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The Changhua Journal of Medicine (2013) 11, 1-7
The Changhua Journal of Medicine
journal homepage: http://www2.cch.org.tw/7477
REVIEW ARTICLE
Diabetes and Mitochondria
Shih-Li Su1,2,, Chen-Ling Kuo2, Chin-Shan Liu2,3,*
1
Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Education Center,
Changhua Christian Hospital, Changhua, Taiwan
2
Vascular & Genomic Center, Changhua Christian Hospital, Changhua, Taiwan
3
Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
Received 1 July 2013; accepted 2 August 2013
*
Corresponding author. Vascular and Genomic Center, Changhua Christian Hospital, 7F, 235 Xuang Road, Changhua 500, Taiwan
E-mail address: [email protected] (C.-S. Liu)
Copyright © 2013, Changhua Christian Hospital.
Introduction
Absolute or relative insulin insufficient functions
will produce abnormal glucose homeostasis that can
induce consequence of a complex metabolic disorders.
After overnight fasting times, blood glucose elevated
over 126 mg/dL, or random postprandial level excess
200 mg/dL, or glycated hemoglobin concentration higher than the threshold of 6.5 gm%, diabetes mellitus can
be diagnosed with or without clinical characteristics [1].
The pathogenesis, triggering factors and underlying
mechanisms behind the development of diabetes and its
complications remain elusive.
Mitochondrion contains double-membrane organelles with multiple essential cellular functions. The mitochondria-specific proteins are encoded and con-trolled
by both the nuclear and mitochondrial genomes [2]. Mitochondria are always recognized for the role in generating cellular adenosine 5'-triphosphate (ATP) via oxidative phosphorylation (OXPHOS). The other me-tabolic
functions include the generation by the tricarboxylic
acid (TCA) cycle of numerous metabolites that function
in cytosolic pathways, oxidative catabolism of amino
acids, ketogenesis, ornithine cycle activity (“urea cycle”)
are also important for cells living and fuel supporting.
All of these related to cell energy production and utility,
therefore, mitochondrion is the power plant of cells. The
primary or secondary alterations in mitochondria related
signaling pathways could be explained multiplicity of
organelle functions and va-riability in the pathophysiology [3].
Mitochondrial diabetes was initially described as
maternally inherited diabetes and deafness syndrome
(MIDD). The origin of MIDD is primary defects in mitochondria mutation with dysfunction. The clinical presentation of MIDD is similar to that of type 1 or type 2
diabetes but accompany with hearing impairment, poor
vision, and seizure disorders [4]. The clinical phenotype of MIDD is heterogeneous, even within the same
family. Some patients may present with isolated diabetes
or impaired glucose tolerance but no overt hearing loss,
whereas others have early-onset diabetes and deafness
and yet others have MELAS syndrome (mitochondrial
encephalopathy, lactic acidosis, and stroke-like episodes). This phenotypic variability has been ascribed in
part to differences in the amount of mutant mitochondria
deoxyribonucleic acid (mtDNA) relative to wild-type
2
mtDNA, which may vary across tissues [5]. We will not
focus on this primary type of mitochondrial defects in
this article. We will discuss about issues of the following sections as mitochondrial dysfunction and diabetes,
diabetes with mitochondrial dysfunction, and hyperglycemia with mitochondria.
Mitochondrial dysfunction and diabetes
When mitochondria produce ATP for cellular energy sources, reactive oxygen species (ROS) sustain
with ATP synthesis. Overloading of ROS will injury the
mitochondria especial in pancreatic beta cells by fragmented DNA then activates a consequent stress pathway
[6]. ROS appear to be produced in larger amounts by
islets from T2DM patients than by those from nondiabetic subjects [7,8,9]. Type2 diabetes subjects’ beta
islet exhibit mitochondrial morphologic abnormalities.
