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THE ROLE OF SUPPLEMENT THERAPY FOR TYPE 2 DIABETES PATIENTS

Focus on antioxidantMakbul Aman MansyurDivision of Endocrine and Metabolism Department of Internal Medicine Faculty of Medicine Hasanuddin University / RS. Dr. Wahidin Sudirohusodo Makassar

Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 2012)DIABETES DEFINITION Long-term damage, dysfunction, and failure of various organs especially the eyes, kidneys, nerves, heart, and blood vessels 2

2000171 million1

2035552 million2

2011366 million2Wild. Diabetes Care. 2004. 27:1047-1053.International Diabetes Federation. IDF Diabetes Atlas. Fifth Edition. 2011

In the first edition of the IDF Diabetes Atlas, released in 2000, the estimated global diabetes prevalence was 151 million. In the newest 5th edition, the estimated diabetes prevalence for 2011 has risen to 366 million, representing 8.3% of the worlds adult population, with a prediction that by 2030 the number of people with diabetes will have risen to 552 million. 3Country/Territory2013MillionsCountry/Territory2035MillionsChina98.4China142.7India65.1India109.0United States of America24.4United States of America29.7Brazil11.9Brazil19.2Russian Federation10.9Mexico15.7Mexico8.7Indonesia14.1Indonesia8.5Egypt13.1Germany7.6Pakistan12.8Egypt7.5Turkey11.8Japan7.2Russian Federation11.2Diabetes is one of the major healthcare burden in IndonesiaIDF Diabetes Atlas 6th edition. @International Diabetes Federation65%IN JUST 22 YEARS5DiabeticRetinopathyLeading causeof blindnessin adultsDiabeticNephropathyLeading cause of end-stage renal diseaseCardiovascularDiseaseStroke2- to 4-fold increase in cardiovascular mortality and strokeDiabeticNeuropathyLeading cause ofnon-traumatic lower extremity amputations8/10 individuals with diabetes die from CV events

UK Prospective Diabetes Study Group. Diab Res 1990; 13: 111. Fong DS, et al. Diab Care 2003; 26 (Suppl. 1): S99S102. Molitch ME, et al. Diab Care 2003; 26 (Suppl. 1): S94S98. Type 2 Diabetes is Associated WithSerious Complications13Every 6 seconds a person dies from diabetes related complications5Goal: To highlight that serious micro- and macrovascular complications of T2DM have a devastating effect on quality of life and impose a heavy burden on healthcare systems.

Main Message: In the UKPDS, 50% of individuals with diabetes already had complications at diagnosis.1 Early detection and treatment of diabetes is essential in order to reduce the impact of its serious complications.

Speaker Notes:Diabetic retinopathy: present in 21% of people at the time T2DM is diagnosed,2 diabetic retinopathy is the leading cause of new blindness among adults aged 2074 years.3 Diabetic nephropathy: present in 18% of people diagnosed with diabetes;4 diabetes is a leading cause of end-stage renal disease.5Stroke: diabetes is associated with a 2- to 4-fold increase in CV mortality and stroke.6 Cardiovascular disease: 75% of individuals with T2DM die from CV causes.7Diabetic neuropathy: present in 12% of people at diagnosis,2 diabetic neuropathy affects approximately 70% of people with diabetes8 and is a leading cause of non-traumatic lower extremity amputations.9Source:1 UKPDS Group. Diabetologia 1991; 34: 877890. 2 UK Prospective Diabetes Study Group. Diabetes Res 1990; 13: 111. 3 Fong DS, et al. Diab Care 2003; 26 (Suppl. 1): S99S102. 4 The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309317.5 Molitch ME, et al. Diab Care 2003; 26 (Suppl. 1): S94S98. 6 Kannel WB, et al. Am Heart J 1990; 120: 672676. 7 Gray RP, Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences.8 Kings Fund. Counting the cost. The real impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996. 9 Mayfield JA, et al. Diab Care 2003; 26 (Suppl. 1): S78S79.Hyperglycemia in diabetic patients lead, via several mechanisms (glucose autooxidation, stimulation of the polyol pathway, imbalance in amounts and ratios of reduced to oxidized forms of redox coenzymes, and formation of advanced glycation end products) to multiple biochemical sequalae aimed to an increase production of reactive oxygen species (ROS).

