Progressive external ophthalmoplegia

Diabetes mellitus is a collection of genetic diseases that share a common phenotype: glucose intolerance. The genetic origins of this disease are being widely investigated. An estimated 0. 19% of the population with diabetes has the disorder owing to one or more mutations in the mitochondrial genome. Diet can affect the expression of the genome as well as the function of its gene products. The antioxidant nutrients serve to protect this very vulnerable genome from oxidative damage. These nutrients may affect mitochondrial DNA transcription and nutrients that affect membrane fluidity affect the function of the gene products.

Introduction

Diabetes mellitus is a collection of genetic diseases with a common phenotype of impaired glucose homeostasis. It affects the largest number of people in developed nations compared with almost any other disease entity of genetic origin. People with diabetes are more likely to be overly fat, and to develop heart disease and renal disease at rates far exceeding those of the general population without diabetes. Other complications include blindness, stroke, and peripheral circulatory problems that may lead to gangrene and amputation. A number of mutations have been identified that phenotype as diabetes yet the prevalence of the genotype does not match the prevalence of phenotype. It has been estimated that there are twice as many people with one or more of these mutations than people who actually have the disease. Clearly there are factors in addition to genetics that play a role in disease development. This review addresses one of the major groups of mutations that phenotype as diabetes. These are the mutations that occur in the mitochondrial genome. Both the diabetes that occurs in the human and that which occurs in the BHE/Cdb rat will be discussed.

Diabetes Phenotypes

People with diabetes are divided into two general categories based on the treatment or management of their abnormal glucose homeostasis. Approximately 10% of the total diabetes population has the very severe type 1 disease that requires daily hormone replacement and careful management of diet and physical activity. These people develop the disease as a result of one or more mutations in the more than 100 genes that encode the components of the immune system. In the majority of these situations, the mutation results in autoimmune disease.1 Autoimmune diabetes is the most frequent disease form in children, but it can strike adults as well. Autoimmune disease is a broad term that covers not only the destruction of the pancreatic islet (insulin-producing) beta-cells but also the self-destruction of thyroid cells (thyroiditis), connective tissue (rheumatoid arthritis), and skin (psoriasis). The phenotype of autoimmune disease is, in general a loss in antigen specificity recognition. The body loses its ability to distinguish foreign proteins from self-proteins. As a result, the body makes antibodies to its own cell proteins and destroys these cells. Diet has little role in the development of autoimmune diabetes but can play an important role in its management.2

A small percentage of people with type 1 diabetes are those who develop the disease as a secondary complication of an infectious disease. In this case, the mutation has to do with the inability of the body to develop sufficient antibodies to specific pathogens. Pathogens such as coxsackie B-4 virus, certain flu viruses, and others are not repelled as quickly in these people as compared with normal people and these pathogens destroy the insulinproducing islet cells.3-5

Most people with diabetes have type 2 diabetes.6 These people manage their abnormal glucose homeostasis through diet and exercise and are generally at lesser risk for secondary diabetes complications than people with type 1 diabetes. As they age, patients with type 2 diabetes may have to add insulin replacement to their management program but this can be postponed if they can aggressively manage their body fatness and increase their daily physical activity.

There are numerous reports of genetic mutations that phenotype as type 2 diabetes.7-14 Mutations in the genes for the islet glucose sensing-insulin release system, in the insulin gene, in the gene for the insulin receptor substrate, in the gene for the enzyme that cleaves proinsulin to insulin, and in the genes for intracellular glucose transporters, as well as in the insulin receptor have been reported. In most cases, the individual mutations account for only a small percentage of the people with the disease. More than one mutation has been reported for many of these genes. For example, Graeme Bell and colleagues" reported a large number of mutations in the pancreatic islet beta-cell glucokinase. Individuals with mutations in this gene develop maturity-onset diabetes of the young (MODY). Glucokinase plays an important role in the glucose-sensing system of the pancreatic beta-cell.11,15,166 Mutations in hepatocyte transcription factors 1alpha and 4alpha also phenotype as MODY. These transcription factors are important in the control of pancreatic glucokinase as well as other enzymes essential to glucose metabolism. Despite the identification of all these mutations, however, collectively they most likely account for less than 1% of the population with diabetes. The same could probably be said for the many other gene mutations that encode essential components in the glucose homeostatic system. Individually, each mutation accounts for only a very small percentage of the population with diabetes mellitus but altogether they can account for a large number of people that phenotype as type 2 diabetes.

Diabetes Mellitus as a Mitochondrial Disease

A third group of people with diabetes have the disease as a result of mutations in the mitochondrial (mt) genome.1738 Estimates of the size of this population group vary from 0.1-9% of the total population with diabetes. These people do not fall into either the type 1 or type 2 groups with respect to management. They fall somewhere in between. They are not excessively fat so weight loss is not part of the management scheme. In addition, exercise might be out of the question if the mt mutation affects muscle ATP production. Several of the mt mutations are characterized by cardiomyopathy and skeletal myopathy in addition to abnormal glucose homeostasis. Hormone replacement therapy is not usually needed at first; with time, however, it might be needed because there is a gradual deterioration in the insulin-producing pancreatic beta-cells with age. The nutritional management of this group of people has not been well explored with respect to these mutations.

To date, 42 different mtDNA mutations have been reported that are associated with diabetes mellitus (Table 1). There may be more but only those with diabetes as the primary disease fit into this category. A number of mt diseases have abnormal glucose homeostasis as a secondary characteristic. These diseases involve the central nervous system and sometimes the neuromuscular system. Clinicians facing these disorders tend to overlook the secondary feature of diabetes. All of the mt disorders have elevated blood lactate levels. This is due to the failure of the mitochondria to fully utilize the end product of glycolysis, pyruvate, which is then converted to lactate.