A hypertrophic, round shape and higher density compare
to a slim, elliptical and low density in normal control
that had been revealed [10]. Pancreatic beta cells’ mitochondrial membrane potential are regulated by uncoupling protein-2 (UCP2). UCP2 can facilitate proton
trickle that will reduce the mitochondrial membrane
potential then diminished the synthesis of ATP. UCP2
also can down regulates insulin secretion. While mitochondrial ROS over-production particular superoxide
(O•−2 ) that could enhance UCP2 activation results in
beta cell dysfunction [11].
Type 2 diabetes is following with progressive decrease in β-cell mass due to marked increase beta cell
S.-L. Su et al.
apoptosis [12]. It’s well known that mitochondria play a
pivotal role in regulating cell apoptotic death [13].
Proapoptotic stimulating agents are released from mitochondrial cytochrome c into the cytoplasm. By the way,
cytochrome c participates in apoptosome formation
which can conduct a series of caspase reaction and subsequent activation then demolished the cell apoptosis.
Insulin resistance was defined as a diminished responsive ability of cells or tissues in normal physiological insulin concentrations. Genetic and environmental
factors, including aging, obesity, lack of exercise, and
stress are considered to causes of insulin resistance. The
molecular and cellular mechanisms of insulin resistance
are relevant to the pathogenesis of type 2 diabetes [14,
15]. The major sites of insulin resistance are the target
tissue of insulin actions e.g. liver, skeletal muscle and
adipose tissues. A possible mechanism may explain the
impaired mitochondrial function which contributes to
insulin resistance due to altered metabolism of fatty acids. Increased tissue lipid load would lead the accumulation of fatty acyl coenzyme A (CoA), diacylglycerols,
ceramides, products of incomplete oxidation, and RO.
These will conduct to experimentally reduced insulin
signaling and action [16, 17]. The other possible mechanisms linking between impaired mitochondrial oxidative
function and insulin resistance persisted. Diminished
ATP synthesis is insufficient for energy requiring functions such as insulin-stimulated glucose uptake. Therefore, insulin cannot perform whole functions [18].
About the relationship between mitochondrial and
pancreatic beta cells, we can make a picture as figure1.
Diabetes and Mitochondria
3
Figure 1: Schematic summary of the proposed role of mitochondrial oxidative stress and β-cell in diabetes mellitus.
Diabetes with Mitochondrial Dysfunctions
The biopsies of type 2 diabetes subjects’ skeletal
muscle demonstrated that size of mitochondria became
smaller size and number per unit volume are relatively
dense [19]. The size of mitochondria appears with positive correlate with whole-body insulin sensitivity. Moreover, mitochondria of offspring of diabetic subjects are
lower in density compared with those of controls [20]. It
is clear that morphological changes in mitochondria
occur in diabetic states. These changes will reduce
NADH oxidoreductase and decline citrate synthase activity in the mitochondria of the diabetes and obese subjects compared with lean subjects.
Besides mitochondrial number and morphology,
mitochondrial metabolism also depends on the dynamic
movement and distribution of the this organelles, such as
fusion or fission, which is essential to maintain the mitochondrial function of ATP synthesis [21]. As mitochondria move within cells, they undergo both fission,
needed for distribution and networking, and fusion,
needed for mixing of the mitochondrial genome. Evidence indicates that obesity in both humans and rodents
is associated with reduced ability of fusion [22]. That
means losing the capacity of change mtDNA. Moreover,
polymorphisms of presenillin-associated rhomboid-like
(PARL) protein which also one kind of fusion protein in
humans is associated with insulin resistance [23].
About 30-40% decrease in oxidative phosphorylation measured by magnetic resonance spectroscopy
(MRS) in insulin resistance related subjects including
type 2 diabetes, lean to normal glucose-tolerant elderly
individuals, and offspring of patients with type 2 diabetes when compare with normal healths [24]. The defect
in oxidative phosphorylation in lean, NGT, insulinresistant offspring of patients with type 2 diabetes is
associated with a decreased metabolic flux through the
tricarboxylic acid (TCA) cycle under basal conditions.
