Revolution in mitochondrial medicine.

A revolution in chemical pathology occurred about 40 years ago with the discovery of a patient with mitochondrial dysfunction. The field of mitochondrial medicine has experienced explosive growth during the last decade. More than 50 mtDNA mutations and several nuclear gene mutations have been identified in affected patients. The recent development of animal models will continue the revolution in mitochondrial medicine by facilitating in depth studies of the molecular pathogenesis and development of novel drug and gene therapy strategies for mitochondrial dysfunction. As we enter the next millennium, we can expect mitochondrial medicine to remain a dynamic and rapidly developing field.

Mitochondrial medicine.

In the mitochondrion, inherited defects have been identified in the electron transport system by which ATP is formed, as well as in the transport and metabolism of fuels. Clinical findings in diseases due to these defects can be related to abnormal accumulations of metabolic intermediates and inadequate or inefficient ATP generation. In the oxidative process within the mitochondrion, chemical oxidants are generated, which can cause cellular damage. As the body's defences against the oxidants decline, oxidative damage appears to contribute to the ageing process itself as well as to age-related degenerative diseases. Understanding in this area has accelerated with knowledge of the synthesis, structure and function of the mitochondrion and its specific DNA. The frontier is expected to advance rapidly as causal relationships between these diseases and mitochondrial dysfunction, and the potential role of antioxidants in therapy, are better defined.

The development of mitochondrial medicine.

I consider mitochondrial medicine a tentative designation for an area within clinical medicine still to be delineated. Its development extends over a period of 35 years, from its discovery in 1959 [1]. Progress had been gradual until recent years when it has become explosive in nature with extensions in many different directions. My presentation is an effort to illustrate this evolution with emphasis on especially important observations which by leaps advanced the area. We are fortunate to have here several of the distinguished investigators, who have contributed so much to those advances. They will share with us their deep knowledge in different aspects of mitochondrial medicine, what is known, what remains to be elucidated, and what the problems are to be encountered in that elucidation.

The development of mitochondrial medicine.

Primary defects in mitochondrial function are implicated in over 100 diseases, 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, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. 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 muscle 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 well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. 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 strategies, 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 called mitochondrial medicine, much more is likely to be achieved within the next few years.

[Physiopathology of mitochondria. From Luft's disease to aging and diabetes]. / Mitokondriernas patofysiologi. Från Lufts sjukdom till åldrande och diabetes.

The first disease due to disturbances in a cell organelle was discovered in 1959-62, and its basis was loose-coupling of oxidative phosphorylation in the skeletal muscle mitochondria accompanied by severe alterations of their structure (Luft's disease). During the 1980s, functional disturbances and structural alterations in the mitochondria were observed in more than 100 disease entities, mainly in parts of the central nervous system and skeletal muscles. A second breakthrough in this area was the discovery in 1963-64 that mitochondria had their own DNA, mtDNA. Following the observation in 1988 of mutations of mtDNA in mitochondrial diseases, such mutations--mainly deletions and point mutations--were observed in almost all mitochondrial diseases. A remarkable extension of the area is the notion that "normal" ageing is accompanied by decreased oxidative phosphorylation and the appearance of mtDNA mutations. During the last two years, such changes have been demonstrated in diseased states in tissues and organs, which are especially reliant on oxygen supply: in the central nervous system (Parkinson's disease, some types of epilepsy and seizures, Huntington's disease, possibly also in Alzheimer's disease); in heart muscle (cardiomyopathies) and in skeletal muscle. Type 2 diabetes or NIDDM engages two tissues most reliant on oxygen consumption, the pancreatic islets (insulin secretion) and skeletal muscle (insulin sensitivity). Both these functions are genetically determined, the latter to a high degree also controlled by "environmental" factors. The evident age factor in the development of NIDDM could be on a par with the "normal" ageing process.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA polymorphisms in the human tyrosine hydroxylase/insulin/insulin-like growth factor II chromosomal region in relation to glucose and insulin responses.

The feasibility of disease association studies using polymorphic DNA markers in the tyrosine hydroxylase/insulin/insulin-like growth factor II chromosomal region was indicated by a high degree of linkage disequilibrium found in haplotypes. Haplotypes were resolved in the parents from Scandinavian nuclear families by studying the segregation of eight DNA polymorphisms. Comparison of observed vs expected frequencies of haplotypes, as well as pairwise measures of linkage disequilibrium, indicated a high degree of linkage disequilibrium. Five restriction fragment length polymorphisms linked to the tyrosine hydroxylase/insulin/insulin growth factor II region of chromosome 11 were investigated in relation to Type 2 (non-insulin-dependent) diabetes mellitus, and to glucose and insulin responses to glucose infusion in healthy subjects. No significant differences in genotype frequencies between Type 2 diabetic (n = 53) and healthy subjects (n = 106) were found. A significant association (p < 0.001) was initially found between genotypes defined by a PstI polymorphism located 5' of the tyrosine hydroxylase gene and the early glucose response to a standardized glucose infusion test in healthy subjects. However, a follow-up study of 112 healthy individuals failed to confirm this finding.

Screening for insulin receptor gene DNA polymorphisms associated with glucose intolerance in a Scandinavian population.