Diabeticsincreased metabolic processes that produce reactive oxygen species (ROS)ROS serve as signaling mechanisms mediate many of the functional & structural vascular abnormalities observed in diabeticsHow do complications occur?EuglycemiamitochondriaATPROS (superoxide)Polyol pathwayAGE pathwayHyperglycemia, Mitochondrial Dysfunction and Diabetic ComplicationHyperglycemiaMitochondrial dysfunctionDiabetic Vascular ComplicationHexosamine pathwayProtein kinase C pathway7Mitochondrial Function :Generating ATP in normal ConditionComplex INADHdehydrogenaseComplex IIsuccinatedehydrogenaseComplex IIIcytochromereductaseComplex IVcytochromeoxidaseUCPComplex V(ATP synthase)F0F1Innermitochondrial membraneMatrixIntermembrane spaceADPATPH+CoQ10

8The mitochondrion is one of the most powerful generators of ROS within cell. In this organelle, the electron deficient dioxygen molecule (O2) is brought close to electron supplier (respiratory chain). A dysfunction in at one step of this respiratory chain may thus result in massive production of ROS (ex : Q10 deficiency).In Normal condition, In the process of energy metabolism pathway , molecule oxygen is essential for the complete metabolisme during ATP production. Even in normal condition, about 04-4% Oxygen is coverted in ROS. But this ROS normally eliminated by antioxidant defense. In abnormal condition (mitochondrial dysfunction), the small quantity of mitochondrial antioxidant would not enough to scavanging this ROS. IN this Situation, Q10 may an alternative option since the molecule act as endogenous antioxidantChapter Twenty One

Carbohydrates, lipids, and proteins are sources of energy for the bodyEnergy is stored in the electrons associated with C-H bondsLipids contain the most of these bonds per gram and so have the highest number of CaloriesA food Calorie contains sufficient energy to elevate 1 liter of water by 1 degree Celsius Energy from foods is converted to ATP: Cell energySources of energy

produce ATP

5 respiration enzyme complexes

1. Complex I: NADH dehydrogenase Transfers e- from NADH to quinone pool & pumps H+.2. Complex II: succinate dehydrogenase Transfers e- from succinate to quinone pool3. Complex III: cytochrome reductase Transfers e- from quinol to cytochrome c & pumps H+.4. Complex IV: cytochrome oxidase Accepts e- from cytochrome c, reduces O2 to H2O & pumps H+. 5. Complex V: (ATP synthase) Harvests H+ gradient & regenerates ATP..Role of mitochondriaEnergy generating metabolismin mitochondriaIn DiabetesUNCOUPLED Electron Transport andOXPHOS in Diabetes (ROS generation and Reduce ATP)(Miller 1998)ComplexIIComplexIII CoQComplexVCytCSuccinateFumazateH+2H+ O2H2O2H+2H+4H+2H+3H+MatrixATPSynthaseComplexIVComplexVIntermembraneSpaceMitochondrialinnermembraneee + O` O2 H2O2 (OH) and ONOOComplexINADHNAD+ee3H+ADP + P1 ATP + H2OROS Hyperglycemia-induced production of superoxide by the mitochondrial electron transport chain.Polyol pathwayNADPH GSH Cell injury Diabetic Vascular injury ROSCytokines & Growth Factor C IL-1, IGF-1, TNF-, MCSF,TGF-, VICAM-1, VEGFProtein Modification Matrix Modification AGES ActivationPKC eNOS Endotheli-1 VEGF, TGF-, PAI-1 NFB NADPH OxidaseHyperglycemiaHexosaminepathway Fructose-6- Phosphate TGF- PAI-1Mitochondrial Dysfunction : Excessive ROS ProductionFree radicals (reactive oxygen species) are known to fuel diabetic vascular complicationsPhysiopathology of diabetic complications1212Excess Free Radicals Arethe Enemies of Human HealthExcess free radicals can cause oxidative damages to:Excess Free radicals can contribute to diseases:Aging, Heart disease, Cancer, Inflammatory-immune injuries, Rheumatoid Arthritis, Diabetes, AIDS, Lupus, Alzheimers disease, Adult Respiratory Distress Syndrome and more

Lipid peroxidation membrane damage Protein damage inactivation of enzimesDNA damage block DNA transcription and cause mutations.Oxidative StressWhat Should You Know?Oxygen is critical for life: respiration and energyOxygen is also implicated in many disease processes. The dangerous form of oxygen is from the formation of free radicals or reactive oxygen species, or pro-oxidants (superoxide anion, hydroxyl radical, hydrogen peroxide)If excess free radicals exist in the human body, oxidative damage occurs

Oxidative Stress = Imbalance between pro-oxidants (free radicals, reactive oxygen species) and anti-oxidants14Antioxidant:An Agent that prevents or inhibits oxidation.

