1, 2006; 55(5): 1450 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
|