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Si usted tiene un mayor riesgo de desarrollar diabetes tipo 2, en el futuro puede ser debido a la composicion de la flora intestinal. La diabetes es un trastorno metabolico incurable, en la que el organismo es incapaz de obtener suficiente energia de los azucares. Teniendo en cuenta el importante impacto de la microbiota intestinal en las enfermedades humanas, como la diabetes tipo 2, numerosos investigadores se han centrado en conocer detalles del microbioma intestinal con el fin de entender plenamente sus caracteristicas moleculares y usando esto para beneficio de la salud humana. Este estudio indica las caracteristicas tipicas de la flora intestinal de los pacientes con diabetes tipo 2. En general, los investigadores encontraron que los individuos sanos tenian tipicamente un mayor numero de bacterias productoras de butirato, por lo que los investigadores tienen la teoria que puede desempenar un papel protector frente a varios tipos de enfermedades.Tambien en los pacientes con diabetes tipo 2, se registro un aumento en el numero de, patogenos oportunistas. Este trabajo establece una base importante para la comprension exhaustiva de las caracteristicas geneticas de la microbiota intestinal y su relacion con el riesgo de tener diabetes tipo 2, asi como proporcionar una nueva forma de clasificar los microbios detectados por secuenciacion masiva. Junjie Qin, Yingrui Li, Zhiming Cai, Shenghui Li, Jianfeng Zhu, Fan Zhang, Suisha Liang, Wenwei Zhang, Yuanlin Guan, Dongqian Shen, Yangqing Peng, Dongya Zhang, Zhuye Jie, Wenxian Wu, Youwen Qin, Wenbin Xue, Junhua Li, Lingchuan Han, Donghui Lu, Peixian Wu, Yali Dai, Xiaojuan Sun, Zesong Li, Aifa Tang, Shilong Zhong, Xiaoping Li, Weineng Chen, Ran Xu, Mingbang Wang, Qiang Feng, Meihua Gong, Jing Yu, Yanyan Zhang, Ming Zhang, Torben Hansen, Gaston Sanchez, Jeroen Raes, Gwen Falony, Shujiro Okuda, Mathieu Almeida, Emmanuelle LeChatelier, Pierre Renault, Nicolas Pons, Jean-Michel Batto, Zhaoxi Zhang, Hua Chen, Ruifu Yang, Weimou Zheng, Songgang Li, Huanming Yang, Jian Wang, S. Science, Technology and Medicine open access publisher.Publish, read and share novel research. Honey and Type 1 Diabetes MellitusMamdouh Abdulrhman1, Mohamed El Hefnawy2, Rasha Ali1 and Ahmad Abou El-Goud1[1] Pediatric Department, Faculty of Medicine, Ain Shams University, Abbasia - Cairo, [2] National Institute of Diabetes, Cairo, Egypt1. Jenkins (1987) defined the glycemic index as the ratio between the blood glucose areas produced after ingestion of a studied sugar compared to the blood glucose area produced after glucose ingestion itself.
Initial studies on the diabetes drug, rosiglitazone, show that the medication may improve memory and cognitive performance of patients with Alzheimer's Disease. Alzheimer's Disease is a condition that affects the patient's brain functions such as memory, thinking, cognition, and psychological behavior.
Alzheimer's disease has no known cure and is caused by protein fragments in the brain called plaques.
There are some therapies that are being studied to at least slow down the progression of the disease. Although widely used and still available to diabetics, this drug has been reported to increase the risk of heart attack among patients.
An FDA-approved drug initially used to treat insulin resistance in diabetics has shown promise as a way to improve cognitive performance in some people with Alzheimer's disease. Working with genetically engineered mice designed to serve as models for Alzheimer's, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The molecule, called extracellular signal-regulated kinase (ERK), becomes hyperactive both in the brains of Alzheimer's patients and in the mice at a disease stage corresponding to mild cognitive impairment in human Alzheimer's. Rosiglitazone brings ERK back into line by activating what's known as the peroxisome proliferator-activated receptor gamma (PPAR?) pathway, which interacts with genes that respond to both PPAR? and ERK.
ERK dysfunction in the Alzheimer's mouse model was discovered several years ago by UTMB associate professor Kelly Dineley, senior author of the Journal of Neuroscience paper.
Now the UTMB research team and other investigators across the world are starting clinical trials to investigate the value of therapies for insulin resistance in early-stage Alzheimer's disease in humans.
According to a University of Texas study, Crazy Ants may become the dominant invasive ant species displacing Fire Ants in the near future.
The 21st Century is just beginning but science and technology are moving in blazing speeds.
Mitochondrial Dysfunction in Insulin Insensitivity and Type 2 Diabetes and New Insights for Their Prevention and ManagementChih-Hao Wang1, Kun-Ting Chi1 and Yau-Huei Wei2, 3[1] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan[2] Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan[3] Department of Medicine, Mackay Medical College, Sanjhih, New Taipei City 252, Taiwan1.
Z Wu, P Puigserver, U Andersson, C Zhang, G Adelmant, V Mootha, A Troy, S Cinti, B Lowell, R. M Pravenec, M Hyakukoku, J Houstek, V Zidek, V Landa, P Mlejnek, I Miksik, K Dudova-mothejzikova, P Pecina, M Vrbacky, Z Drahota, A Vojtiskova, T Mracek, L Kazdova, O Oliyarnyk, J Wang, C Ho, N Qi, K Sugimoto, T Kurtz, 2007Direct Linkage of Mitochondrial Genome Variation to Risk Factors for Type 2 Diabetes in Conplastic Strains. I Talior, M Yarkoni, N Bashan, H Eldar-finkelman, 2003Increased Glucose Uptake Promotes Oxidative Stress and PKC-delta Activation in Adipocytes of Obese, Insulin Resistant MiceAm. J Mu, Brozinick JT Jr, Valladares O, Bucan M, Birnbaum MJ (2001A Role for AMP-Activated Protein Kinase in Contraction- and Hypoxia-Regulated Glucose Transport in Skeletal Muscle.Mol. S Imai, L Guarente, 2010Ten Years of NAD-Dependent SIR2 Family Deacetylases: Implications for Metabolic DiseasesTrends Pharmacol. M Lagouge, C Argmann, Z Gerhart-hines, H Meziane, C Lerin, F Daussin, N Messadeq, J Milne, P Lambert, P Elliott, B Geny, M Laakso, P Puigserver, J Auwerx, 2006Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1alpha. Esto de de acuerdo con una nueva investigacion metagenomica de un consorcio internacional de cientificos, que analizaron el microbioma (conjunto de microorganismos) que habita en el intestino humano.
