Diabetes Mellitus Glucose

Type 2 diabetes mellitus is a heterogenous syndrome with polygenic origin. Type 2 diabetes mellitus involves both defective insulin secretion and peripheral insulin resistance (1). There is a progressive deterioration in β-cell function over time regardless of the type of therapy. Pancreatic islets are found to be at 50% of normal functional capacity at time of diagnosis; reduction in function is generally found 10 to 12 years before diagnosis (2). Cases of diabetes mellitus 2 are increasing in the developed world; the center for disease control and prevention has characterized this increase as an epidemic (3). Currently interventions to treat type 2 diabetes include insulin therapy of newly diagnosed, selective activation of ATP sensitive K+ channels using drugs such as diazoxide, and the use of anti-apoptotic drugs such as thiazolidinediones.

Glucotoxicity and Lipotoxicity

Glucose is the key physiological regulator of insulin secretion. Adverse effects of chronic hyperglycemia encompass three characteristics: glucose desensitization, β-cell exhaustion, and glucotoxicity. Glucose desensitization refers to rapid and reversible refractoriness of β-cell secretion that occurs after short exposure to elevated glucose (4). β-cell exhaustion refers to the depletion of intracellular insulin storage after prolonged exposure of β-cell to various secretagogue (5). Considerable evidence from previous studies suggests that chronic hyperglycemia impairs glucose-induced-insulin secretion (GSIS) and insulin gene expression; this condition can be defined by the term glucotoxicity (6). Impairment of insulin gene expression includes the down regulation of two β-cell cell transcription factor pancreatic duodenum homeobox-1 (7) and the activator of the rat insulin promoter element 3b1 (8). There also appears to be an increase in insulin gene transcriptional repressor CCAAT/enhancer binding protein (9). Mechanisms of glucotoxicity also involves the generation of oxidative stress. In vitro experiment show that islets chronically exposed to elevated glucose level have impaired β-cell function and increased apoptosis, which can be prevented by the use of N-acetyle-cysteine (NAC), an antioxidant (10). In an in vivo model, treatment of Zucker diabetic fatty rats with NAC also normalized plasma glucose levels and restored insulin secretion (11). In a study involving islets isolated from 13 DM2 patients, Del Guerra and colleagues demonstrated that markers of oxidative stress such as nitrotyrosine and 8-hydroxy-2-deoxyguanosine concentration were significantly higher in DM2 than control islets (12).

More than 80% of type 2 diabetic individuals are obese; these individuals often have elevated levels of plasma free fatty acids because of expanded and more lipolytically active adipose tissue stores (13). Free fatty acids are essential fuel of β-cell in normal conditions and are deleterious when chronically present at elevated levels. Mild elevation in FFA plays an important role in sustaining normal insulin secretion. However, excessive FFA can induce β-cell apoptosis both in vitro and in ZDF rat islets (15). Exposure of cultured human islets to palmitate is also highly toxic and induces β-cell apoptosis, decreased β-cell proliferation, and function (16). However, it has been suggested that a precondition for lipotoxicity may be hyperglycemia. Poitout and colleagues demonstrates that normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, while normalization of plasma lipid level has no effect. The group also showed prolonged in vitro exposure of isolated islets to fatty acids decrease insulin gene expression only in the presence of high glucose concentration (1).

Liptoxicity and Oxidative Stress

Various clinical studies demonstrate that patients with type 2 diabetes are subjected to chronic oxidative stress. Pro-oxidant markers for oxidative tissue damage such as 8-hydroxy-deoxyguanine, hydroperoxides, and 4-hydroxy-2-nonenal proteins are reported to be elevated in serum, plasma, white blood cells, and pancreatic biopsies of patients with type 2 diabetes (17). The islets themselves also seem to have the lowest intrinsic antioxidant capacity of any of the metabolic tissues. Islets contain relatively low activities of major antioxidant enzymes Cu/Zn superoxide dismutase, Mn superoxide dismutase, catalase, and glutathione peroxidase (18). One of the most important downstream effectors of oxidative stress is the IKK/NF-κB pathway. NF-κB/IkBα is activated by the phosphorylation of serine residues on IκBα by IKK. Phosphorylation of IκBα leads to its degradation by the 26S proteasome (19). Chronic levels of FFA cause peripheral and hepatic insulin resistance. Boden and colleagues shows FFA induced hepatic insulin resistance is associated with the activation of NF-κB pathway; a 6.4 fold increase in IKK activity, NF-κB (+73%) and a concomitant decrease (-50%) in IκBα abundance. The changes in IKK, IκBα, and NF-κB were accompanied by increase in hepatic expression of inflammatory cytokines such as IL-1β, TNF-α, and IL-6 (20). In an IKK-β knockout mice model, the inactivation of IKK-β also leads to the protection of fat induced skeletal muscle insulin signaling defects (21).

The compound salicylate has been shown to prevent the activation of NF-κB by inhibiting the activity of IKK-β (22). In light of this discovery, various studies have tried to demonstrate the effect of salicylate on preventing peripheral and hepatic insulin resistance caused by elevated FFA. Salicylate has been shown to prevent lipid induced skeletal muscle insulin resistance and hepatic insulin resistance (21). Yuan and colleagues were also able to demonstrate that high doses of salicylates were able to reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Even a 50% reduction in IKK-β activity significantly improves in vivo glucose and lipid metabolism (23).