Antioxidants are substances or nutrients in our foods which can slow or prevent the damaging effects of oxygen radicals, highly reactive chemicals that play a part in atherosclerosis, some forms of cancer, and reperfusion injuries

A NEW THERAPEUTIC APPROACH: THE CAUSAL ANTIOXIDANT THERAPYInterrupting the overproduction of O2 - by the mitochondrial electron-transport chain would normalize the pathways involved in the development of diabetic complications.even optimal control of blood glucose could not prevent complications suggesting that alternative treatment strategies are needed.The Diabetes Control and Complications trial N Engl J Med 1993,329(14):977-986.

ExogenousAntioxidants

EndogenousAntioxidants

(from food)(made in body)

Antioxidants in the Management of Diabetes.

17Coenzyme Q10: UbiquinoneCoQ10 is a fat-soluble compound synthesized by the body and also consumed in the dietEndogenous synthesis decreases after age 20. Believed to fall off rapidly in middle age, accelerating the aging processCoQ10 is required for energy production and as antioxidantExercise increases catabolism of and need for CoQ10Disease or other stress impairs intake and absorption of the substrate

is an essential cofactor (an endogenously synthesized compound) that acts as an electron carrier in the mitochondrial electron transport chain and is necessary for ATP production.Brownlee et al reported that this is the site of O2- generation under hyperglycemic condition. Functions of Coenzyme Q10: Antioxidant

50 times more antioxidant power than Vitamin E neutralize free-radical an effective lipid-soluble antioxidant continuously go through an oxidation-reduction state hold electrons loosely in its reduced form regenerate -tocopherol from the -tocopheroxyl radical. interact with dihydrolipoic acid. Dihydrolipoic acid reduces ubiquinone to ubiquinol inhibit lipid peroxidation occurs when cell membranes and low-density lipoproteins (LDL) are oxidized ex vivoMay prevent signs of skin aging

19CoQ10 and Type 2 Diabetes and Insulin ResistanceSingh et al, 1999. oral treatment with coenzyme Q10 60 mg twice daily 8 weeks The patients receiving coenzyme Q10 had reduced plasma levels of insulin and glucose.Hodgson et al. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 DM (Eur J Clin Nutr. 2002). oral dose of 100mg CoQ twice daily for 12 weeks.

The effects of oral treatment with coenzyme Q10 (60 mg twice daily) were examined in a randomized, double-blind trial of 30 patients with coronary heart disease. After 8 weeks of treatment, the patients receiving coenzyme Q10 had reduced plasma levels of insulin (fasting and 2-hr), glucose

CoQ10 is a lipid soluble antioxidantIn higher concentrations, it scavenges O2- Improves endothelial dysfunction in diabetes.

Hodgson et al. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 DM (Eur J Clin Nutr. 2002). oral dose of 100mg CoQ twice daily for 12 weeks.Watts et al. Coenzyme Q10 improves endothelial dysfunction of the brachial artery in Type2 (Diabetologia 2002).Singh et al. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease (J Hum Hypertens. 1999 ) the oral treatment with Q10 (60 mg twice d) for 8 weeks

Thomas et al. Cosupplementation With Coenzyme Q Prevents the Prooxidant Effect of -Tocopherol and Increases the Resistance of LDL to Transition MetalDependent Oxidation Initiation . (Arterioscler Thromb Vasc Biol. 1996).Burke et al. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension (South Med. J 2001) 12-week with twice daily 60 mg of oral

Human body, only produce small amount of ALASource from the diet also limited. Consumption of ALA from food has not yet been found in detectable increase in ALA human plasma Powerful antioxidant In lipid and water phase and may cycle GSHClinically effective in hyperglycemia A Dietary Factor that Potentially Improves Antioxidant DefensesROSSafe CompoundROS Scavenger-lipoic acidan essential cofactor for several mitochondrial enzyme complexes (PDH) that catalyze critical reactions related to energy production

