Curr Pharm Des. 2013 Feb 20
.
Mitochondrial dysfunction and
oxidative stress in insulin resistance.
Abstract
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.
Abstract
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.
Abstract
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.
Abstract
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
Summary
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.
Abstract
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.
Abstract
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.