That diabetes may be due to one or more mutations in the mtDNA is a fairly recent observation despite the fact that this genome has been fully sequenced and mapped for several decades. At first, mutations in this genome were thought to be rare and to result in diseases of the neuromuscular system or just the central or sensory system.39-46 However, it is now recognized that a variety of common diseases might be due to mutations in mtDNA. In addition to diabetes mellitus, cardiomyopathy, renal disease, a form of epilepsy with ragged red fibers (MERRF), Leber's hereditary optic neuropathy (LHON), neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS), progressive external ophthalmoplegia (PEO), and Leigh's disease are diseases that result from mutations in the mt genome. Parkinson's disease 47 and Alzheimer's disease48-50 have also been attributed to mtDNA mutation, but the documentation for these diseases is not as strong as that for the other diseases.

All of these diseases are maternally inherited because most of the mitochondria in the embryo come from the oocyte. At fertilization the mitochondria in the sperm, located in the midpiece of the tail, disappear by some unknown mechanism.51-54 The ratio of sperm mitochondria to oocyte mitochondria in the fertilized egg is estimated to be 1:1000. Thus, mutations are inherited from the mother, not the father. In the instance of mitochondrial diabetes, this diabetes is maternally inherited. Mutations in the maternal mtDNA can occur spontaneously or can be inherited through several generations. How these mutations occur is not known although speculations abound regarding their origin.

Mitochondrial Genetics In Mitochondrial Diseases

Mitochondrial disease develops when one or more mutations occur in the mtDNA. This genome encodes 13 components of oxidative phosphorylation (OXPHOS) as well as its own tRNAs and ribosomes. Transcription and translation of the structural genes are not well understood. There are promoter regions for both the light strand and the heavy strand of this circular double-stranded genome but the factors that bind to these regions are only now being elucidated. Two nuclear encoded transcription factors have been identified: mitochondrial transcription factor a (mtTFA or Tfam) and mitochondrial termination factor (mTERF).55-59 In addition, insulin,60 some of the steroid hormones,61,62 thyroid hormone,61 vitamin D,65 and retinoic acid 62,66 probably play as important a role in the expression of the mt genome as in the expression of the nuclear genome.

The role of mtTFA in mt gene expression and tissue function has been explored using transgenic mice.61 Tissue-specific threshold effects on structural gene expression were found in mice that had the Tfam gene disrupted in heart and skeletal muscle. Tfam is the gene for mitochondrial transcription factor a and affects mtDNA and mtRNA levels. In this study heterozygous null mutant mice were studied with respect to ATPase 8 gene expression. There were no homozygous mutant mice because the loss of Min was lethal. The heterozygous mice had levels of mtRNA and mtDNA that were, respectively, 29% and 26% of the normal level in heart and 66% and 60% of the normal level in the skeletal muscle. Only the heart had decreased ATPase 8 protein levels, and decreased respiration that led to dilated cardiomyopathy and atrioventricular conduction blocks. Skeletal muscle had normal ATPase 8 protein levels, normal respiration, and normal morphology. This study highlighted the dependence of mt transcription on nuclear encoded transcription factors and showed the importance of mitochondrial gene expression in the regulation of respiration and the phenotypic expression of a mitochondrial disease-causing mutation.

In addition to mutation in the genes that regulate mt gene expression, mutation in any one of the mt structural genes or the tRNAs can affect mitochondrial function and hence tissue function. Mitochondrial disease can result from base substitution, base depletion, base deletions, and base duplications in these genes.61-74 In addition, mitochondrial disease can be the result of several independent mtDNA mutations and one mtDNA mutation can cause several different diseases. This multiplicity of disease states is attributed to the unique character of mtDNA.

There are thousands of mitochondria within a cell and each mitochondrion contains 8-10 copies of mtDNA. Both mutant and wild-type mtDNA can exist within a given cell and within a given tissue. Tissues vary in the percent mutant mtDNA. This phenomenon is called heteroplasmy. When a cell contains all mutant or all wild-type mtDNA it is a homeoplasmic cell. It should be noted that individual cell heteroplasmy might not be reflected by mean tissue heteroplasmy, which makes the link between percent heteroplasmy and phenotypic expression even more complicated. In dividing cells, selection occurs against cells with a high percent ofmutant mtDNA.75 However, the proportion of mutant mtDNA can change over time such that a heteroplasmic mutation drifts towards homeoplasmy. This is more of a problem in terminally differentiated cells (i.e., neurons). Mitochondrial turnover is more rapid than whole-cell turnover. In terminally differentiated cells, there is very little selection against mutant mtDNA and so some drift occurs. The inheritance of mutant versus wild-type mtDNA is random.76,77 Thus, a pedigree can occur with family members containing various degrees of heteroplasmy and various phenotypes.

Both heteroplasmic and homeoplasmic mutations are associated with mitochondrial disease. Typically heteroplasmic mutations are in highly conserved nucleotides in the active site of the enzyme or tRNA. These mutations would be lethal if homeoplasmic. By contrast, homeoplasmic mutations usually occur in less conserved nucleotides outside of the active site of the enzyme or tRNA. They are thought to result in milder OXPHOS defects and late onset of disease. This probably explains the age of onset of Alzheimer's disease48-50 and Parkinson's disease.47 One of these is in the tRNA for glycine. The base substitution is outside the active site of the tRNA^sup Gln^ and is only moderately conserved throughout evolution. Nonetheless, its presence is associated with these degenerative brain diseases. Mutation in the mt cytochrome c gene has also been found to be associated with Alzheimer's disease. Late-onset diabetes owing to a mt mutation might also be explained in this way.