Sobre todo la diabetes tipo 2 se ha convertido en un problema mundial alarmante en los ultimos anos. En este estudio, realizaron la secuenciacion masiva del ADN microbiano intestinal de 345 pacientes chinos con diabetes tipo 2 e identificadoron aproximadamente 60.000 marcadores asociados a la enfermedad que podrian ser utiles para la deteccion y caracterizacion de la diabetes tipo 2. Estos cambios en la composicion de las bacterias intestinales han sido reportados recientemente en pacientes con cancer colorrectal y envejecimiento de la poblacion.
C-peptide following equivalent amount of glucose, sucrose or honey in non-diabetics.Table 1.
Introduction Type 1 diabetes mellitus is by far the most common metabolic and endocrinal disease in children (Peters & Schriger, 1997).
ResultsNo significant difference was found between patients (diabetics) and controls (non-diabetics) as regards the age and anthropometric measures (table 1). He stated that the glycemic response to food affects the insulin response which in turn is also potentiated by other non-glucose dependent factors in this food (Ostman et al., 2001). Initial lab test on rosiglitazone appears to restore the brain signals needed for proper brain cognition. It is a type of dementia that slowly progresses throughout the whole of the brain destroying healthy brain cells. These plaques form into the alzheimer protein that is responsible for the destruction of healthy brain cells.
This past few years, doctors are looking at some drugs that treat diabetes such as insulin (see video), metformin (see report on Related Links below), and just recently, rosiglitazone.
For patients with insulin resistance, rosiglitazone makes fat cells more responsive to insulin. The FDA Food and Drug Administration panel has placed significant restrictions on its distribution and use. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer's on the behavior of a key brain-signaling molecule. This excessive activity leads to improper synaptic transmission between neurons, interfering with learning and memory. But putting together the protein, gene and memory pieces of the puzzle required a multidisciplinary translational research team including animal cognitive neuroscientists, biochemists, molecular biologists, mass spectrometrists, statisticians and bioinformaticists.
C Wallace, 2005A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: a Dawn for Evolutionary Medicine. T Cronin, M Mazur, J Telser, 2007Free Radicals and Antioxidants in Normal Physiological Functions and Human DiseaseInt.
A Maassen, Jahangir Tafrechi RS, Janssen GM, Raap AK, Lemkes HH,’t Hart LM (2006New Insights in the Molecular Pathogenesis of the Maternally Inherited Diabetes and Deafness Syndrome.Endocrinol. Y Park, W Lee, 2007The Depletion of Cellular Mitochondrial DNA Causes Insulin Resistance through the Alteration of Insulin Receptor Substrate-1 in Rat Myocytes.Diabetes Res. G Fantus, 2001Enhanced Sensitivity of Insulin-Resistant Adipocytes to Vanadate is Associated with Oxidative Stress and Decreased Reduction of Vanadate (+5) to Vanadyl (+4).J. N Li, J Song, L Zhang, LeMaire SA, Hou X, Zhang C, Coselli JS, Chen L, Wang XL, Zhang Y, Shen YH (2009Activation of the AMPK-FOXO3 Pathway Reduces Fatty Acid-Induced Increase in Intracellular Reactive Oxygen Species by Upregulating Thioredoxin. S Banks, N Kon, C Knight, M Matsumoto, R Gutierrez-juarez, L Rossetti, W Gu, D Accili, 2008Sirt1 Gain of Function Increases Energy Efficiency and Prevents Diabetes in MiceCell Metab. Ha habido un enorme incremento en el numero de pacientes con diabetes tipo 2, incluso a una edad mas joven.
The major dietary component responsible for fluctuations in blood glucose levels is carbohydrate. Type 1 diabetes is caused by the loss of insulin-secreting ? cells of the pancreas, which leads to a deficiency of insulin in the human body.
M Spiegelman, 1999Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1. J Butte, S Crunkhorn, K Cusi, R Berria, S Kashyap, Y Miyazaki, I Kohane, M Costello, R Saccone, E. I Shulman, 2004Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes.N.
J Shaw, 2011The AMPK Signalling Pathway Coordinates Cell Growth, Autophagy and Metabolism.Nat.
H Shen, 2010Metformin Reduces Intracellular Reactive Oxygen Species Levels by Upregulating Expression of the Antioxidant Thioredoxin via the AMPK-FOXO3 PathwayBiochem.
Tanto los factores geneticos, asi como los factores ambientales juegan un papel en el desarrollo de la enfermedad. Este estudio del microbioma tambien sirve como un modelo para futuras investigaciones sobre los marcadores de otras enfermedades que pudieran estar relacionadas con las bacterias intestinales. Samnata et al (1985) defined the peak incremental index of a certain sugar as the ratio between the maximal increments of the glucose level after ingestion of the sugar compared to the maximal increment produced after ingestion of glucose.
