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L M 't Hart

Publications and source records attributed to L M 't Hart.

9 recordsLinked to original sources
PubMed2006

Mitochondrial diabetes and its lessons for common Type 2 diabetes.

Multiple pathogenic pathways are able to deregulate glucose homoeostasis leading to diabetes. The 3243A>G mutation in the mtDNA (mitochondrial DNA)-encoded tRNALeu,UUR gene was found by us to be associated with a particular diabetic subtype, designated MIDD (maternally inherited diabetes and deafness). This mutation causes an imbalance in the mitochondrion between proteins encoded by the nuclear and mitochondrial genomes, resulting in a gradual deterioration of glucose homoeostasis during life. Remarkably, carriers of the 3243A>G mutation are generally not obese. The mutation also results in enhanced radical production by mitochondria. We propose that this mutation leads to the development of diabetes due to an inappropriate storage of triacylglycerols within adipocytes. The result is a fatty acid-induced deterioration of pancreatic beta-cell function. In combination with an enhanced radical production in the beta-cell due to the mutation, this leads to an age-dependent, accelerated decline in insulin production. In common Type 2 (non-insulin-dependent) diabetes, which is generally associated with obesity, a decline in mitochondrial function in adipose cells seems to result in an inappropriate scavenging of fatty acids by beta-oxidation. As a consequence, a systemic overload with fatty acids occurs, leading to an enhanced decline in beta-cell function due to lipotoxicity.

DNA, Mitochondrial↗
PubMed2006

Novel mitochondrial DNA length variants and genetic instability in a family with diabetes and deafness.

We have identified two locations with novel multiplasmic length variants in the mitochondrial DNA of a family with diabetes and deafness. At nt568 in the D-loop, the 6-bp polycytidine tract was found to be variable in length up to a total of 12 residues. A second region with length variants was found at nt8281 in the intergenic COII-tRNA(Lys) region, which consists of two copies of the 9-bp repeat CCCCCTCTA. Only the second repeat occurs in a heteroplasmic C(9-14)A form with both T residues largely deleted. In addition, the mtDNA contained a number of new homoplasmic point mutations. Both length variants are stably inherited in a maternal way with no major changes in their length distribution. In contrast, during culture of fibroblasts from the proband the average length of the polycytidine tracts is increased at both locations indicating a fibroblast-specific genetic instability. Cybrid cells containing mtDNA from the proband proliferate less efficient than cybrids with wild-type mtDNA in co-culture experiments, suggesting functional consequences of the mtDNA length variants or the additional homoplasmic point mutations. Since oxygen consumption was not severely affected, these mutation seem less detrimental for mitochondrial function than the A3243G diabetogenic mutation and most other pathogenic mtDNA mutations. The contribution of mtDNA length variants to the phenotype of members of this family is discussed.

Adult↗
PubMed2002

A case of a de novo A3243G mutation in mitochondrial DNA in a patient with diabetes and deafness.

A female individual with symptoms of the Maternally Inherited Diabetes and Deafness syndrome (MIDD) was diagnosed positive for the A3243G mutation in her mitochondrial DNA. Heteroplasmy levels were 18% in DNA from leucocytes and 55% in oral mucosa DNA. This finding corroborates the diagnosis of MIDD. Normally, this mutation is present in all the individuals within the maternal lineage of the pedigree. In this particular pedigree the mutation was undetectable in the mother of the proband and her three brothers. Paternity testing using polymorphic chromosomal DNA markers supported the assumed family relationship. We conclude that we are dealing in this proband with the de novo appearance of the A3243G mutation that has reached high heteroplasmy values in at least two tissues within one generation. This observation supports the hypothesis that during embryogenesis mitochondrial DNA goes through a genetic bottleneck with a limited number of segregating units.

Adult↗
PubMed2000

HLA-DQ polymorphism and degree of heteroplasmy of the A3243G mitochondrial DNA mutation in maternally inherited diabetes and deafness.

AIM: Maternally inherited diabetes and deafness (MIDD) associates with a mutation at position 3243 in mitochondrial DNA. Phenotypic expression of MIDD includes Type 1-like and Type 2-like diabetes. This study examined whether HLA-DQ phenotype and the degree of heteroplasmy in leucocyte and oral mucosa DNA influence clinical expression of the 3242 mutation. METHODS: In a group of 20 unrelated probands with MIDD, eight with Type 1- like diabetes, 12 with Type 2-like diabetes, HLA-DQ type and degree of heteroplasmy for the 3243 mutation were determined. HLA-DQA1/DQB1 phenotypes were categorized as predisposing, neutral or protective for autoimmune-mediated Type 1 diabetes. RESULTS: No differences were observed between Type 1 and Type 2-like MIDD groups with respect to the cumulative frequency of protective and predisposing HLA-DQ types. Predisposing HLA-DQ types are more prevalent in MIDD patients than in the control population (P < 0.05). Degrees of heteroplasmy for the 3243 mutation showed large variations in patients, ranging from 1 to 52% in leucocyte DNA. A strong correlation was seen between heteroplasmy in leucocyte DNA and DNA from oral mucosa cells (r = 0.89, P < 0.001). No correlation was observed between the degree of heteroplasmy and diabetic phenotype, even when group size was extended with diabetic relatives of patients with MIDD. The age of diagnosis of diabetes was not correlated with heteroplasmy, but the degree of heteroplasmy tended to decrease with age. CONCLUSIONS: The phenotype of diabetes in MIDD appears to be independent of HLA-DQ phenotype and degree of heteroplasmy in leucocyte and oral mucosa DNA indicating that other, as yet unknown, factors modulate clinical expression of the 3243 mutation.