Another feature of mitochondrial disease development is that clinical signs will only develop when the percent mutation load reaches a certain level. This is known as the threshold effect. This effect relates to the fact that disease symptoms occur when mitochondrial ATP production falls below some minimum threshold level; it has been extended to the theory that a threshold level of mutant mtDNA must exist in a cell before clinical symptoms will be observed. An example of this is the 8993 mutation in the ATPase 6 gene.78-83 When this mutation is present in less than 60%, it phenotypes as diabetes; if present in less than 90% of mtDNA, it phenotypes as NARP (neurogenic muscle weakness, ataxia, retinitis pigmentosa). When present at greater than 90% mutant mtDNA, however, the much more serious maternally inherited Leigh's syndrome develops.

Heteroplasmy can be different between tissues and lead to different phenotypes of the same genotype. This is one explanation given for the various phenotypes seen with the 3243 mutation in the tRNA^sup Leu(UUR)^ gene. This gene is thought to be an etiologic hotspot for mutation. Note in Table 1 how many different mutations have been reported for this gene with respect to diabetes. Other diseases are also associated with mutation here. Whereas it has been argued that other factors besides the tRNA^sup Leu(UUR)^ mutation contribute to the different phenotypes,84 extensive data point to this mutation as the sole cause of the disease in these patients. Defects in mitochondrial protein synthesis and respiration occur in cybrids-in vitro blending of cells with normal nuclei and abnormal mitochondria, or vice versa-with mitochondria from patients carrying this mutation.85,86 This mutation can be suppressed by a mutation in the anticodon of tRNA^sup Leu(CUN)^ that enables it to decode UUR leucine.87 In addition, when cybrids were compared between patients with the tRNA^sup Leu(UUR)^ mutation genotype and diabetes versus those with progressive kidney disease phenotypes, there was no difference in mitochondrial function, suggesting that haplotype played no role in determining phenotype.ee There was no difference in the percent heteroplasmy between the two distinct phenotypes. This again points out that tissues can vary in percentage of mutated mtDNA and this variation can dictate the disease that is first observed. In each condition the tissue compromise is probably related to the mtDNA mutation directed-compromise of mitochondrial metabolism. Both the pancreas and the kidneys have large requirements for the ATP produced by the mitochondria and should a shortfall in this production occur owing to mutation-dictated mitochondrial malfunction, tissue function will be affected.

Tissue-specific effects can also be due to different biochemical thresholds and ATP needs. Rossignol et al.89 showed in isolated mitochondria that different complexes within different tissues have different thresholds. For example, 60% of ATP synthase activity needs to be inhibited in brain mitochondria for respiration to be affected. However, more inhibition of ATP synthase must occur in kidney, even more in liver, more in muscle, and yet more in heart. By contrast, inhibition of complex IV affects muscle = heart > liver > kidney = brain. Thus, the same mutation would have a very different effect on respiration in different tissues, resulting in different phenotypes. In vivo, different tissues can also have different thresholds owing to their different respiration needs.90 In this respect, brain (and optic nerve) > skeletal muscle > cardiac muscle > kidney > liver.

Thus, it is clear that mitochondrial genetics is much more complicated than nuclear genetics. The phenotypic expression of mitochondrial mutant genotypes depends on the degree of cellular heteroplasmy, tissue-specific heteroplasmy, and threshold effects owing to tissue enzyme interactions and tissue needs for OXPHOS producing ATP

Mitochondrial Metabolism

Mitochondria are the central integrators of intermediary metabolism because of their role in ATP synthesis. Although ATP can be generated via substrate phosphorylation in both the cytosol and mitochondria, the main source of cellular ATP is from OXPHOS. The mechanism of OXPHOS has been extensively reviewed and will not be covered here. Briefly, hydrogen ions are carried as substrates into the mitochondrial compartment by the NADand FAD-linked shuttles. The substrates are metabolized by the citric acid cycle and the resultant H+ is sent to the respiratory chain. The hydrogen ions are joined to oxygen to form water. The set of protein complexes that synthesize water comprise the respiratory chain. Coupled to water synthesis is the formation of ATP by the F^sub 1^F^sub 0^ATPase.

The respiratory chain consists of four multiprotein complexes. Complex I, the NADH-ubiquinone complex is the site of entry for protons carried by NAD into the chain. NADH is oxidized, ubiquinone is reduced, and four protons are pumped from the mitochondrial matrix to the intermembrane space. In mammals there are at least 42 subunits in this complex, seven of which are encoded on mtDNA (NDI, 2, 3, 4, 4L, 5, and 6). Complex II, succinate:ubiquinone oxidoreductase is the site of entry for protons carried by FAD into the chain via ubiquinone. It contains four subunits, all of which are nuclear encoded. No protons are pumped at this site. Complex III, ubiquinone cytochrome-c oxidoreductase or the bc^sub 1^/cytochrome-c reductase accepts electrons from ubiquinone. In this reaction, ubiquinone is oxidized, electrons are transferred to cytochrome b then c^sub 1^ and four protons are pumped into the intermitochondrial space. This complex contains 11 subunits in mammals, one of which (cytochrome b) is encoded by mtDNA. Lastly, complex IV, cytochrome-c oxidase, accepts electrons through the soluble cytochrome c and transfers them to oxygen. This process pumps four protons into the intermitochondrial space. This complex contains 13 subunits of which the three major subunits (COX I, II, and III) are encoded on mtDNA. All of these complexes are embedded in the inner mitochondrial membrane.