The significance of insulin receptor gene variants in the aetiology of Type 2 (non-insulin-dependent) diabetes mellitus has been investigated by analysis of restriction fragment length polymorphisms in a genetically homogeneous Swedish population. Seven polymorphisms were analysed, spanning functionally important regions of the insulin receptor locus. Four of these polymorphisms were mapped more accurately within the gene compared to previous studies. The genotype distribution was compared in 76 Type 2 diabetic patients and 84 healthy control subjects. No significant differences were found in the distribution of genotypes between diabetic and control subjects at the p less than 0.01 level. In order to study the possible association between quantitative measures of glucose metabolism and these DNA polymorphisms, the fasting glucose and insulin concentrations were compared in the different genotype groups of control subjects and mildly diabetic patients treated with diet. No differences in fasting glucose or insulin concentrations were found at the p less than 0.005 level of significance. In conclusion, no significant associations were found between insulin receptor gene DNA polymorphisms and glucose intolerance.

Evaluation of comprehensive program for diabetes care at primary health-care level.

The Swedish National Board of Health and Welfare published its first diabetes health-care program in 1977. The impact of the program was evaluated in the Stockholm County after 4 yr. The results showed that the educational program had reached greater than or equal to 1 staff member in 86% of the 104 primary health-care centers (PHCCs). Several organizational changes had taken place as a result of the program. The 10 "best" PHCCs were compared with a random sample of the centers with regard to patient outcomes. Patients from the 10 best centers had gotten a more comprehensive education, were more knowledgeable about foot care, tested glucose more often, and used less medication. The metabolic control was the same for both groups of patients. The PHCC staffs reported the following roadblocks to change: lack of knowledge of diabetes care, insufficient cooperation between staff members, poor contact with specialists, and absence of guidelines for diabetes care. The staffs in the best centers spent twice as much time in staff meetings and continuing education as those from the random sample of centers. The findings led us to formulate a new strategy for the program. The main objective of the new approach is to create organizational changes within the centers. Thus, local knowledge and creativity can be utilized. Preliminary data demonstrate that 84% of the locally developed plans for reorganization of diabetes care had been accomplished within 1 yr.

Glucose tolerance, insulin release, and insulin sensitivity in normal-weight women with previous gestational diabetes mellitus.

Out of 57 women with previous histories of gestational diabetes (GD), 23 were of normal weight postpartum and willing to participate in three studies characterizing oral glucose tolerance (OGTT), insulin responsiveness to intravenous glucose (glucose infusion test, GIT), and insulin sensitivity (somatostatin, insulin, and glucose infusion test, SIGIT). The experiments were performed 6-36 mo after cessation of breast-feeding. The control group comprised 10 healthy women with normal OGTT matched for age and weight. Among subjects with previous histories of GD, 9 had normal, 8 borderline, and 6 decreased OGTT. As a group, women with previous histories of GD have significantly decreased insulin response and insulin sensitivity. Furthermore, all 14 with borderline and decreased OGTT demonstrated a low early insulin response during GIT (5-min value below the upper border of the lower quartile of normals), whereas insulin sensitivity was normal in 6 and low in 8 (glucose values attained during SIGIT were lower or higher, respectively, than the lower border of the upper quartile of controls). The women with previous histories of GD and normal OGTT exhibited normal (n = 4) and low (n = 5) insulin responses. Three of the former subjects had low and the remaining 6 had normal insulin sensitivity. In conclusion, as many as 60% of normal-weight women with previous histories of GD had borderline or decreased OGTT 6-36 mo postpartum. This derangement could be due to impaired early insulin response, which in some subjects was combined with low insulin sensitivity. Follow-up of women with previous histories of GD might enlighten the pathogenesis of non-insulin-dependent diabetes mellitus.

Genetic regulation of the kinetics of glucose-induced insulin release in man. Studies in families with diabetic and non-diabetic probands.

Insulin release and sensitivity were estimated from glucose and insulin curves obtained at a glucose infusion test performed on altogether 601 subjects belonging to 155 nuclear families. Ascertainment was through one of the parents, and 96 of the probands had diabetes with clinical onset after the age of 30 years, while 59 were healthy subjects. Three variables obtained by a computer model were analysed, i.e. the glucose regulation of insulin release by a direct stimulatory event (KI) and time-dependent modulatory events (KP) as well as insulin sensitivity (KG). Complex segregation analysis revealed that the variables are genetically regulated, but there was no evidence for a major locus. The children of the diabetics did not differ from those of the non-diabetics as far as insulin release is concerned.

Retinal microangiopathy and pigment epithelial lesions in subjects with normal, borderline, and decreased oral glucose tolerance.

Retinal fluorescein angiography was performed in 150 subjects: 64 with normal fasting blood glucose and normal oral glucose tolerance test (OGTT), 49 with borderline, and 37 with decreased OGTT. Microaneurysms were noted in only two subjects, both with decreased OGTT. Minute changes in the retinal pigment epithelium (RPE) were seen in 23% of the 64 normal persons, in 35% of those with borderline, and 49% of those with decreased OGTT (p less than 0.05). The impact of glucose intolerance was more pronounced in subjects under the age of 50 years, RPE changes being rare (7%) in those with normal OGTT but occurring in 32% of those with borderline or decreased OGTT (p less than 0.01). The corresponding figures among subjects aged 50 or more were 55% and 57%, respectively. We conclude that at least half of the subjects above 50 years show RPE alterations, and that minimal changes in glucose metabolism may precipitate the development of such changes at an earlier age.