Type 2 diabetes, known as non-insulin-dependent diabetes mellitus (NIDDM), is characterized by insulin resistance of insulin-responsive tissues, such as the muscle and adipose tissues. F Eriksson, A Subramanian, S Sihag, J Lehar, P Puigserver, E Carlsson, M Ridderstrale, E Laurila, N Houstis, M. J Yang, Y Zhao, 2006Substrate and Functional Diversity of Lysine Acetylation Revealed by a Proteomics Survey. Hasta ahora, los cientificos se han centrado principalmente en la identificacion de marcadores geneticos en el propio ser humano. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction and failure of various organs especially the eyes, kidneys, nerves, heart and blood vessels (American Diabetes Association, 2001). He also mentioned that both the glycemic and the peak incremental indices are closely related, highly dependent and positively correlated to the plasma glucose produced after ingestion of any given sugar. Inability of glucose disposal in these tissues after a meal leads to the elevation of glucose level in the blood circulation of the patients.
N Sack, 2008PGC-1alpha Integrates Insulin Signaling, Mitochondrial Regulation, and Bioenergetic Function in Skeletal Muscle.J. K Radda, S Neubauer, K Clarke, 2003Abnormal Cardiac and Skeletal Muscle Energy Metabolism in Patients with Type 2 Diabetes. Sin embargo, la investigacion reciente ha demostrado que otros factores, tales como la flora intestinal, desempenar un papel en el desarrollo de la diabetes tipo 2.
The glycemic effect of any foodstuff is defined as its effect on blood glucose level postprandially.
Therefore, any change in the plasma glucose level after ingestion of a certain sugar will markedly affect both the glycemic index and the peak incremental index. Subsequently, the long-term effect of hyperglycemia may induce inflammation and oxidative damage to other organs and result in many complications such as cardiovascular disease, blindness, amputations and renal failure [1]. I Shulman, 2007Mitochondrial Dysfunction due to Long-Chain Acyl-CoA Dehydrogenase Deficiency Causes Hepatic Steatosis and Hepatic Insulin Resistance.Proc. Both the glycemic index (GI) and the peak incremental index (PII) are used to assess the glycemic effect of different food stuffs (Jenkins et al., 1981).
Hence, the glycemic and the peak incremental indices measure how fast and how much a food raises blood glucose levels.
Unfortunately, type 2 diabetes has high prevalence compared to type 1 diabetes in modern societies because the pathogenesis of this disease is quite complicated, multi-factorial, and is strongly associated with lifestyle, dietary habits, and environmental toxins.
J Mandarino, 2003Coordinated Reduction of Genes of Oxidative Metabolism in Humans with Insulin Resistance and Diabetes: Potential Role of PGC1 and NRF1. Jennie et al (2003) who studied the use of low glycemic index diets in the management of diabetes found that diets with low glycemic indices (GI), compared with conventional or high-GI diets, improved overall glycemic control in individuals with diabetes, as assessed by glycemic index, peak incremental index, reduced HbA1c and fructosamine. Foods with higher index values raise blood sugar more rapidly than foods with lower index values do in case of the glycemic index and much more in case of peak incremental index. In light of these findings, many biomedical researchers and clinicians have made great efforts to better understand the pathophysiology of insulin resistance and to explore new avenues for the therapy of type 2 diabetes [2].2. They concluded that using low-GI foods in place of conventional or high-GI foods has a clinically useful effect on postprandial hyperglycemia similar to that offered by pharmacological agents that target postprandial hyperglycemia. In our study, no statistically significant differences were found between diabetic patients and non-diabetic controls regarding the glycemic and the peak incremental indices of the studied sugars. Similarly, the American Diabetes Association (2002) stated that the use of low-GI foods may reduce postprandial hyperglycemia.Honey is the substance made when the nectar and sweet deposits from plants are gathered, modified and stored in the honeycomb by honey bees. On the other hand, both the GI and PII of honey were significantly lower when compared with sucrose in patients and controls.

Similarly, Samnata et al (1985), who studied the glycemic effect of glucose, sucrose and honey in 12 normal volunteers, eight patients with insulin-dependent diabetes mellitus (IDDM) and six patients with non-insulin-dependent diabetes mellitus (NIDDM), found no significant differences between the normal volunteers and diabetic patients regarding the glycemic and peak incremental indices of both sugars. Overview of mitochondriaMitochondria play important roles in energy metabolism, apoptosis and biosynthesis of heme and pyrimidine nucleotides because many vital biochemical reactions take place in the organelles.
C Groop, 2003PGC-1alpha-Responsive Genes Involved in Oxidative Phosphorylation are Coordinately Downregulated in Human Diabetes. It is composed primarily of the sugars glucose and fructose; its third greatest component is water. Since the glycemic index (GI) is the ratio between the area under curve (AUC) of the studied sugar and the AUC of glucose, and the peak incremental index (PII) is the ratio between the maximal blood glucose increment of the studied sugar and that of glucose; it may be expected that both GI and PII will be the same in both diabetics and non-diabetics.
They are also called the powerhouse of mammalian cells because they generate a majority of ATP required by the cells. The roles of sirtuins in the maintenance of glucose homeostasis and their defects in insulin resistance and type 2 diabetes5.1. Mitochondria contain key enzymes involved in the tricarboxylic acid (TCA) cycle, ? oxidation of fatty acids and the electron carriers of the respiratory chain.
Metabolic intermediates generated from catabolism of carbohydrates and lipids by TCA cycle and ? oxidation provide reducing equivalents (NADH and FADH2), which are funneled into the electron transport chain that consists of a series of respiratory enzyme complexes I, II, III and IV. Glucose and fructose, the major constituents of honey, account for about 85% of the honey solids.