The pumping of protons into the intermembrane space creates a proton motive force that consists of a proton gradient and a membrane potential. This proton motive force is then used by F^sub 1^F^sub 0^ATPase, the ATP synthase or complex V, to form ATP. The Fo portion of the complex is embedded in the inner mitochondrial membrane and is connected to the F^sub 1^ portion by a stalk. The F^sub 1^ portion projects out into the mitochondrial matrix. Figure 1 illustrates the structure of this complex and its relationship to the respiratory chain. Two of the subunits of the F^sub 0^ are encoded by the mtDNA. These are subunit a (ATPase 6) and subunit A6 (ATPase 8). The ATPase moves and rotates as it captures the energy of the respiratory chain and uses this energy to make ATP This movement is an essential feature of its activity. As mentioned above in the section on mitochondrial diseases, if mutations occur in any one of the mt genes that encode any of these proteins, OXPHOS will be compromised. If the compromise is of sufficient magnitude, noticeable clinical conditions will develop.

OXPHOS and Nutritional State

Environmental factors such as diet can also play a role by altering mitochondrial mutation rate. Mutation as a result of free radical attack on the genome has been reported to be a feature of aging. Diets rich in long-chain polyunsaturated fatty acids that can be radicalized could be causative factors if such diets do not provide adequate free radical suppression nutrients as well. Vitamin E, ascorbic acid, and carotenes can serve this purpose. Selenium, copper, manganese, and magnesium all play roles in the free radical scavenging system that in turn limits free radical damage to the mt genome. Thus, nutrients can affect mitochondrial gene expression by limiting damage to the genome.

Diet plays another role in mt gene expression and that is by affecting gene transcription. An example is the effect retinoic acid has on mtDNA transcription.62,66 Diet can also influence the environment in which the gene product functions. An example of this is the effect of dietary fat on the composition and fluidity of the inner mitochondrial membrane.91 In this example, a diet rich in saturated fat reduces inner membrane fluidity and this reduction impairs the movement of the F^sub 1^F^sub 0^ATPase, reducing its efficiency to trap the energy generated by the respiratory chain into the high-energy bond of ATP. Hence, such diets reduce OXPHOS efficiency. These dietary effects were shown in studies with the BHE/Cdb rat, a rat that has two mutations in the mt ATPase 6 gene.91

The BHE/Cdb Rat

The BHE parent strain rats were originally developed by the Bureau of Home Economics USDA by crossing albino Osborn-Mendel rats from Yale with hooded rats from The Pennsylvania State University. Through selective breeding of the parent BHE strain, the BHE/Cdb strain was developed. The breeding selected against obesity and hydronephrosis and for lipemia and maturity-onset glycemia. This selective breeding was done so as to obtain an animal model that simulated a human with type 2 diabetes in the absence of obesity. In the course of breeding these animals it was convenient to use maternal lines for tracking the progeny. Progeny of dams that were normoglycemic at 300 days of age were discarded. Only those of glycemic females were kept in the breeding pool. The metabolic features of this strain have been reviewed.38,92,93 Table 2 lists some of the key features of the BHE/Cdb rat compared with normal rats. At the time the strain was developed, maternally inherited diabetes as a result of mutation in the mtDNA was unknown. Since that time, there has been a growing database on humans suggesting that these rats might be a suitable model for the human that develops mt diabetes.38

Shown in Figure 2 is a comparison of the BHE/Cdb ATPase 6 base sequence with that published by Gadaleta et al.94 One of the mutations shown in Figure 2 at bp 8204 results in a base substitution from aspartic acid to asparagine in the hydrophobic proton channel, altering the charge ratio in the channel. The second mutation at bp 8289 results in the substitution of threonine for serine in the portion of the subunit that acts as an anchor for the protein in the inner mt membrane. This substitution alters the structure of subunit a such that its mobility is affected. The threonine substitution changes the protein conformation from an amino acid loop to a pleated sheet. Recall from the previous discussion of OXPHOS that the F^sub 1^F^sub 0^ATPase needs not only a functional proton channel, but also the ability to move within the mt membrane. The change in structure would lend a degree of rigidity to the subunit altering its free movement within the membrane and impairing ATP synthesis. Thus, both the mutation in the proton channel and the structural mutation may explain the impaired OXPHOS seen in these rats. In addition, these mutations, the impaired glucose tolerance, and the impaired ATP synthesis efficiency are maternally inherited.95

The change in both proton channel and ATPase 6 structure are probably quite mild defects. When the physiologic condition of the animal is altered either through diet or through hormonal alteration, however, defective OXPHOS becomes apparent. As described above, changing the dietary fat source from corn oil or menhaden oil to hydrogenated coconut oil results in a less fluid membrane. This changed environment for the ATPase results in a significant decrease in ATP synthesis efficiency.91

Perturbation of thyroid hormone status also affects OXPHOS. Normally, thyroid hormone increases overall mitochondrial enzyme activities, increases intracellular and mitochondrial calcium flux, and results in an overall increase in ATP production.96 It also alters the mitochondrial membrane lipid composition and increases the phospholipid unsaturated fatty acid content of rats fed coconut oil.97 Mitochondrial beta-oxidation was increased in thyroxine-treated rats, but membrane fluidity and state 3 respiration with Krebs cycle intermediates were not affected.91 Isolated F^sub 1^F^sub 0^ATPase complexes from BHE/Cdb rats were less sensitive than Sprague-Dawley rats to inhibition by high doses of oligomycin.98 However, the reverse was shown in isolated mitochondria. Hepatic mitochondria from BHE/Cdb rats were more sensitive to inhibition of OXPHOS by low to moderate doses of oligomycin. This increased sensitivity to inhibition of OXPHOS is similar to the results of studies of human fibroblasts with the T8993G mutation in the F^sub 0^ATPase 6 gene.99 Altered calcium metabolism has also been shown by mitochondria from BHE/ Cdb rats.100 Excess calcium inhibited OXPHOS and this inhibition occurred at lower levels of added calcium in mitochondria from BHE/Cdb rats than in mitochondria from Sprague-Dawley rats.