222223Alpha Lipoic Acid - An anti-oxidant 400 times stronger than Vitamin "C" or "E". Considered the universal anti-oxidant because it is both fat and water-solubleStrong antioxidant protection and enhanced antioxidant recyclingEnhanced biological energy production also an effective anti-inflammatory.Protects against CVDClinically effective in hyperglycemia Claims that lipoic acid slows aging of the brain and has anti-aging benefits seem to be related to is potent antioxidant properties

-lipoic acidThe defence against oxidative stress by increasing the synthesis of anti-oxidants like glutathione.Directly scavenge ROS and RNS.With Dihydrolipoic acid (DHLA), regenerate endogenous antioxidants: glutathione, coenzyme Q10, vitC, vitE

-lipoic acidROLE IN SIGNAL TRANSDUCTIONActivates insulin receptors, leads to a cascade of substrate phosphorylation that causes the translocation of glucose transporters.Involved in the regulation of the NF-kB and Akt signaling pathways. Rudich et al. Diabetologia 1999..

ALA is also involved in the regulation of the nuclear factor-kappa B (NF-kB) and Akt signaling pathways [24].NF-kB has been shown to regulate genes related to inflammationand cell cycle control, which have been implicated inthe development of atherosclerosis, insulin resistance, pancreatic cell cycle and even increasing chemosensitivity ofmitotic lesions [25]. Results of cell line studies have shownthat physiologic amounts of ALA inhibit NF-kB nucleartranslocation, thus preventing its downstream effects on targetgene expression [26]. ALA offers the potential for improvedmolecular therapeutic strategies.TREATMENT OF DIABETIC NEUROPATHYSeveral studies have demonstrated the benefits of ALA in symptomatic polyneuropathy and improve neuropathic deficits.Ziegler, et al1995; Ziegler, et al1999, Reljanovic et al, 1999; Ruhnau et al, 1999; Ametov et al, 2003; Ziegler, et al 2006. TREATMENT OF INSULIN RESISTANCEALA has shown therapeutic potential in the area of insulin resistance.

Jacob et al,1995; Jacob et al,1999; Kamenova, 2006; Midaoui and Jacques de Champlain, 2002; Karen and William, 2002; Timmers et al; 2010.

L-CarnitineCarnitine is known as avitamin like and amino acid like substance facilitate transport of long-chain fatty acids across the inner mitochondrial membrane for -oxidation, promoting energy availability and preventing toxic accumulation of long-chain fatty acids. Mingrone,1999Carnitine transports FA inside the mitochondria where they are burnt to produce energy (-oxidation)Carnitine-deficiency hypoglycemia due to reduced gluconeogenesis resulting from impaired fatty acid oxidation, resulting in muscle weakness (Reye's syndrome)..

Carnitin: Fatty acid trasporter to mitochondriaCarnitine, is a quaternary amine (-hydroxy--N-trimethyammonium butyric acid-M.W. 161.2), and is known as a vitamin like and amino acid like substance.1 Synthetic carnitine occurs as both D & L isomers; however, only Lcarnitine is physiologically active. The main function of carnitine in the body is facilitation lipid oxidation by transporting long-chain fatty acids into the inner mitochondria region where they undergo -oxidation.2 In order for fattyacids (from food intake or adipose tissue) to produce energy they must be changed into acylCoAs prior to -oxidation; however, since acylCoAs can not cross cell walls, carnitine comes into place to help with the transportation through the mitochondrial wall.3 Therefore, without carnitine, most of the dietary lipids cannot be used as an energy source and our body would accumulate fatty-acids resulting in obesity. In humans, carnitine is absorbed in the small intestinalmucosa by sodium-dependent active transport and by passive transpoet.4 In blood, carnitine does not need protein for a carrier, and is present in the free or acylcarniitne form. Carnitine and its short-chain esters facilitate transport of long-chain fatty acids across the inner mitochondrial membrane for -oxidation, promoting energy availability and preventing toxic accumulation of long-chain fatty acids.Mechanism of action of L-acetyl carnitine, which, through the esterification of its alcoholic groups with acetyl-CoA. Mingrone,1999