Also, Shambaugh et al (1990) found that sucrose caused higher blood sugar readings than honey in normal volunteers. The proton gradient generated from the electron transport chain across the inner membrane is then utilized by Complex V to drive the phosphorylation of ADP to produce ATP in mitochondria to meet the energy need of the cell [3]. In the study of Samnata et al (1985), honey ingestion in both diabetics (IDDM) and non-diabetics also resulted in a significantly lower PII compared to the glucose and sucrose.
The principal oligosaccharides in blossom honeys are disaccharides: sucrose, maltose, turanose, erlose.
In the study done by Al-Waili (2004), honey compared with dextrose and sucrose caused a lower elevation ofplasma glucose levels (PGL) in both diabetics (IDDM) and normal subjects. Defects in the secretion or function of adipokines as an important contributor to insulin resistance or type 2 diabetes6.1. Each mammalian cell contains several hundreds to more than a thousand of mitochondria, and each mitochondrion contains 2-10 copies of mtDNA to meet different energy needs of the cells. Also, Watford (2002) demonstrated that very small amounts of fructose, which is the main component of honey, could increase hepatic glucose uptake and glycogen storage, as well as reduce peripheral glycemia which could be beneficial in diabetic patients. Most importantly, mtDNA is naked, compact, and has no efficient DNA repair systems, which renders it prone to free radical attack and oxidative damage, and thereby increases its risk of acquiring DNA mutations. H Westphal, 2007Small Molecule Activators of SIRT1 as Therapeutics for the Treatment of Type 2 Diabetes. In the study performed by Agrawal et al (2007), honey was found to produce an attenuated postprandial glycemic response especially in subjects with glucose intolerance. More than one hundred mutations in mtDNA have been reported to be associated with human diseases [4]. They referred these results to the possibility that the glucose component of honey might be poorly absorbed from the gut epithelium. Also, Tirgoviste et al (1983) studied blood glucose and plasma insulin responses to various carbohydrates in type 2 diabetes, and they found that the increase in plasma glucose was significantly higher after administration of more refined carbohydrates such as glucose than after the complex ones such as honey. Regulation of mitochondrial biogenesisThe mitochondrial biogenesis of the human cells is controlled by extracellular stimuli such as low temperature, thyroid hormone, fasting, and exercise through up-regulation of the master control, peroxisome proliferator-activated receptor gamma co-activator 1??(PGC-1?).
Meanwhile, Oizumi et al (2007) and Arai et al (2004) found that consumption of a palatinose (a disaccharide found in honey)-based balanced formula suppressed postprandial hyperglycemia, glycemic and peak incremental indices and produced beneficial effects on the metabolic syndrome–related parameters (namely, the lipid profile and visceral fat accumulation) in diabetic patients. PGC-1? can promote nuclear respiratory factor 1 (NRF-1) and NRF-2 to transcribe their target genes that produce many nuclear DNA-encoded mitochondrial proteins and mitochondrial transcription factor A (mtTFA), which is a key transcriptional factor for the expression of genes encoded by the mitochondrial genome. Measurement of C-peptide, however, provides a fully validated means of quantifying endogenous insulin secretion. They stated the reason of this observation to be due to the fact that although palatinose is completely absorbed, yet it has the specific characteristics of delayed digestion and absorption as reported by Dahlquist et al (1963) and Lina et al (2002). Improvement of the biogenesis and function of mitochondria by exercise and pharmaceutical agents for treatment of insulin resistance and type 2 diabetes8.1.
A great majority of the nuclear DNA-encoded proteins are translocated from the cytosol to mitochondria and are assembled with mtDNA-encoded proteins to form functional respiratory enzyme complexes on the inner membrane. C-peptide is co-secreted with insulin by the pancreatic cells as a by-product of the enzymatic cleavage of proinsulin to insulin.
Our results showed that honey, compared to glucose and sucrose, caused a significant elevation in the C-peptide levels in non-diabetic subjects. Meanwhile, in diabetic patients, the plasma C-peptide levels did not differ significantly between the three types of sugars. ROS and antioxidant enzyme system in mitochondriaMitochondria are also the major source of intracellular reactive oxygen species (ROS). Aim of the studyThe aim of this work was to compare the effects of honey, sucrose and glucose on plasma glucose and C-peptide levels in children and adolescents with type 1 diabetes mellitus.3. To our knowledge, no similar work was done to study the effects of honey on C-peptide levels in type 1 diabetes mellitus. Within mitochondria, the superoxide anions (O2.-) are produced in the reaction between O2 and the electrons leaked out from Complex I and III of the respiratory chain. However, several studies were performed in healthy and in type 2 diabetic patients to evaluate the effects of honey on the insulin and C-peptide levels, and the results were controversial. In the study of Al Waili (2003), inhalation of honey solution, when compared with hyperosmolar dextrose and hypoosmolar distilled water, resulted in a significant elevation of plasma insulin and C-peptide in both normal individuals and in patients with type 2 diabetes mellitus. There is a set of enzymatic and non-enzymatic ROS-scavenging system to protect cells from the assault by ROS.
All subjects were within 68–118% and 77–125% of their ideal body weight and height, respectively. The H2O2 can be reduced to H2O by catalase (CAT), glutathione peroxidase (GPx) or a group of small cysteine-containing proteins such as thioredoxins (Trx) and peroxiredoxins (Prx) [7-9]. Nevertheless, overproduction of ROS by defective mitochondria and inefficient antioxidant enzyme system may cause oxidative damage to cellular components such as DNA, especially mtDNA, proteins, and lipids of target tissues in aging and age-related diseases [10]. It has been reported that mitochondrial defects caused by mtDNA mutation or oxidative stress also play a role in insulin resistance or diabetes [11-13].3.
Mitochondrial dysfunction contributes to insulin resistance and type 2 diabetesIn the early 1990s, diabetes has been discovered to be one of the symptoms associated with some of the mitochondrial diseases such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD) syndrome, and patients with these syndromes frequently harbor an A to G transition at nucleotide position 3243 of mtDNA [11]. The patients were recruited from the regular attendants of the children clinic of the National Institute of Diabetes in Cairo, Egypt.