Defects in OXPHOS can explain type 2 diabetes in these rats in two ways. First, because ATP synthesis from glucose is limited by OXPHOS, BHE/Cdb rats may compensate by preferentially oxidizing fatty acids. Increased lipolysis has been reported together with increased circulating fatty acids and glycerol. This glycerol serves as a substrate for gluconeogenesis. Both lipolysis and gluconeogenesis are increased in BHE/Cdb rats compared with control rats.92,93 Because protein synthesis is energetically expensive, an ATP synthesis shortfall could suppress protein synthesis leaving more amino acids available for gluconeogenesis as well. Second, as discussed earlier, mitochondrial ATP synthesis is required for glucose-stimulated insulin secretion. BHE/Cdb rats have agerelated reduced pancreatic insulin stores and impaired glucose-stimulated insulin release.101 Thus, both hyperglycemia and impaired glucose tolerance may be related to the mitochondrial defect in ATP synthesis efficiency.

Defects in calcium handling by the mitochondria can also lead to type 2 diabetes by potentiating the effect of the mutation in the F^sub 0^ATP synthase. Precise concentrations of calcium are needed to regulate F^sub 0^ATP synthase, 11 and therefore ATP synthesis. When calcium accumulates in the mitochondria it becomes toxic. This would become a major problem in the beta-cell because every time insulin is secreted calcium enters the cell and increases in the mitochondria.103 If calcium efflux from the mitochondria is inefficient, as suggested by Kim and Berdanier,100 then this calcium would accumulate slowly over time. This would initially stimulate ATP synthesis and insulin secretion leading to hyperinsulinemia. Once a threshold level of calcium was reached, the calcium would become toxic and result in defective glucose-stimulated insulin secretion. Both initial hyperinsulinemia and age-dependent decreases in glucose-stimulated insulin secretion are seen in the BHE/Cdb rat,101 as well as in humans104,105 and other nonobese animal models of type 2 diabetes.106

Future Directions

The preceding text has reviewed the role of mtDNA mutations in the development of diabetes mellitus. A rat model that mimics human mt diabetes has also been described. Work with this model has shown that diet plays an important role in the phenotypic expression of the genotype. This is probably true for the human as well but nutrition studies have not been conducted on humans with diabetes-causing mutations. As described above, nutrients can have effects at several different levels with respect to phenotypic expression. Specific nutrients can up-regulate the expression ofthe mt genome, can protect it from free radical damage, and can provide an optimal environment for the action of the mt gene products. All of these effects can modify the phenotype as well as when the phenotype appears.

Not only can nutrients have these effects, so too can hormones and perhaps drugs. Using the BHE/Cdb rats, nutriceuticals as well as pharmaceuticals could be studied; through these studies we may gain new insight into how the expression of the mt genome can be manipulated. The goal of such research would open new doors to the successful management of diabetes not only after the clinical symptoms have appeared but before the appearance of such symptoms (i.e., preventive measures). Because we know that mt diabetes is maternally inherited, the next logical step would be to identify individuals with mt DNA mutations and then design a strategy to prevent phenotypic expression of the genotype as long as possible. In turn, this would provide the paradigm for identifying and quantifying nutrient needs and tolerances based on genetics (in addition to age and gender) that would maximize an individual's potential for health and minimize the potential for disease.

Karvonen M, Tuomilehto J, LaPorte R. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin dependent) diabetes mellitus. Diabetologia 1993;36:883-92

Berdanier CD. Diet autoimmunity and insulin dependent diabetes: a controversy. Proc Soc Exp Biol Med 1995;209:223-30

Szopa TM, Titchener PA, Portwood ND, Taylor KW. Diabetes due to viruses-some recent developments. Diabetologia 1993;36:687-95

Bae Y-S, Eun H-M, Yoon J-W. Molecular identification of diabetic viral gene. Diabetes 1989;38:31620

Leiter EH, Wilson GL. Viral interaction in pancreatic B cells. In: Repeleers D, Lefebrore P, eds. Pathology of the endocrine pancreas. New York, NY: Springer Verlag, 1998;8-105

CDC/DHHS In: Geiss LS, ed. Diabetes surveillance. Atlanta, GA: Centers for Disease Control, U.S. Department of Health & Human Services, 1997,235 p Vanheim CM, Rotter JI. Genetics of diabetes mellitus. In: Alberti KGMM, DeFronzo R, Keen H, et al., eds. International textbook of diabetes. New York, NY: Wiley, 1992;31-98

Stoffel M, Froguel PH, Takeda J, et al. Human glucokinase gene: isolation, characterization and identification of two missence mutations linked to early onset noninsulin dependent (type 2) diabetes mellitus. Proc Natl Acad Sci U S A 1992;89:7698-702 Bell GI, Froguel P, Nishi S, et al. Mutations in the human glucokinase gene and diabetes mellitus. Trends Endocrinol Metab 1993;4:86-90