Intracellular superoxide scavenger, which is associated with a reduction in xanthine oxidase activity and known to possess free radical scavenging activity, improving mitochondrial function reducing DNA damage.Di Giacomo etal. Neurochem Res 1993; Vanella et al. Cell Bil Toxicol,2000.L-CarnitineAcetyl-L-carnitine (ALC) is deficient in DM.Scarpini et al. , J Peripher Nerv Syst 1:157163, 1996Ido et al. Diabetes 43:14691477, 1994 Carnitine may improve insulin sensitivity in diabetic resistant insulinMingron, J Am Coll Nutri. 1999Di Giacomo C, Latteri F, Fichera C, Sorrenti V, Campisi A, CastorinaC, Russo A, Pinturo R, Vanella A: Effect of acetyl-L-carnitine onlipid peroxidation and xanthine oxidase activity in rat skeletalmuscle. Neurochem Res 1993, 18(11):1157-1162.Vanella A, Russo A, Acquaviva R, Campisi A, Di Giacomo C, SorrentiV, Barcellona ML: L -propionyl-carnitine as superoxide scavenger,antioxidant, and DNA cleavage protector. Cell Biol Toxicol2000, 16(2):99-104

TREATMENT OF DIABETIC NEUROPATHYl-Carnitine in the treatment of painful diabetic neuropathy and its effect on plasma -endorphin levels. Cakir et al. Current Therapeutic Research. 2000.Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. 52-week ALC: 500 and 1,000 mg/day t.i.d. Sima et al. Diabetes Care, 2005. Effect of L-carnitine on diabetic neuropathy and ventricular dispersion in patients with diabetes mellitus. LC 2 g/day for 10 months. Hizir et al. Turk J Med Sci 2010.

Effect of L-carnitine on diabetic neuropathy and ventricular dispersion in patients with diabetes mellitus. Hizir et al. Turk J Med Sci2010; 40 (2): 169-175

decrease oxidative stress and improve endothelial cell functioningEffects of L-carnitine treatment on oxidant/antioxidant state and vascular reactivity of streptozotocin-diabetic rat aorta.Irat et al.J Pharm Pharmacol2003.Effects of carnitine supplementation on flow-mediated dilation and vascular inflammatory responses to a high-fat meal in healthy young adults. 3 weeks 2 g/day Volek et al. Am J Cardiol.2008. Effect of oral acetyl L-carnitine arginate on resting and postprandial blood biomarkers in pre-diabetics. 3g/d 8 weeks. Bloomer et al., Nutrition & Metabolism 2009.

L-Carnitine Improves Glucose Disposal in Type 2 Diabetic Patients. infusion of L-carnitine (0.28 mmole/kg bw/mnt 2 hr. Mingrone etal., Journal of the American College of Nutrition, 1999Ameliorating Hypertension and Insulin Resistance in Subjects at Increased Cardiovascular Risk Effects of Acetyl-L-Carnitine Therapy. Ruggenenti etal,. Hypertension. 2009. improves insulin sensitivity in insulin resistant diabetic patientsJ Pharm Pharmacol.2003 Oct;55(10):1389-95.Effects of L-carnitine treatment on oxidant/antioxidant state and vascular reactivity of streptozotocin-diabetic rat aorta.Irat AM,Aktan F,Ozansoy G.Am J Cardiol.2008 Nov 15;102(10):1413-7. doi: 10.1016/j.amjcard.2008.07.022. Epub 2008 Sep 11.Effects of carnitine supplementation on flow-mediated dilation and vascular inflammatory responses to a high-fat meal in healthy young adults.Volek JS Effect of oral acetyl L-carnitine arginate on resting and postprandial blood biomarkers in pre-diabetics. 3g/d 8 weeksNutrition & Metabolism 2009, 6:25

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Working together to fight and improve diabetes symptoms and prevent complications Alpha Lipoid Acid Functions as a co-enzyme in carbohydrate metabolism, Increases number or activation of GLUTs and Slows the development of diabetic neuropathy and recycling an antioxidant Ubiquinone Boost energy, enhances immune system and an anti oxidant, serves as a coenzyme for several of the key enzymatic steps in production of energy, lower blood pressure, prevent atherosclerosis L- Carnitine: Helps in oxidation of fatty acids, role in oxidative phosphorylation. Carnitine may improve insulin sensitivity in diabetic resistant insulin, body weight lossand It may improve diabetic neuropathy.The Three Musketeers

Take Home Message Hyperglycemia induce Diabetic Complication through excessive ROS generation (Mitochondrial dysfunction) Modifying Diabetes should be done for Hba1c treatment and endothelial monitoring to reduce risk of CVDCausal antioxidant therapy, Coenzim Q10, L-carnitine and -lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good for such a strategy.

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