However, until recent years diabetes has been usually thought as a secondary effect of aging or age-related diseases in patients with an mtDNA mutation. The study was approved by the local ethical committee, and an informed written consent was obtained from at least one parent of each subject before the study. Several recent studies provided the linkage between mitochondrial dysfunction or defects in mitochondrial biogenesis and the pathogenesis of insulin resistance or type 2 diabetes [12-22]. These studies showed that the tissues of mice and human subjects with insulin insensitivity or type 2 diabetes displayed lower expression levels of the genes encoding subunits constituting respiratory enzymes, decrease in the activities of respiratory enzyme complexes, decreased expression of genes involved in mitochondrial biogenesis, mutation or deletion of mtDNA, decrease in the bioenergetic capacity, or defects in ? oxidation of fatty acids. In summary, impairment in the mitochondrial OXPHOS function was a common observation in insulin-responsive muscle and adipose tissues of diabetic mice or patients. Most importantly, the amplitude of the decline of mitochondrial function was found to be related to the severity of diabetic symptoms and insulin resistance. The honey dose for each patient was calculated based on the fact that each 100 gm of the honey used in this study contained 77.3 gm sugars. These findings support the notion that mitochondrial dysfunction is one of the major etiological factors for insulin resistance and type 2 diabetes.4. Mitochondrial DNA alteration causes insulin resistance and type 2 diabetesIn order to prove the concept that mitochondrial dysfunction is involved in the development of insulin resistance, chemical treatments and genetic manipulation have been used to impair mitochondria by alteration of the quantity or quality of mtDNA. Venous blood was sampled just before ingestion and then every 30 min postprandial for 2 h thereafter. Park and Lee [23] observed a decrease of insulin sensitivity and impaired activation of insulin signaling in mtDNA-depleted muscle cells after chronic treatment with a low dose of ethidium bromide (EtBr).
Moreover, repletion of mtDNA by removal of EtBr revealed that the defects in insulin response could be recovered [23].
In addition, defects in oxidative phosphorylation caused by treatment of oligomycin A, an inhibitor of Complex V, also resulted in a decline of insulin-stimulated glucose uptake and inactivation of Akt and IRS-1 in the insulin signaling pathway in murine C2C12 myotube cells [25]. Overproduction of ROS impairs insulin signalingExcess ROS production from defective mitochondria has been considered as one of the possible unifying factors leading to insulin resistance. Increased concentration of glucose in the culture medium was found to significantly increase the ROS level and led to insulin resistance in mouse adipocytes and rat primary adipocytes and this effect could be prevented by pre-treatment of the adipocytes with the antioxidant N-acetylcysteine [26, 27].
After administration with ROS-scavenging enzymes, the insulin sensitivity of muscle cells was found to be improved in diabetic mice [28]. Recent studies also demonstrated that the amount of superoxide anions generated by mitochondria was increased in four different animal models of insulin resistance. Furthermore, it was reported that by addition of mitochondria-targeting superoxide dismutase mimetics to decrease the level of ROS could alleviate insulin resistance in the insulin-insensitive animals [29]. The mechanisms underlying the disruption of insulin signaling by overproduction of ROS have been extensively investigated in the past decade. Accumulation of fatty acids impairs insulin signalingIt is thought that impaired lipid metabolism resulted from defects in ? oxidation of fatty acids is involved in the disturbance of insulin signaling. Accumulation of intracellular lipids by the decreased activities of carnitine palmitoyl transferase (CPT), which transports long-chain fatty acids into mitochondria, and long-chain acyl-CoA dehydrogenase (LCAD), an enzyme involved in ? oxidation of fatty acids, led to insulin resistance in insulin-targeting cells [31]. Loss of mild stress-induced AMPK? activation may lead to insulin resistanceLow concentration of ROS is a normal byproduct of cellular functions and is known as the secondary messenger in the regulation of intracellular signaling to adapt to the extracellular environment. But prolong exposure to oxidative environment may lead to oxidative damage to tissue cells and development of diseases.
Recent studies revealed that activation of AMPK by low dose of ROS is involved in the activation of antioxidant defense system, the influx of glycolysis and lipid metabolism [33, 34].
The activation of the downstream targets of AMPK, including GLUT4, PFK2, and ACC, enhances the ? oxidation of fatty acids and the basal and insulin-stimulated glucose uptake. Besides, activated AMPK can directly phosphorylate the forkhead transcription factor 3a (FOXO3a) to promote its nuclear translocation and formation of a transcription complex, which in turn up-regulates the expression of thioredoxin and peroxiredoxin [35].
It has been shown that activation of the AMPK-FOXO3a pathway via AICAR or metformin, an antidiabetic drug, can decrease the intracellular ROS level to improve insulin sensitivity in epithelial cells [35, 36]. These findings indicate that mild oxidative stress-elicited activation of AMPK and FOXO3a may safeguard glucose homeostatsis and redox status in healthy subjects. Taken together, the decrease in the sensitivity and capacity of the response to low-level oxidative stress may play a role in insulin insensitivity and type 2 diabetes.5. Introduction of sirtuinsSirtuins are a highly conserved family of proteins that exhibit NAD+-dependent protein deacetylase and ADP-ribosyltransferase activities. Mammals contain seven sirtuins that are confined in different subcellular compartments and regulate diverse functions, such as intermediary metabolism, energy homeostasis, and oxidative stress. SIRT1, SIRT6 and SIRT7 are primarily localized to the nucleus, SIRT2 is a cytosolic protein, and SIRT3, SIRT4 and SIRT5 are all located in mitochondria. Sirtuins can regulate the function of enzymes or transcription factors by deacetylation of target proteins to cope with nutrient deprivation or metabolic stress. In addition to getting involved in the regulation of aging and longevity, some of the sirtuins have emerged as important regulators of glucose homeostasis. SIRT1 and type 2 diabetesAccumulating evidence has established that SIRT1 contributes to the pathogenesis of type 2 diabetes through its effect on oxidative metabolism of the liver, skeletal muscle, adipose tissue, and pancreatic ? cells, which indicate that mammalian sirtuins play an essential role in the pathogenesis of diabetes and aging-associated metabolic diseases [37].