10. Chiu KC, Tanizawa Y, Permutt MA. Glucokinase variants in the common form of diabetes. Diabetes 1993;42:579-82

11. Matschinsky FM, Liang Y, Keavan P, et al. Glucokinase as pancreatic 13 cell glucose sensor and diabetes gene. J Clin Invest 1993;2:2092-8

12. Velho G, Blanche H, Vaxillaire M, et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY families. Diabetologia 1997;40:217-24

13. Kahn SE, Halban PA. Release of incompletely processed proinsulin is the cause of the disproportionate proinsulinemia. Diabetes 1997;46:172532

14. Dreyer M, Matthaei S, Kuhnau J, Rudiger HW. Prolonged plasma half life of insulin in patients with a genetic defect of high affinity binding sites. Horm Metab Res 1986;18:247-9

15. Matschinsky FM. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996;45:223-41

16. Gerbitz KD, Paprotta A, Brdiczka D. Mitochondria and diabetes: genetic, biochemical and clinical implications of the cellular energy circuit. Diabetes 1996;45:113-26

17. Gerbitz KD. Does the mitochondrial DNA play a role in the pathogenesis of diabetes? Diabetologia 1992;35:1181-6

18. Gerbitz KD, Paprotta A, Jaksch M, et al. Diabetes is one of the heterogenous phenotypic features of a point mutation in the tRNA gene. FEBS Left 1993; 321:194-6

19. Reardon W, Ross RJ, Sweeney MG, et al. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 1992;340:13769

20. Alcolado JC, Alcolado R. Importance of maternal history on non insulin dependent DNA defects. BMJ 1991;302:1178-80

21. Alcolado JC, Majid A, Brockington M, et al. Mitochondrial gene defects in patients with NIDDM. Diabetologia 1994;37:372-6

22. Alcolado JC, Thomas AW. Maternally inherited diabetes mellitus: the role of mitochondrial DNA defects. Diabet Med 1995;12:102-8

23. Suzuki S. Clinical characterization of diabetes mellitus in families with mitochondrial myopathies. Nippon Rinsho 1994;52:2606-10

24. Suzuki S, Hinokio Y, Hirai S, et al. Diabetes with mitochondrial tRNA'Y3 mutation. Diabetes Care 1994; 17:1428-32

25. Suzuki S, Tsukuda K, Atsumi Y, et al. Clinical picture of a case of diabetes and mitochondrial tRNA mutation at position 3271. Diabetes Care 1996;19: 1304-5

26. Hinokio Y, Suzuki S, Komatu K, et al. A new mitochondrial DNA deletion associated with diabetic amytryphy, diabetic myontrophy, and diabetic fatty liver. Muscle Nerve 1995;3:SI42-9

27. Gebhart SS, Shoffner JM, Koontz D, et al. Insulin resistance associated with maternally inherited diabetes and deafness. Metabolism 1996;45:526-31

28. Oka Y, Katagiri H, Ishihara H, et al. B-Cell loss and glucose-induced signaling defects in diabetes mellitus caused by mitochondrial tRNA leu(UUR) gene mutation. Diabet Med 1996;13:S98-102

29. van der Ouweland JMW, Lemkes HHPJ, et al. Mutation in mitochondrial tRNA'*Iu(uu") gene in a large pedigree with maternally transmitted type 11 diabetes and deafness. Nat Genet 1992;1:398-71

30. Velho G, Byrne MM, Clement K, et al. Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNAI-(ul") gene mutation. Diabetes 1996;45:478-87

31. Dunbar DR, Moome PA, Swingler RJ, et al. Maternally inherited partial direct tandem duplication of mitochondrial DNA associated with diabetes mellitus. Hum Mol Genet 1993;2:1619-24

32. Schultz JB, Klockgether T, Dichgans J, et al. Mitochondrial gene mutations and diabetes mellitus. Lancet 1993;341:438-49

33. Sue CM, Holmes-Walker DJ, Morris JGL, et al. Mitochondrial gene mutations and diabetes mellitus. Lancet 1993;341:437-8

34. Ballinger SW, Shoffer JM, Hedaya EV, et al. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet 1992;1:11-5

35. Ballinger SW, Shoffner JM, Gebhart S, et al. Mitochondrial diabetes revisited. Nat Genet 1994;7: 458-9

36. Mathews CE, McGraw RA, Berdanier CD. A point mutation in the mitochondrial DNA of diabetes prone BHE/Cdb rats. FASEB J 1995;9:1638-42

37. Mathews CE, McGraw RA, Dean R, Berdanier CD. Inheritance of a mitochondrial DNA defect and impaired glucose tolerance in BHE/Cdb rats. Diabetologia 1999;42:35-41

38. Mathews CE, Berdanier CD. Non insulin dependent diabetes mellitus as a mitochondrial genomic disease. Proc Soc Exp Biol Med 1998;219:97-108

39. Lestienne R Mitochondrial DNA mutations in human disease: a review. Biochimie 1992;74:12330

40. Wallace DC. Diseases of the mitochondrial DNA. Ann Rev Biochem 1992;61:1175-212

41. Shanske S, DiMauro S. Mitochondrial myophathies: biochemical aspects. Current Topics in Bioenergetics 1994;17:21-57

42. Wallace DC. Mitochondrial DNA mutations and diseases of energy metabolism. J Bioenerg Biomembr 1994;26:241-50

43. Schon EA, Hirano M, DiMauro S. Mitochondrial encephalomyopathies: clinical and molecular analysis. J Bioenerg Biomembr 1994;26:291-9