While the effect of prolonged exposure to FFA and peripheral insulin resistance has been studied in depth and has reached a consensus, there is much need for the study of prolonged elevated FFA exposure on β-cell function and insulin signaling cascade. Acute increase in FFA increases insulin secretion in vitro and in vivo; but the prolonged effect of FFA on GSIS in vivo is very controversial. In lean healthy subjects a 24 hour to 48 hour lipid infusion has been reported to increase, not significantly change, or decrease insulin secretion. In obese insulin resistant individuals a 48 hour lipid infusion has been reported to reduce insulin secretion by 20%, but there is also a 50% increase in plasma insulin concentration. In people with type 2 diabetes a 48 hour lipid infusion did not appear to further decrease insulin secretion (24). Despite these contradictions, there is mounting evidence that suggests prolonged exposure in FFA does indeed decrease β-cell function in individuals predisposed to diabetes. Hence the goal of the current project is to understand the mechanism of lipotoxicity on β-cell function, insulin signaling, GSIS in vitro and in vivo and to demonstrate the effect of inhibiting IKK on β-cell function

HMB 499Y Literature Review

Diabetes Mellitus 2 and Mechanisms of Liptoxicity

References:

1. Poitout V, Robertson R. 2002. Secondary β-cell failure in type 2 diabetes a convergence of glucotoxicity and lipotoxicity. Endocrinology 143:339-342

2. Wajchenberg B. 2007. β-cell failure in diabetes and preservation by clinical treatment. Endocrine Reviews 28:187-218

3. Gerberding, Louise J. 2007. Diabetes, Disabling Disease to Double by 2050, CDC, http://www.cdc.gov/nccdphp/publications/aag/ddt.htm. Retrieved on February 8^th 2008

4. Kilpatrick E, Robertson R. 1998. Differentiation between glucose-induced desensitization of insulin secretion and β-cell exhaustion in the HIT-T15 cell line. Diabetes 47:606-611

5. Leahy J, Bumbalo L, Chen C. 1994. Diazoxide cause recovery of β-cell glucose responsiveness in 90% pancreatectomized diabetic rats. Diabetes 43:173-179

6. Robertson R, Harmon J, Tran P, Tanaka Y, Takahashi H. 2003. Glucotoxicity in β-cell: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52:581-587

7. Olson L, Redmon J, Towle H, Robertson R. 1993. Chronic exposure of HIT cells to high glucose concentration paradoxically decreases insulin gene transcription and alters binding of insulin gene regulator protein. J Clin Invest 92:514-519

8. Sharma A, Olson L, Robertson R, Stein R. 1995. The reduction of insulin gene transcription in HIT-T15 β-cell chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression. Mol Endocrinol 9:1127-1134

9. Lu M, Seufert J, Habener J. 1997. Pancreatic β-cell specific repression of insulin gene transcription by CCAAT/enhancer binding protein β. Inhibitory interactions with basic helix-loop-helix transcription factor E47. J Biol Chem 272:28349-28359

10. Tajiri Y, Moller C, Grill V. 1997 Long term effects of aminoguanidine on insulin release and biosynthesis: evidence that the formation of advanced glycosylation end products inhibits β-cell function. Endocrinology 138:273-280

11. Tanaka Y, Gleason C, Tran P, Harmon J, Robertson R. 1999. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 96:10857-10862

12. Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, SbranaS, Torri S, Polera M, Boggi U, Mosca F, Del Prato S, Marchetti P. 2005. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54:727-735

13. Goh T, Mason T, Gupta N, So A, Lam T, Lam L, Lewis G, Mari A, Giacca A. 2006. Lipid induced β-cell dysfunction in vivo in models of progressive β-cell failure. Am J Physiol Endocrinol Metab 292:E549-E560

14. Gremlich S, Bonny C, Waeber G, thorens B. 1997. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem 272:30261-30269

15. Shimabukuro M, Higa M, Zhou Y, Wang M, Newgard C, Unger R. 1998. Lipoapoptosis in β-cell of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 273:32487-32490

16. Maedler K, Oberholzer J, Bucher P, Spinas GA, Donath MY. 2003. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic β-cell turnover and function. Diabetes 52:726-733

17. Robertson R, Harmon J, Tran P, Poitout V. 2004. β-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53:S119-S124

18. Grankvist K, Marklund S, Taljedal I. 1981. CuZn-Superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 199:393-398

19. Kumar A, Takada Y, Boriek A, Aggarwa B. 2004. Nuclear factor - kB: its role in health and disease. J Mol Med 82:434-448

20. Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, Xiang X, Luo Z, Ruderman N. 2005. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kB pathway in rat liver. Diabetes 53:3458-3465

21. Kim J, Kim Y, Fillmore J, Chen Y, Moore I, Lee J, Yuan M, Li Z, Karin M, Perret P, Shoelson S, Shulman G. 2001. Prevention of fat-induced insulin resistance by salicylate. The Journal of clinical investigation 108:437-446

22. Kim J, Wi J, Youn J. 1996. Plasma free fatty acids decrease insulin stimulated skeletal muscle glucose uptake by suppressing glycolysis in conscious rats. Diabetes 45:446-453

23. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li Z, Karin M, Shoelson S. 2001. Reversal of obesity and diet induced insulin resistance with salicylates or targeted disruption of IKKβ. Science 293:1673-1677

24. Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cust K. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52:2461-2474