Increasing evidence has suggested that SIRT1 provides overall protection against type 2 diabetes. SIRT1-overexpressing transgenic mice showed significant protection from the adverse effects of high-fat diet, including hepatic inflammation and impaired insulin sensitivity [38, 39]. In addition, administration of resveratrol and SIRT1-activating compounds was found to improve glucose homeostasis and insulin sensitivity in diet-induced and genetically-predisposed type 2 diabetic mice [40, 41]. It has been reported that certain sequence variations of the SIRT1 gene is strongly associated with type 2 diabetes and obesity in a Dutch population [42].
SIRT3 and type 2 diabetesIn recent years, it has become increasingly clear that reversible lysine acetylation is an important posttranslational modification of mitochondrial proteins for the regulation of their proper function [43]. A number of proteomics studies have revealed that many key metabolic enzymes are acetylated in mitochondria and that their enzymatic activities are regulated by changes in acetylation in response to environmental stimuli [44]. Among seven members of the sirtuin family, three sirtuins (SIRT3, SIRT4 and SIRT5) are primarily located and exert functions in mitochondria.
It is a remarkable fact that SIRT3 is the most important one regarding the regulation of mitochondrial function because it is responsible for deacetylation of the majority of mitochondrial proteins [45].

SIRT3 has been shown to control multiple key metabolic pathways through its deacetylase activity in response to nutrient deprivation. For example, SIRT3 can deacetylate and activate the mitochondrial enzyme acetyl-CoA synthetase 2 (AceCS2). The oxidation of acetate is required for the generation of ATP and heat under low-glucose or ketogenic condition [46, 47]. Besides, SIRT3 has been shown to deacetylate long-chain acyl-CoA dehydrogenase (LCAD) during fasting and thereby promotes ?-oxidation of fatty acids in the liver mitochondria [48]. Recently, some studies provide critical insights into the connection between SIRT3 and the pathogenesis of type 2 diabetes and metabolic syndrome. It has been demonstrated that the SIRT3 expression in skeletal muscle is reduced in animal models of type 1 and type 2 diabetes and that results in the decrease of mitochondrial bioenergetic function and over-production of ROS, which in turn disturbs insulin signaling pathway leading to insulin insensitivity [49]. These findings suggest that decreased SIRT3 expression and activity could contribute to the metabolic abnormalities in skeletal muscle and pathogenesis of diabetes mellitus. On the other hand, mitochondrial dysfunction induced by SIRT3 deficiency in pancreatic ? cells might contribute to the defects in insulin secretion upon stimulation with various insulin secretagogues [50].
In a recent study, Hirschey and coworkers [51] showed that loss of SIRT3 and resultant mitochondrial protein hyperacetylation contribute to obesity, hyperlipidemia, insulin resistance, and steatohepatitis.
In addition, they identified a single nucleotide polymorphism in the human SIRT3 gene, which causes a loss of the enzyme activity of SIRT3 and is highly associated with the prevalence of metabolic syndrome. Thus, site-specific acetylation of mitochondrial proteins and the development of new SIRT3-targeted drugs may serve as therapeutic tools to regain normal cellular redox status and energy homeostasis in the patients with diabetes and insulin resistance, as well as some of the mitochondrial diseases.6. Regulation of glucose homeostasis by adipocyte-derived adipokinesThe adipose tissue has traditionally been considered as the site for lipid storage in the human body. In recent years, a growing number of studies have revealed that adipose tissues can perform endocrine function in secreting several adipokines, which can modulate the intermediary metabolism and glucose homeostasis in the peripheral tissues.
Adipocyte-derived adipokines can be divided into two groups according to their action in the regulation of glucose metabolism in the mammals.
One group is called as “anti-hyperglycemic adipokines”, which include leptin, adiponectin, omentin, and visfatin. They enhance insulin sensitivity in the peripheral tissues to increase glucose utilization and decrease the glucose level in blood circulation.
Another group of adipokines is termed “pro-hyperglycemic adipokines” or “pro-inflammatory adipokines”, which include resistin, TNF-?, and RBP4 since they tend to result in an increase of blood glucose and systemic inflammation.
Adiponectin improves insulin sensitivityAdiponectin has been considered the most important adipokine due to its higher concentration in blood than the others and a decrease in its level is highly correlated with type 2 diabetes [54].
Several clinical studies demonstrated that the plasma level of adiponectin in obese subjects or patients with type 2 diabetes was significantly lower compared with those of normal subjects, and that blood glucose was higher and insulin sensitivity was largely decreased in mice with adiponectin deficiency [55, 56].
Besides, administration or overexpression of adiponectin in mice can enhance insulin sensitivity and glucose utilization to ameliorate the symptoms of insulin resistance [57-59].
This indicates that dysregulation of secretion of adipokines from adipose tissues is an important contributor for the pathogenesis of type 2 diabetes.
Thus, adiponectin has become the most attractive adipokine and its function has been gradually unraveled. The underlying mechanism of adiponectin in improvement of insulin sensitivity and fatty acid ? oxidation in skeletal muscle has been demonstrated by Yamauchi and his colleagues [60]. They showed that the phosphorylation and activation of AMPK is stimulated when adiponectin binds to adiponectin receptor 1 (AdipoR1), which is a seven-transmembrane receptor specifically expressed in the skeletal muscle. In turn, AMPK can induce GLUT4 translocation to the plasma membrane for the increase of glucose uptake.