44. Schon EA, Bonilla E, DiMauro S. Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr 1997;29:131-49

45. Mazat J-P, Letellier T, Bedes F, et al. Mitochondrial diseases. Mol Cell Biochem 1997;174:143-8

46. Schon EA, Grossman MH. Mitochondrial diseases: genetics. Biofactors 1998;7:191-5

47. Lucking CB, Kosel P, Mehracin P, Graeber MB. Absence of the mitochondrial A7237T mutation in Parkinson's disease. Biochem Biophys Res Commun 1995;211:700-4

48. Davis RE, Miller S, Herrnstadt C, et al. Mutations in mitochondrial cytochrome c oxidase genes segregate with late onset Alzheimer disease. Proc Natl Acad Sci U S A 1997;94:4526-31

49. Hutchin T, Cortopassi G. A mitochondrial DNA is associated with increased risk of Alzheimer's disease. Proc Natl Acad Sci U S A 1995;92:6892-5

50. Schagger H, Georg T Human diseases with defects in oxidative phosphorylation 2. FF,,ATPase synthase defects in Alzheimer's disease revealed by blue polyacrylamide gel electrophoresis. Eur J Biochem 1995;227:916-21

51. Hiraoka J-I, Hirao Y-H. Fate of sperm tail compo

nents after incorporation into hamster egg. Gamete Res 1988;19:369-80

52. Kaneda H, Hayashi J-1, Takahama S, et al. Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. Proc Natl Acad Sci U S A 1992;92:4542-6

53. Sutovsky P, Navara CS, Schatten G. Fate of the sperm mitochondria and the incorporation, conversion and disassembly of the sperm tail structures during bovine fertilization. Biol Reprod 1996;55: 1195-205

54. Ankel-Simons F, Cummins JM. Misconceptions about mitochondria and mammalian fertilization: implications for theories on human evolution. Proc Natl Acad Sci U S A 1996;93:13859-63

55. Fisher RP, Clayton DA. A transcription factor required for promoter recognition by human mitochondrial RNA polymerase: accurate initiation at the heavyand light-strand promoters dissected and reconstituted in vitro. J Biol Chem 1985;260:11330-8

56. Fisher RP, Clayton DA. Purification and characterization of human transcription factor 1. Mol Cell Biol 1988;8:3496-509

57. Kruse B, Narasimhan N, Attardi G. Termination of transcription in human mitochondria: identification and purification of a DNA binding protein factor that promotes termination. Cell 1989;58:391-7

58. Fisher RP, Topper JN, Clayton DA. Promotor selection in human mitochondria involves binding of transcription factor to orientation-independent upstream elements. Cell 1987;50:247-58

59. Fisher RP, Lisowsky T, Parisi MA, Clayton DA. DNA wrapping and bending by a mitochondrial high mobility-like transcription activator protein. J Biol Chem 1992;267:3358-67

60. Huang X, Eriksson KF, Vaag A, et al. Insulin regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle. Diabetes 1999;48:1508-14

61. Demonacos CV, Karayanni N, Hatzoglou E, et al. Mitochondrial genes as sites of primary action of thyroid hormones. Steroids 1996;61:226-32

62. Umesono K, Murakami KK, Thompson CC, Evans RM. Direct repeats as selective elements for the thyroid hormone, retinoic acid and vitamin D3 receptors. Cell 1991;65:1255-66

63. Enrique JA, Fernandez-Silva P, Garrido-Perez N, et al. Direct regulation of mitochondrial RNA synthesis by thyroid hormone. Mol Cell Biol 1999;19: 657-70

64. Casas F, Rochard P, Rodier A, et al. A variant form of the nuclear triiodothyronine receptor c-erbAa 1 plays a direct role in regulation of mitochondrial RNA synthesis. Mol Cell Biol 1999;19:7913-24

65. Chou S-Y, Hannah SS, Lowe KE, et al. Tissue specific regulation by vitamin D status of nuclear and mitochondrial gene expression in kidney and intestine. Endocrinology 1995;136:5520-6

66. Everts HE. The effects of vitamin A on mitochondrial function and gene expression in diabetesprone BHE/Cdb rats [dissertation]. Athens, GA: University of Georgia, 2000,267 p

67. Larsson N-G, Wang J, Wilhelmsson H, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice.

Nat Genet 1998;18:231-6

68. Wang J, Wilhelmsson H, Graff C, et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial gene expression. Nat Genet 1999;21: 133-8

69. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717-20

70. Poulton J, Brown MS, Cooper A, et al. A common mitochondrial DNA variant is associated with insulin resistance in adult life. Diabetologia 1998;41: 54-8

71. Rotig A, Bessis J-L, Romero N, et al. Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus and cerabellar ataxia. Am J Hum Genet 1992;50:364-70

72. Moraes CT, Shanske S, Tritschler H-J, et al. Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Am J Hum Genet 1991;48:492-6

73. Poulton J, Deadman ME, Gardiner RM. Duplications of mitochondrial DNA in mitochondrial myopathy. Lancet 1989;236-8

74. Poulton J, Deadman ME, Gardiner RM. Tandem direct duplications of mitochondrial DNA in mitochondrial myopathy: analysis of nucleotide sequence and tissue distribution. Nucleic Acids Res 1989; 17:10223-7

75. Shoffner JM, Lott MT, Voljavec AS, et al. Spontaneous Kearns-Sayre/chronic external opthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip replication model and metabolic therapy. Proc Natl Acad Sci U S A 1989;86: 7952-6

