Top

Diabetologia

Published in:

01-07-2006 | Article

α-Lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells

Authors: E. D. Targonsky, F. Dai, V. Koshkin, G. T. Karaman, A. V. Gyulkhandanyan, Y. Zhang, C. B. Chan, M. B. Wheeler

Published in: Diabetologia | Issue 7/2006

Abstract

Aims/hypothesis

The antioxidant compound α-lipoic acid (α-LA) possesses antidiabetic and anti-obesity properties. In the hypothalamus, α-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK). Given the therapeutic potential of α-LA for the treatment of type 2 diabetes and obesity, and the importance of AMPK in beta cells, we examined the effect of α-LA on pancreatic beta cell function.

Materials and methods

Isolated rat islets and MIN6 beta cells were treated acutely (15–90 min) or chronically (18–24 h) with α-LA or the known AMPK-activating compounds 5′-amino-imidazole-4-carboxamide ribonucleoside (AICAR) and metformin. Insulin secretion, the AMPK-signalling pathway, mitochondrial function and cell growth were assessed.

Results

Acute or chronic treatment of islets and MIN6 cells with α-LA led to dose-dependent rises in phosphorylation of the AMPK α-subunit and acetyl CoA carboxylase. Chronic exposure to α-LA, AICAR or metformin caused a reduction in insulin secretion. α-LA inhibited the p70 s6 kinase translational control pathway, and inhibited MIN6 growth in a manner similar to rapamycin. Unlike AICAR and metformin, α-LA also acutely inhibited insulin secretion. Examination of the effect of α-LA on mitochondrial function showed that acute treatment with this compound elevated reactive oxygen species (ROS) production and enhanced mitochondrial depolarisation induced by Ca²⁺.

Conclusions/interpretation

This study is the first to demonstrate that α-LA directly affects beta cell function. The chronic effects of α-LA include AMPK activation and reductions in insulin secretion and content, and cell growth. Acutely, α-LA also inhibits insulin secretion, an effect probably involving the ROS-induced impairment of mitochondrial function.

Lovell MA, Xie C, Xiong S, Markesbery WR (2003) Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. J Alzheimers Dis 5:229–239PubMed

Piotrowski P, Wierzbicka K, Smialek M (2001) Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. Folia Neuropathol 39:147–154PubMed

Mervaala E, Finckenberg P, Lapatto R et al (2003) Lipoic acid supplementation prevents angiotensin II-induced renal injury. Kidney Int 64:501–508PubMedCrossRef

Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J (2003) Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production. Am J Hypertens 16:173–179PubMedCrossRef

Bitar MS, Wahid S, Pilcher CW, Al Saleh E, Al Mulla F (2004) Alpha-lipoic acid mitigates insulin resistance in Goto–Kakizaki rats. Horm Metab Res 36:542–549PubMedCrossRef

Khamaisi M, Potashnik R, Tirosh A et al (1997) Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats. Metabolism 46:763–768PubMedCrossRef

Konrad T, Vicini P, Kusterer K et al (1999) alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care 22:280–287PubMedCrossRef

Konrad D, Somwar R, Sweeney G et al (2001) The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes 50:1464–1471PubMedCrossRef

Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A (2000) Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia 43:294—303PubMedCrossRef

10.

Blumenthal SA (1984) Inhibition of gluconeogenesis in rat liver by lipoic acid. Evidence for more than one site of action. Biochem J 219:773—780PubMed

11.

Hardie DG (2004) The AMP-activated protein kinase pathway—new players upstream and downstream. J Cell Sci 117:5479–5487PubMedCrossRef

12.

Shaw RJ, Kosmatka M, Bardeesy N et al (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 101:3329–3335PubMedCrossRef

13.

Mu J, Brozinick JT Jr, Valladares O, Bucan M, Birnbaum MJ (2001) A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 7:1085–1094PubMedCrossRef

14.

Iglesias MA, Ye JM, Frangioudakis G et al (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51:2886–2894PubMedCrossRef

15.

Minokoshi Y, Kim YB, Peroni OD et al (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343PubMedCrossRef

16.

Yamauchi T, Kamon J, Minokoshi Y et al (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295PubMedCrossRef

17.

Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174PubMed

18.

Kim MS, Park JY, Namkoong C et al (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10:727–733PubMedCrossRef

19.

Salt IP, Johnson G, Ashcroft SJ, Hardie DG (1998) AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochem J 335:533–539PubMed

20.

Da Silva Xavier G, Leclerc I, Salt IP et al (2000) Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression. Proc Natl Acad Sci U S A 97:4023–4028PubMedCrossRef

21.

Da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, Rutter GA (2003) Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem J 371:761–774PubMedCrossRef

22.

Tsuboi T, Da Silva Xavier G, Leclerc I, Rutter GA (2003) 5′-AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics. J Biol Chem 278:52042–52051PubMedCrossRef

23.