Bi-directional regulation of the biogenesis and function of mitochondria by adiponectinBecause the decrease of adiponectin expression and the biogenesis and function of mitochondria have been observed concurrently in adipose tissues of diabetic mice and human subjects [22], some researchers made an effort to elucidate the connection between these two cellular events.
Koh and coworkers demonstrated that the biogenesis and function of mitochondria are important for the maintenance of the adiponectin level in adipocytes [61]. They found that adiponectin expression and the mitochondrial content in adipose tissues were both reduced in obese mice, and these changes could be reversed by the administration of rosiglitazone, a mainstay drug used for treatment of diabetes. Induction of mitochondrial biogenesis via adenoviral overexpression of nuclear respiratory factor-1 (NRF-1) in cultured adipocytes increased the expression of adiponectin. Besides, they found that inhibition of mitochondrial function by a respiratory inhibitor or uncoupler decreased the level of adiponectin in plasma through activation of ROS-dependent kinase such as JNK.
This finding suggests that mitochondrial function is linked to adiponectin synthesis in adipocytes, and explain the observation that mitochondrial dysfunction is associated with the defects of secretion and function of adiponectin, which may lead to systemic insulin resistance in obesity and type 2 diabetes.On the other hand, a recent study also showed that adiponectin can increase the activity of PGC-1? and enhance the biogenesis and respiratory function of mitochondria in muscle cells [62]. Adiponectin ultimately causes an increase in the expression of PGC-1? by CaMK, a downstream target of CaMKK, and increase in the activity of PGC-1? by deacetylation of SIRT1.
These events may in turn elevate the biogenesis and function of mitochondria in muscle cells.
This new insight into the up-regulation of mitochondrial function by adiponectin signaling accounts for the long-term effect of adiponectin on the gene expression and provides a biochemical mechanism by which adiponectin improves insulin sensitivity of the muscle.7.
Environmental toxins in mitochondrial dysfunction and insulin insensitivityBecause of the increasing prevalence of type 2 diabetes and metabolic syndrome in westernized and industrialized countries, type 2 diabetes is thought as an “epidemic disease”. With this consideration in mind, scientists conjectured that one of the causative factors for type 2 diabetes is probably related to the environmental impact of industrialization. A growing body of evidence has indicated that the cause of type 2 diabetes and metabolic syndrome is strongly associated with some environmental pollutants and mitochondrial toxins. Persistent organic pollutants (POPs), which are organic compounds present in many herbicides, insecticides, rodenticides, industrial products and wastes, are resistant to photolytic degradation and other chemical or biological destruction processes. Owning to these chemical characteristics, POPs can be present for a long time in our environment and are accumulated in the human body.
POPs cause insulin insensitivityBy analysis of the results from National Health and Nutrition Examination Survey in 1999-2000, Lee and colleagues found that the prevalence rate of type 2 diabetes was highly correlated with the serum concentration of POPs of the American population [64, 65]. Contamination of POPs in the human diets might be a contributor to the pathogenesis of metabolic diseases including the diabetes.
For example, atrazine (ATZ, 2-chloro-4-ethylamine-6-isopropylamino-S-triazine), one of the herbicides, has been extensively used in the corn fields of the United States since the early 1960s.
Interestingly, the time and areas of ATZ usage are matched with the timing of increase in the incidence of obesity and other metabolic syndromes [66, 67]. In addition, long-term exposure of Australian outdoor workers to pesticides was found to associate with the disturbance of glucose homeostasis, including higher blood glucose and insulin resistance in these subjects [68]. It was demonstrated that mice fed with a high-fat diet with POPs-contaminated farmed salmon fillet would exaggerate insulin resistance, visceral obesity, and glucose intolerance [69]. However, remission of the above symptoms was observed in the mice fed with farmed salmon fillet containing low level of POPs [69]. Furthermore, the mortality rate of diabetes was positively correlated with the concentration of exposed pesticides [70].
The results revealed that increased serum levels of some POPs were highly associated with the incidence of adiposity, dyslipidemia, and insulin resistance in a healthy population.
Impairment of mitochondrial dysfunction by POPsSeveral studies have demonstrated that environmental toxins could cause oxidative damage to mitochondria, the organelles are most susceptible to extrinsic toxins including POPs.
It has been shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), one of the POPs, caused a loss of mitochondrial membrane potential and increase of ROS production in mammalian cells.
Recently, some animal studies revealed that POPs could result in insulin insensitivity by impairment of mitochondrial function.
It was found that chronic exposure to POPs led to mitochondrial dysfunction, morphological disruption of mitochondria, decreased activities of respiratory enzymes and decreased oxygen consumption rate in the liver and skeletal muscle of mice [74]. Besides, POPs were found to down-regulate the expression of leptin in adipose tissues and inactivated insulin signaling pathway in the skeletal muscle [75]. These subsequently resulted in insulin resistance, hyperlipidemia, abdominal obesity, and hepatosteatosis in mice and the severity of these symptoms was more pronounced in the mice fed on high-fat diets. Moreover, mitochondria could be the primary organelles involved in the initiation of inflammation, leading to chronic damage in the affected cells or organs.
High level of polychlorinated biphenyls (PCBs) could promote accumulation of lipids and expression of pro-inflammatory adipokines, which decreased the expression of adiponectin and the insulin-stimulated glucose uptake in the adipose tissue, leading to systemic obesity and obesity-associated atherosclerosis [76].
