Diabetes mellitus in Kearns-Sayre Syndrome

Tanabe, Yuzo; Miyamoto, Shigeki; Kinoshita, Yoshihiko; Yamada, Kazutaka; Sasaki, Nozomu; Makino, Eiichi; Nakajima, Hideto

doi:10.1159/000116225

Cited by 27 publications

(14 citation statements)

References 20 publications

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“…In addition, defective insulin secretion and regional adiposity may be more important than skeletal muscle mitochondrial function in the development of glucose intolerance with aging (5), raising the possibility that the link between mitochondrial dysfunction and insulin resistance is tenuous. Consistent with this idea, human mitochondrial mutations cause myopathy and diabetes that is due to insulin secretory failure, usually in the absence of insulin resistance (3,6,41).…”

Section: Discussionmentioning

confidence: 79%

UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction

Han

Nolte

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. UCPmediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction. Am J Physiol Endocrinol Metab 286: E347-E353, 2004. First published November 12, 2003 10.1152/ajpendo.00434.2003.-To address the potential role of lipotoxicity and mitochondrial function in insulin resistance, we studied mice with high-level expression of uncoupling protein-1 in skeletal muscle (UCP-H mice). Body weight, body length, and bone mineral density were decreased in UCP-H mice compared with wild-type littermates. Forelimb grip strength and muscle mass were strikingly decreased, whereas muscle triglyceride content was increased fivefold in UCP-H mice. Electron microscopy demonstrated lipid accumulation and large mitochondria with abnormal architecture in UCP-H skeletal muscle. ATP content and key mitochondrial proteins were decreased in UCP-H muscle. Despite mitochondrial dysfunction and increased intramyocellular fat, fasting serum glucose was 22% lower and insulin-stimulated glucose transport 80% higher in UCP-H animals. These beneficial effects on glucose metabolism were associated with increased AMP kinase and hexokinase activities, as well as elevated levels of GLUT4 and myocyte enhancer factor-2 proteins A and D in skeletal muscle. These results suggest that UCP-H mice have a mitochondrial myopathy due to depleted energy stores sufficient to compromise growth and impair muscle function. Enhanced skeletal muscle glucose transport in this setting suggests that excess intramyocellular lipid and mitochondrial dysfunction are not sufficient to cause insulin resistance in mice.

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Section: Discussionmentioning

confidence: 79%

UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction

Han

Nolte

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…Can an increase in the incidence of insulin-dependent diabetes mellitus (IDDM) be on the basis of environmental exposure or other factors involving the mitochondrial genome? (147)(148)(149). The earlier the onset of mitochondrial myopathy in these conditions, the more frequent was its association with IDDM (150).…”

Section: Diabetes Mellitusmentioning

confidence: 99%

The development of mitochondrial medicine.

Luft¹

1994

Proc. Natl. Acad. Sci. U.S.A.

270

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Primary defects in mitochondrial function are implicated in over 100 diseses, and the list continues to grow. Yet the first mitochondrial defect-a myopathy-was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (i) euiation of the steps involved in mitochondrial biosynthesis, and (Ni) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal t ission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscie and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as weli as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes meflitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic sttegies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be cafled mitochondrial medicine, much more is likely to be achieved within the next few years.In 1959, the first biochemical studies of a cell organelle in humans were undertaken, following observations made at the bedside of a patient with striking symptoms, never before encountered. These clinical observations, first, led to an idea about the origin ofthe symptoms and, second, to studies of the particular organelle: the mitochondrion (1). The pathophysiology of the mitochondria developed gradually over the years as relevant discoveries were made in biochemistry, cell biology, and molecular biology. During the past few years the field mitochondrial medicine has expanded dramatically, in several directions. I here provide a short review concentrating on those aspects most relevant to clinical medicine. In the accompanying review (174), Wallace describes the molecular, biological, and evolutionary implications of mitochondrial diseases.The Birth of Mitochondrial Medicine (1959)(1960)(1961)(1962): Luft DiseaseThe first patient found to have a mitochondrial disease was a 30-year-old woman who developed clinical symptoms at the age of 7. Her dominant symptoms were enormous perspiration combined with markedly increased fluid intake but without polyuria; extremely high caloric intake (above 3000 kcal per day) at a stable body weight of 38 kg and a body height of 159 cm; and general weakness, particularly prominent in her musculature. The do...

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“…Kadowaki et al [9] and Awata et al [10] demonstrated a significant reduction of maximal insulin secretory capacity and early secretion response of insulin to glucose administration in diabetic patients with the 3243 bp mutation. Several additional reports demonstrated reduced insulin secretion in diabetes with other mitochondrial diseases, such as CPEO and KSS [22,25]. In contrast, Van den Ouweland et al [5] and Sue et al [13] showed substantial rises in insulin concentrations in several diabetic subjects with the mutation.…”

Section: Discussionmentioning

confidence: 95%

“…Several lines of evidence suggest that CPEO including Kearns-Sayre syndrome (KSS) is frequently associated with IDDM [20][21][22]. Recent reports also suggest that the MELAS-related mitochondrial gene mutation of tRNA I"zu(uum (3243) associates with maternally inherited diabetes and with neurosensory deafness [5,6,[9][10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

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Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNA L E U ( U U R ) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)

et al. 1994

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Summary Recent evidence suggests possible linkage between diabetes mellitus and mitochondrial gene mutation. We surveyed mitochondrial tRNA LzU(uua) (3243) mutation in 7 mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) families and identified 24 mutated subjects (7 MELAS probands and 17 non-MELAS relatives) as well as 11 non-mutant family members. An OGTT in the 24 mutant relatives revealed 14 diabetic subjects, 3 with impaired glucose tolerance and 7 with normal glucose tolerance and all non-mutant family members as having normal glucose tolerance. Insulinogenic index was significantly reduced in the mutant diabetic subjects and those with impaired and normal glucose tolerance in comparison with the normal control subjects and the non-mutant members. Urinary 24-h C-peptide immunoreactivity excretion was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance, compared with the control subjects and the non-mutant family members. Plasma C-peptide immunoreactivity 6 rain after glucagon injection was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance compared with the control subjects and the non-mutant family members. Si, an index of insulin sensitivity of the four mutant subjects was within normal range. Islet cell antibodies were negative in sera of eight mutated diabetic subjects, 2 and 6 with impaired and normal glucose tolerance, respectively. Diabetic retinopathy and nephropathy were demonstrated in 7 (50 %) and 12 (85.7 %) of 14 mutant diabetic subjects, respectively. Neurosensory deafness was demonstrated in 12 (85.7 %) of 14 mutated diabetic subjects, (66.7 %) of 3 mutated impaired glucose tolerant subjects, but not detected in 6 mutated normal glucose tolerant subjects and 11 non-mutant family members. These findings suggest that the tRNA Lzu(uuR) mutation is associated with pancreatic beta-cell secretory defect of insulin. [Diabetologia (1994) 37: 818-825]

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Diabetes mellitus in Kearns-Sayre Syndrome

Cited by 27 publications

References 20 publications

UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction

UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction

The development of mitochondrial medicine.

Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNA L E U ( U U R ) gene: a study in seven families with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)

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