Wang X, Li H, De Leo D et al (2004) Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic beta-cell line MIN6. Diabetes 53:129–140PubMedCrossRef

24.

Heron-Milhavet L, Haluzik M, Yakar S et al (2004) Muscle-specific overexpression of CD36 reverses the insulin resistance and diabetes of MKR mice. Endocrinology 145:4667–4676PubMedCrossRef

25.

Koshkin V, Bikopoulos G, Chan CB, Wheeler MB (2004) The characterization of mitochondrial permeability transition in clonal pancreatic beta-cells. Multiple modes and regulation. J Biol Chem 279:41368–41376PubMedCrossRef

26.

Leclerc I, Woltersdorf WW, Da Silva Xavier G et al (2004) Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab 286:E1023–E1031PubMedCrossRef

27.

Kefas BA, Cai Y, Kerckhofs K et al (2004) Metformin-induced stimulation of AMP-activated protein kinase in beta-cells impairs their glucose responsiveness and can lead to apoptosis. Biochem Pharmacol 68:409–416PubMedCrossRef

28.

Corton JM, Gillespie JG, Hawley SA, Hardie DG (1995) 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229:558–565PubMedCrossRef

29.

Scarlett JL, Sheard PW, Hughes G, Ledgerwood EC, Ku HH, Murphy MP (2000) Changes in mitochondrial membrane potential during staurosporine-induced apoptosis in Jurkat cells. FEBS Lett 475:267–272PubMedCrossRef

30.

Rowinsky EK (2004) Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 16:564–575PubMedCrossRef

31.

Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590PubMedCrossRef

32.

Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL (1995) Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature 377:441–446PubMedCrossRef

33.

Hara K, Yonezawa K, Kozlowski MT et al (1997) Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 272:26457–26463PubMedCrossRef

34.

Dicter N, Madar Z, Tirosh O (2002) Alpha-lipoic acid inhibits glycogen synthesis in rat soleus muscle via its oxidative activity and the uncoupling of mitochondria. J Nutr 132:3001–3006PubMed

35.

Maechler P, Wollheim CB (2001) Mitochondrial function in normal and diabetic beta-cells. Nature 414:807–812PubMedCrossRef

36.

Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa F (1999) Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 264:687–701PubMedCrossRef

37.

Saris NE, Karjalainen A, Teplova VV, Lindros KO (1998) The stimulation of the mitochondrial permeability transition by dihydrolipoate and alpha-lipoate. Biochem Mol Biol Int 44:127–134PubMed

38.

Lee WJ, Song KH, Koh EH et al (2005) Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun 332:885–891PubMedCrossRef

39.

Lee WJ, Lee IK, Kim HS et al (2005) Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arterioscler Thromb Vasc Biol 25:2488–2494PubMedCrossRef

40.

Richards SK, Parton LE, Leclerc I, Rutter GA, Smith RM (2005) Over-expression of AMP-activated protein kinase impairs pancreatic {beta}-cell function in vivo. J Endocrinol 187:225–235PubMedCrossRef

41.

Pende M, Kozma SC, Jaquet M et al (2000) Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice. Nature 408:994–997PubMedCrossRef

42.

Kneteman NM, Lakey JR, Wagner T, Finegood D (1996) The metabolic impact of rapamycin (sirolimus) in chronic canine islet graft recipients. Transplantation 61:1206–1210PubMedCrossRef

43.

Bell E, Cao X, Moibi JA et al (2003) Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets. Diabetes 52:2731–2739PubMedCrossRef

44.

Paty BW, Harmon JS, Marsh CL, Robertson RP (2002) Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets. Transplantation 73:353–357PubMedCrossRef

45.

Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205PubMedCrossRef

46.

Hawley SA, Pan DA, Mustard KJ et al (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2:9–19PubMedCrossRef

47.

Marchetti P, Del Guerra S, Marselli L et al (2004) Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 89:5535–5541PubMedCrossRef

48.

Yamashita T, Eto K, Okazaki Y et al (2004) Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta-cell lipotoxicity model overexpressing sterol regulatory element-binding protein-1c. Endocrinology 145:3566–3577PubMedCrossRef

Title: α-Lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells
Authors: E. D. Targonsky
F. Dai
V. Koshkin
G. T. Karaman
A. V. Gyulkhandanyan
Y. Zhang
C. B. Chan
M. B. Wheeler
Publication date: 01-07-2006
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 7/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0265-9

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

α-Lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells

Abstract

Aims/hypothesis

Materials and methods

Results

Conclusions/interpretation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Aims/hypothesis

Materials and methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 7/2006

Antipsychotic drugs and diabetes—an application of the Austin Bradford Hill criteria

Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes

Common variants in MODY genes increase the risk of gestational diabetes mellitus

PEGylated glucagon-like peptide-1 displays preserved effects on insulin release in isolated pancreatic islets and improved biological activity in db/db mice

Correlates of health-related quality of life in type 2 diabetes

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page