[25]. Type 2 diabetes subjects easy have impaired recovery of intracellular phosphocreatinine concentration
following exercise [26,27]. This suggests a mitochondrial defect in oxidative phosphorylation possible contributes to the impairment in exercise capacity in these
insulin-resistant individuals.
From above mentions, diabetes subjects have decreased variety of mitochondrial activities compared
with healthy individuals. We can make a summary as
figure 2.
4
S.-L. Su et al.
Figure 2: Schematic summary of the proposed role of diabetes affect mitochondria function
Hyperglycemia and Mitochondria
Hyperglycemia will increase the response of oxidative stress then enhance mitochondrial damage [28]. The
fasting blood glucose and hemoglobin A1c (HbA1c)
have been shown to be correlated to phosphocreatinine
recovery half-time [27]. It’s possible that hyperglycemia
could have adverse effects on mitochondrial biogenesis
and/or function in patients with type 2 diabetes. Significant improvement of diabetes glycemic control does not
affect skeletal muscle mitochondrial respiration and contents [29]. Skeletal muscle mitochondrial respiration was
approximately 20% lower in patients with type 2 diabetes compared with age- and BMI-matched control subjects. The differences were eliminated when data were
normalized to citrate synthase activity. Mitochondrial
respiration and content was not improved after significant improvements in glycemic control. Severe hyperglycemia inhibited respiration reversibly due to block
electron transport via increased ROS production. The
dynamic changes in mitochondrial morphology are associated with high glucose-induced overproduction of
ROS. Mitochondria became fragmentation rapidly with
a concomitant increase in ROS formation after exposure
to high glucose concentrations [30].
Chronic persisted hyperglycemia will induce tissue
damage by different mechanisms, include: activated
protein kinase C (PKC) isoforms synthesis as the second
messenger diacylglycerol (DAG), increased hexosamine
pathway flux, increased advanced glycation end product
(AGE) formation, and increased polyol pathway flux.
Hyperglycemia also induced superoxide over-production
and inhibited glucose-6-phosphate dehydrogenase which
is the causal link between high glucose and the pathways
responsible for hyperglycemias damage [31]. Diabetes is
typically accompanied by increased production of free
radicals and/or impaired antioxidant defense capabilities,
indicating a principal contribution for ROS in the onset,
progression, and pathological complications of diabetes
[32]. Mutations in mtDNA and decreases in mtDNA
copy number have been linked to the pathogenesis of
type 2 diabetes [33]. The relationship between mtDNA
and type 2 diabetes has revealed the influence of the
mitochondria of nuclear-encoded glucose transporters,
glucose-stimulated insulin secretion, and nuclear encoded uncoupling proteins in β-cell glucose toxicity.
Therefore, hyperglycemia could affect mitochondria continuously. We can make a summary as figure 3.
Diabetes and Mitochondria
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Figure 3 : Schematic summary of the proposed role of hyperglycemia affect mitochondria function
Conclusion
Acknowledgements
The relationships between mitochondria and diabetes are complex. Reciprocal causation and interaction
make a vicious cycle. Mitochondria over produce ROS
will create pancreatic beta cells damages including
apoptotic changes and loss normal function. Beside beta
cell, mitochondria also play the roles on the insulin classic target tissue such as skeletal muscle, liver and adipocytes. Insulin resistance will be provoked especial mitochondria loss its regular function.
Diabetes will generate mitochondrion deviation including small and dense morphological alternation, diminished fusion ability and oxidative phosphorylation.
That will illuminate the reason of diabetes patient with
fatigue and exercise intolerance. Chronic and acute hyperglycemia also deteriorate the mitochondria's defense
ability and increase free radicals. Poor compensatory
reaction including copy numbers and mutant mtDNA,
accompany by low respiratory contents, which will
cause exacerbation of mitochondrial function. Day by
day, chronic complications will be developed.
This article can provide a little knowledge as a
bridge between mitochondria and diabetes. Further literatures survey and laboratory trials still needed.
This work is supported by the Changhua Christian
Hospital under the grant number 100-CCH-IRP-23.
Conflicts of interest statement
There are no competing interests and none to declare.
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