Adolescent↗
PubMed2000

Maternally inherited diabetes and deafness (MIDD): unusual occult exocrine pancreatic manifestation in an affected German family.

The mitochondrial (mt) 3243 DNA mutation is an underlying cause of maternally inherited diabetes and deafness (MIDD) syndrome and the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We report an affected German MIDD pedigree with maternal lineage over three generations. The index patient, her mother, her maternal aunt and her maternal grandmother all suffered from diabetes and premature hearing loss and were positive on testing for the mt 3243 DNA mutation. The 27-year-old index patient had a history of grand mal seizures. As sequela of abdominal ultrasound and confirmed by magnetic resonance cholangio-pancreaticography, she was diagnosed with chronic pancreatitis with pancreatic calcifications and pancreatic duct dilation, although she was completely asymptomatic and with no signs of steatorrhoea. She did not have gallstones and the common bile duct was normal. A possible etiopathogenic pathway for pancreatitis could be a suppressive effect of the mt 3243 mutation on the oxidative phosphorylation in affected mitochondria. Although pancreatitis and pancreatic dysfunction in association with the mt 3243 mutation, especially in patients with comorbidity of MELAS and diabetes, has previously been described as a rare manifestation, this case is specific because of the discrepancy of advanced morphological pancreatic alterations and complete lack of pancreatogenic symptoms.

Adult↗
PubMed1996

Evaluation of the importance of maternal history of diabetes and of mitochondrial variation in the development of NIDDM.

In 79 South Indian nuclear pedigrees ascertained via probands with NIDDM and both parents living, parental diabetic status was established through previously diagnosed NIDDM (n = 97) or oral glucose tolerance testing (n = 61). There was no significant difference between diabetes prevalence in mothers and fathers (60 vs 53 (76% vs 67%), respectively, p = 0.22). 'Age at diabetes diagnosis' survival curves did differ according to parental gender (p = 0.02) but this may reflect gender differences in health provision rather than pathophysiology. No maternal excess effects of the magnitude evident in previous studies were detected, suggesting either ethnic differences or overestimation of the maternal effect when reported histories of parental diabetes have been used. The tRNA(Leu(UUR) gene region was studied for diabetes-associated variation given the role of mutations in this gene in some pedigrees displaying maternal transmission of NIDDM. None of 142 unrelated South Indian NIDDM subjects displayed the MELAS mutation at nt3243. However, sequencing identified two variants of potential importance: (a) at nt3290 in the tRNA(Leu(UUR) gene, seen in 7/142 diabetic and 1/85 control subjects (p = 0.11), (b) at nt3316 in the ND1 gene (4/142 vs 1/85 subjects, respectively (p = 0.51)). Further studies are needed to determine the relevance of these variants to the development of NIDDM.

Adult↗
PubMed1996

Heteroplasmy levels of a mitochondrial gene mutation associated with diabetes mellitus decrease in leucocyte DNA upon aging.

We showed previously that a mutation in the mitochondrial tRNALeu(UUR) gene at position 3243 associates with maternally inherited diabetes and deafness (MIDD). This mutation shows heteroplasmy in DNA from peripheral blood and other tissues. To examine whether heteroplasmy levels in peripheral blood DNA change upon aging, heteroplasmy levels were determined in DNA samples from peripheral blood, collected recently and 1.5-6 years ago, from 18 individuals carrying the 3243 mutation. It was found that 17 out of 18 carriers showed a decrease upon aging (P = 0.001), the average change being -0.69 +/- 0.61% per year. These data indicate a continuous selection against haematopoietic (precursor) cells carrying high levels of the 3243 mutation. Moreover, they imply that heteroplasmy levels may decrease below the detection limit if DNA from peripheral blood is analyzed from elderly individuals. DNA from oral mucosa cells was found to be a good alternative as heteroplasmy levels for the 3243 mutation are on the average 1.7 fold higher than in DNA from peripheral blood.

Adolescent↗
PubMed1996

The molecular basis and clinical characteristics of Maternally Inherited Diabetes and Deafness (MIDD), a recently recognized diabetic subtype.

Diabetes mellitus comprises a number of diseases with hyperglycemia as hallmark. Currently, multiple genetic factors are being recognized which contribute to the development of diabetes or which may modulate its clinical expression. This review presents an overview of our current knowledge on a diabetic subtype which associates with a single mutation in mitochondrial DNA. Based on the triad of Maternal Inheritance, Diabetes and Deafness we propose the name Maternally Inherited Diabetes and Deafness (MIDD) for this syndrome. In Northwestern Europe MIDD affects approximately 1.3% of all diabetic individuals.

Adult↗