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Mitochondrial Dysfunction in Diabetes

10 Chronic Diseases linked to mitochondrial dysfunction

Listed below are current articles and published clinical studies documenting the
strong link between Mitochondrial Dysfunction and Diabetes.
Oxid Med Cell Longev. 2014 May 4.
Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies:
toward mitochondria-targeted clinical strategies.
Beyond the disorders recognized as mitochondrial diseases, abnormalities in function and/or ultrastructure of mitochondria have been reported in several unrelated pathologies. These encompass ageing, malformations, and a number of genetic or acquired diseases, as diabetes and cardiologic, haematologic, organ-specific (e.g., eye or liver), neurologic and psychiatric, autoimmune, and dermatologic disorders.
The mechanistic grounds for mitochondrial dysfunction (MDF) along with the occurrence of oxidative stress (OS) have been investigated within the pathogenesis of individual disorders or in groups of interrelated disorders. We attempt to review broad-ranging pathologies that involve mitochondrial-specific deficiencies or rely on cytosol-derived prooxidant states or on autoimmune-induced mitochondrial damage. The established knowledge in these subjects warrants studies aimed at elucidating several open questions that are highlighted in the present review.
The relevance of OS and MDF in different pathologies may establish the grounds for chemoprevention trials aimed at compensating OS/MDF by means of antioxidants and mitochondrial nutrients.
Diabetes. 2014 July
Inflammation, defective insulin signaling, and mitochondrial dysfunction as
common molecular denominators connecting type 2 diabetes to Alzheimer disease.
A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss.

Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease.
Hum Mol Genet. 2014 June
Loss of TFB1M results in mitochondrial dysfunction
that leads to impaired insulin secretion and diabetes.
We have previously identified Transcription Factor B1 Mitochondrial (TFB1M) as a Type 2 Diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D we created a β-cell specific knockout of Tfb1 m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1 m-/- mice exhibited retarded glucose clearance due to impaired insulin secretion. β-Tfb1 m-/- islets released less insulin in response to fuels, contained less insulin and secretory granules, and displayed reduced β-cell mass.
Moreover, mitochondria in Tfb1 m-deficient β-cells were more abundant with disrupted architecture. TFB1M is known to control mitochondrial protein translation by adenine-dimethylation of 12S ribosomal RNA (rRNA). Here, we found that levels of TFB1M and mitochondrial encoded proteins, mitochondrial 12S rRNA methylation, ATP production and oxygen consumption were reduced in β-Tfb1 m-/- islets. Furthermore, levels of reactive oxygen species in response to cellular stress were increased while induction of defense mechanisms was attenuated. We also show increased apoptosis and necrosis as well as infiltration of macrophages and CD4+-cells in the islets. Taken together, our findings demonstrate that Tfb1 m-deficiency in β-cells caused mitochondrial dysfunction and subsequently diabetes due to combined loss of β-cell function and mass.
These observations reflect pathogenetic processes in human islets: using RNA sequencing, we found that the TFB1M risk variant exhibited a negative gene-dosage effect on islet TFB1M mRNA levels, as well as insulin secretion. Our findings highlight the role of mitochondrial dysfunction in impairments of β-cell function and mass, the hallmarks of T2D.
Mol Hum Reprod. 2014 June
Developmental programming of obesity and insulin resistance:
does mitochondrial dysfunction in oocytes play a role?
Insulin resistance is a key defect associated with obesity, type 2 diabetes and other metabolic diseases. While a number of factors have been suggested to cause defects in insulin action, there is a very strong association between inappropriate lipid deposition in insulin target tissues and the development of insulin resistance. In recent times, a large number of studies have reported changes in markers of mitochondrial metabolism in insulin resistant individuals, leading to the theory that defects in mitochondrial substrate oxidation are responsible for the buildup of lipid intermediates and the development of insulin resistance.
The primary support for the mitochondrial theory of insulin resistance comes from studies in skeletal muscle, however there is recent evidence in murine models that mitochondrial dysfunction in oocytes may also play a role. Oocytes from obese or insulin resistant mice have been shown to exhibit abnormalities in many different mitochondrial parameters, including mitochondrial morphology and membrane potential.
Here we review the findings regarding the link between mitochondrial dysfunction and insulin resistance, and propose that abnormalities in mitochondrial metabolism in oocytes may predispose to the development of obesity and insulin resistance and thus contribute to the inter-generational programming of metabolic disease.
Curr Pharm Des. 2013 Feb 20
Mitochondrial dysfunction and oxidative stress in insulin resistance.
Evidence is mounting of the involvement of mitochondrial dysfunction in insulin resistance, diabetes and associated complications. This review aims to provide an overview of the effects of insulin resistance on mitochondrial function in several tissues.

We consider the pathogenesis of insulin resistance from a mitochondrial perspective and contemplate potential beneficial effects of strategies aimed at modulating mitochondrial function in insulin resistance, including insulin and insulin-sensitizing drugs, antioxidants, and selectively targeting antioxidants to mitochondria.
Antioxid Redox Signal
2013 Feb 24

Mitochondria and Metabolic Homeostasis.
Mitochondrial function is fundamental to metabolic homeostasis. In addition to converting nutrient flux into energy molecule ATP, the mitochondria generate intermediates for biosynthesis and reactive oxygen species (ROS) that serves as a secondary messenger to mediate signaling transduction and metabolism. Alterations of mitochondrial function, dynamics and biogenesis have been observed in various metabolic disorders including aging, cancer, diabetes and obesity.