Taken the findings from the epidemiological survey and the above observations together, we suggest that the mitochondrial dysfunction resulted from environmental pollutants or toxins play a role in the pathogenesis and prevalence of type 2 diabetes and insulin resistance.8. Improvement of the biogenesis and function of mitochondria by exercise and pharmaceutical agents for treatment of insulin resistance and type 2 diabetesIn light of the observations of mitochondrial impairment and increased oxidative stress in the patients with type 2 diabetes, it has been thought that an increase of mitochondrial function or scavengers of ROS may be effective therapies for these patients.
Biomedical researchers and clinicians have made considerable efforts in looking for possible ways to improve insulin sensitivity in target tissues through up-regulation of the mitochondrial function or antioxidant defense system. Anti-diabetic drugsClinically, the thiazolidinediones (TZDs) have been commonly used to treat patients with type 2 diabetes by increasing insulin sensitivity of the muscle and adipose tissues.
These drugs include pioglitazone, rosiglitazone, and troglitazone, which belong to the group of PPAR? agonists and can up-regulate the expression of PGC-1?, a master control of mitochondrial biogenesis, and a set of genes involved in the regulation of oxidative metabolism [77].
Recent studies revealed that these drugs not only increase insulin sensitivity of cells, but also significantly improve the mitochondrial biogenesis, function and morphology in vitro and in vivo [78, 79].
Regular exerciseIt is worth mentioning that mitochondrial biogenesis can be up-regulated by regular exercise through the activation of PGC-1? and its downstream targets including mtTFA and nuclear respiratory factors NRF1 and NRF2 [80, 81], which regulate the expression of a number of polypeptides constituting the respiratory enzyme complexes. These molecular events culminate in the increase of the bioenergetic function of mitochondria and thereby improve the insulin sensitivity of the animals or human subjects doing regular exercise [82]. In light of these laboratory findings and the documentation that exercise can alleviate the symptoms of patients with type 2 diabetes [83], we suggest that the increase of the biogenesis and function of mitochondria is one of the key underlying mechanisms by which exercise improves the insulin sensitivity of patients with type 2 diabetes. Natural products and chemicalsResveratrol (3,5,4'-trihydroxystilbene), a polyphenol and a well-known antioxidant, has been demonstrated to be able to promote mitochondrial biogenesis and fatty acid ? oxidation as well as insulin sensitivity in a mouse model [84].
Resveratrol treatment was found to lead to the decrease of PGC-1? acetylation through activation of SIRT1 and thereby increased the activity of PGC-1?. In turn, an array of oxidative metabolism-related genes was up-regulated and mitochondrial OXPHOS was also elevated in the muscle tissues of the mice that had been treated with resveratrol.
Moreover, resveratrol increased insulin sensitivity in the muscle and protected mice from obesity or insulin resistance when fed on a high-fat diet [40]. Additionally, epigallocatechin-3-gallate (EGCG), which is the most effective and abundant catechin in green tea, has been reported to have the antioxidant, anti-obesity and anti-cancer activities [85].
Several studies on cultured adipocytes and animal models demonstrated that EGCG decreased intracellular levels of ROS and inhibited extracellular signal-related kinases (ERK) activation. Moreover, EGCG was found to activate the AMPK to elevate mitochondrial function and ?-oxidation of fatty acids to decrease the accumulation of lipids [86]. All of these downstream effects of EGCG would be of great use to improve insulin sensitivity of the target tissue cells.
On the other hand, attention should be paid to the therapeutic potential of pyruvate in the treatment of diabetes.
Pyruvate, an intermediate located at the key position of glucose metabolism, has been involved in anaerobic glycolysis and aerobic respiration.
Some beneficial effects were reported about the administration of pyruvate to patients harboring with A3243 or A8344G mutation of mtDNA [87]. Pyruvate can not only improve the intracellular redox status by elimination of hydrogen peroxide via non-enzymatic reaction, but also increases ATP production by oxidation of NADH to NAD+ by lactate dehydrogenease (LDH). The high level of NAD+ may also enhance the activity of SIRT3, an NAD+-dependent deacetylase.
Increase of antioxidant defense Treatment of lipoic acid, an antioxidant, could not only decrease the intracellular ROS but also enhance insulin-stimulated glucose utilization in skeletal muscle of diabetic animals with insulin resistance. In addition to its antioxidant activity, lipoic acid was found to significantly increase mitochondrial biogenesis and function, including oxygen consumption rate and ?-oxidation of fatty acids in adipocytes [90].
All of these effects of lipoic acid were enhanced by co-treatment of cells with acetyl L-carnitine (ALCAR), another mitochondrial nutrient [91]. These findings suggest that lipoic acid improves insulin sensitivity of adipocytes through its ability to elevate the antioxidant capacity and to enhance mitochondrial function.
In addition, several studies have demonstrated that increasing antioxidant capacities by addition of cell- permeabilized MnSOD [29, 30] or overexpression of catalase [92, 93] and GPx3 [94] to reduce intracellular ROS could improve insulin sensitivity in cultured cells or mice. Taken together, the above-mentioned observations clearly indicate that therapeutic agents targeting to mitochondria or antioxidant defense system could ameliorate the symptoms or insulin insensitivity in cultured cells and animals, and perhaps also in the patients. These findings also support the notion that mitochondrial function is essential for the maintenance of insulin sensitivity and glucose homeostasis in the human body.9. Concluding remarksThis chapter has provided an overview of recent advances in the understanding of mitochondrial role in the insulin insensitivity and type 2 diabetes, including the clinical observations and possible mechanisms of the insulin insensitivity induced by mitochondrial dysfunction in the insulin-responsive tissues.
These events culminate in the inactivation of the insulin signaling pathway and result in insulin insensitivity in muscle and adipocytes. Improvement of insulin sensitivity and glucose homeostasis may be achieved by the strategy to up-regulate mitochondrial biogenesis, function and antioxidant defense through exercise, therapeutic agents, and dietary supplement of antioxidants or natural products (Figure 1).

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