76. Mathews PM, Brown RM, Morten K, et al. Intracellular heteroplasmy for disease-associated point mutations in mtDNA: implications for disease expression and evidence for mitotic segregation of heteroplasmic units of mtDNA. Hum Genet 1995; 96:261-6

77. Holme E, Tulinius MH, Larsson N-G, Oldfors A. Inheritance and expression of mitochondrial point mutations. Biochem Biophys Acta 1995;1271:24956

78. Jenuth JP, Peterson AC, Fu K, Shoubridge RA. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet 1996;14:146-9

79. deVries DD, van Engelen BGM, Gabreels FJM, et al. A second missence mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol 1993;34:410-6

80. Pastores GM, Santorelli FM, Shanske S, et al. Leigh's syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation. Am J Med Genet 1994;50:265-70

81. Houstek J, Klement P, Hermanska J, et al. Altered properties of mitochondrial ATP synthesis in patients with a T-G mutation in the ATPase 6 (subunit a) at position 8993 of mtDNA. Biochem Biophys Acta 1995;1271:349-56

82. Obayashi T, Hattori K, Sugiyama S, et al. Point mutations in mitochondrial DNA in patients with

hypertrophic cardiomyopathy. Am Heart J 1992; 124:1263-7

83. Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. American Journal of Genetics 1990;46:428-36

84. Odawara M, Sasaki K, Yamashita K. Prevalence and clinical characterization of Japanese diabetes mellitus with an A to G mutation at nucleotide 3243 of the tRNAt(uuR) gene. J Clin Endocrinol Metab 1995;80:1290-6

85. Chomyn A. Mitochondrial genetics `98. The myoclonic epilepsy and ragged red fiber mutation provides new insights into human mitochondrial function and genetics. Am J Hum Genet 1998;62:74550

86. King MP, Koga Y, Davidson M, Schon EA. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with tRNAleu(UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Mol Cell Biol 1992;12:4807

87. Meziane AE, Lehtinen SK, Hance N, et al. A tRNA suppressor mutation in human mitochondria. Nat Genet 1998;18:350-6

88. van den Ouweland JMW, Maechler P, Wolheim CB, et al. Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA'(wR) gene. Diabetes 1994;43:746-52

89. Rossignol R, Malgat M, Mazat JP, Letellier T Threshold effect and tissue specificity: implications for mitochondrial cytopathies. J Biol Chem 1999;274: 33426-33

90. Brown MD, Voljavec AS, Lott MT, et al. Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative disease. FASEB J 1992;6:2791-6

91. Kim MJC, Berdanier CD. Nutrient-gene interactions determine mitochondrial function: effect of dietary fat. FASEB J 1998;12:243-8

92. Berdanier CD. NIDDM in the non-obese BHE/Cdb rat. In: Shafrir E, ed. Lessons from animal diabetes. London: Smith Gordon, 1994;231-46

93. Berdanier CD. The BHE rat: an animal model for the study of non insulin dependent diabetes. FASEB J 1991;5:2139-44

94. Gadaleta G, Pepe G, DeCandia G, et al. The com

plete nucleotide sequence of the rattus norvigigus mitochondrial genome: cryptic signals revealed by comparative analysis between vertebrates. J Mol Evol 1989;28:497-516

95. Mathews CE, McGraw RA, Dean R, Berdanier CD. Inheritance of a mitochondrial defect. Diabetologia 1999;42:35-41

96. Soboll S. Thyroid hormone action in mitochondrial energy transfer. Biochem Biophys Acta 1993; 1144: 1-16

97. Berdanier CD. Interaction of dietary fat type and thyroxine on the hepatic phospholipid fatty acids of BHE rats. Nutrition 1988;4:295-9

98. Kim SB, Berdanier CD. Oligomycin sensitivity of mitochondrial F,FoATPase in diabetes prone BHE/ Cdb rats. Am J Physiol 1999;277:E702-7

99. Vazquez-Memiji ME, Shanske S, Sanlorelli FM. Comparative biochemical studies of ATPase in cells from patients with T8993G or T8993C mitochondrial mutations. J Infect Dis 1998;21:829-35

100. Kim SB, Berdanier CD. Further studies on oxidative phosphorylation in BHE/Cdb rats: increased 'responsiveness to the calcium ion. J Nutr Biochem 1998;10:31-6

101. Liang Y, Bonner-Weir S, Wu YJ, et al. In situ glucose uptake and glucokinase activity of pancreatic islets in diabetes and obese rodents. J Clin Invest 1994;93:2473-81

102. Das AM, Byrd DJ, Brodehl J. Regulation of the mitochondrial ATP-synthase in human fibroblasts. Clin Chim Acta 1994;231:61-8

103. Rutter GA, Theler J-M, Murgia M, et al. Stimulated Ca2+ influx raises mitochondrial CaF+ to supramicromilar levels in pancreatic 13-cell line: possible role in glucose and agonist-induced insulin secretion. J Biol Chem 1993;268:22385-90

104. Cerasi E, Nesher R, Gadot M, et al. Insulin secretion in obese and non obese NIDDM. Diabetes Res Clin Pract 1995;28:S27-37

105. Polansky KS, Sturis J, Bell GI. Non insulin dependent diabetes mellitus-a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 1996;334:777-83

106. Nakajima K, Morikawa A, Makino I. Natural history of fi-cell dysfunction in spontaneously diabetic Chinese hamsters. Diabetes Res Clin Pract 1994; 24:131-42

Dr. Berdanier is with the Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA.

Copyright International Life Sciences Institute and Nutrition Foundation Mar 2001
Provided by ProQuest Information and Learning Company. All rights Reserved