However, the mechanisms responsible for mitochondrial changes and the pathways leading to metabolic disorders remain to be defined. In the last few years, tremendous efforts have been devoted to addressing these complex questions and led to significant progress. In a timely manner, the Forum on Mitochondria and Metabolic Homeostasis intends to document the latest findings in both original research article and review articles, with the focus on addressing three major complex issues:

(1) mitochondria and mitochondrial oxidants in aging - the oxidant theory (including mitochondrial ROS) being revisited by a hyperfunction hypothesis and a novel role of SMRT in mitochondria-mediated aging process being discussed;
(2) impaired mitochondrial capacity (e.g., fatty acid oxidation, OXPHOS for ATP synthesis) and plasticity (e.g., the response to endocrine and metabolic challenges, and to calorie restriction) in diabetes and obesity;
(3) mitochondrial energy adaption in cancer progression - a new view being provided for H+-ATP synthase in regulating cell cycle and proliferation by mediating mitochondrial OXPHOS, oxidant production, and cell death signaling. It is anticipated that this timely Forum will advance our understanding of mitochondrial dysfunction in metabolic disorders.
Front Med. 2013 Mar

Mechanisms of insulin resistance in obesity.
Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts.

However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria.

The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.
PLoS One. 2013
Relationships between Mitochondrial Function and
Metabolic Flexibility in Type 2 Diabetes Mellitus.
INTRODUCTION: Mitochondrial dysfunction, lipid accumulation, insulin resistance and metabolic inflexibility have been implicated in the etiology of type 2 diabetes (T2D), yet their interrelationship remains speculative. We investigated these interrelationships in a group of T2D and obese normoglycemic control subjects.
METHODS: 49 non-insulin dependent male T2D patients and 54 male control subjects were enrolled, and a hyperinsulinemic-euglycemic clamp and indirect calorimetry were performed. A muscle biopsy was taken and intramyocellular lipid (IMCL) was measured. In vivo mitochondrial function was measured by PCr recovery in 30 T2D patients and 31 control subjects.
RESULTS: Fasting NEFA levels were significantly elevated in T2D patients compared with controls, but IMCL was not different. Mitochondrial function in T2D patients was compromised by 12.5% (p<0.01). Whole body glucose disposal (WGD) was higher at baseline and lower after insulin stimulation. Metabolic flexibility (ΔRER) was lower in the type 2 diabetic patients (0.050±0.033 vs. 0.093±0.050, p<0.01). Mitochondrial function was the sole predictor of basal respiratory exchange ratio (RER) (R(2) = 0.18, p<0.05); whereas WGD predicted both insulin-stimulated RER (R(2) = 0.29, p<0.001) and metabolic flexibility (R(2) = 0.40, p<0.001).
CONCLUSIONS: These results indicate that defects in skeletal muscle in vivo mitochondrial function in type 2 diabetic patients are only reflected in basal substrate oxidation and highlight the importance of glucose disposal rate as a determinant of substrate utilization in response to insulin.
Trends in Endocrinology & Metabolism,
05 July 2012

Mitochondrial dysfunction in pancreatic β cells
In pancreatic β cells, mitochondria play a central role in coupling glucose metabolism to insulin exocytosis, thereby ensuring strict control of glucose-stimulated insulin secretion. Defects in mitochondrial function impair this metabolic coupling, and ultimately promote apoptosis and β cell death. Various factors have been identified that may contribute to mitochondrial dysfunction.

In this review we address the emerging concept of complex links between these factors. We also discuss the role of the mitochondrial genome and mutations associated with diabetes, the effect of oxidative stress and reactive oxygen species, the sensitivity of mitochondria to lipotoxicity, and the adaptive dynamics of mitochondrial morphology.

Better comprehension of the molecular mechanisms contributing to mitochondrial dysfunction will help drive the development of effective therapeutic approaches.
Antioxid Redox Signal 2010 Apr

Mitochondrial dysfunction in diabetes: from molecular mechanisms
to functional significance and therapeutic opportunities.
Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes.

Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q.

Finally, we address the potential for targeting mitochondria in the therapy of diabetes.
Endocrinol Metab Clin North Am. 2008 Sep
Mitochondrial dysfunction in type 2 diabetes and obesity.
Insulin resistance in skeletal muscle is a major hallmark of type 2 diabetes mellitus (T2D) and obesity that is characterized by impaired insulin-mediated glucose transport and glycogen synthesis and by increased intramyocellular content of lipid metabolites.

Several studies have provided evidence for mitochondrial dysfunction in skeletal muscle of type 2 diabetic and prediabetic subjects, primarily due to a lower content of mitochondria (mitochondrial biogenesis) and possibly to a reduced functional capacity per mitochondrion.

This article discusses the latest advances in the understanding of the molecular mechanisms underlying insulin resistance in human skeletal muscle in T2D and obesity, with a focus on possible links between insulin resistance and mitochondrial dysfunction.


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