An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be associated with the maternally transmitted clinical phenotype of NIDDM and sensorineural hearing loss in white and Japanese pedigrees. We have detected this mutation in 25 of 50 tested members of five white French pedigrees. Affected (mutation-positive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The present report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in seven mutation-positive individuals who have a range of glucose tolerance from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin secretion was evaluated during two experimental protocols: the first involved the measurement of insulin secretory responses during intravenous glucose tolerance test, hyperglycemic clamp, and intravenous injection of arginine. The second consisted of the administration of graded and oscillatory infusions of glucose and studies to define C-peptide kinetics. This protocol was aimed at assessing two sensitive measures of beta-cell dysfunction: the priming effect of glucose on the glucose-insulin secretion rate (ISR) dose-response curve and the ability of oscillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of between- and within-subject variability. However, all subjects, including those with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tolerance, glucose failed to prime the ISR response, entrainment of ultradian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subjects with overt diabetes. In conclusion, the pathophysiological mechanisms responsible for the development of NIDDM and insulin-requiring diabetes in this syndrome are complex and might include defects in insulin production, glucose toxicity, and insulin resistance. However, our data suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosphorylation and implicate the glucose-sensing mechanism of beta-cells.
"Similarly, inconsistent results were reported regarding non-diabetes individuals with the m.3243ANG mutation. While some studies showed no abnormalities in glucose and insulin metabolism suggesting the absence of detectable abnormalities before the development of DM (Maassen et al., 2004), another study demonstrated impaired insulin secretion in non-diabetic subjects with the m.3243ANG mutation (Velho et al., 1996). Overall, these studies suggest that the main mechanism of DM in subjects with the m.3243ANG mutation is impaired insulin secretion rather than insulin resistance. "
[Show abstract][Hide abstract] ABSTRACT: The m.3243A>G mutation in the mitochondrial gene MT-TL1 leads to a wide clinical spectrum ranging from asymptomatic carriers to MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) at the severe end. Diabetes mellitus (DM) occurs in mitochondrial diseases, with the m.3243A>G mutation being the most common mutation associated with mitochondrial DM. The pathogenesis of mitochondrial DM remains largely unknown, with previous studies suggesting that impaired insulin secretion is the major factor. In this study we used stable isotope infusion techniques to assess glucose metabolism in vivo and under physiological conditions in 5 diabetic and 11 non-diabetic adults with the m.3243A>G mutation and 10 healthy adult controls. Our results revealed increased glucose production due to increased gluconeogenesis in both diabetic and non-diabetic subjects with the m.3243A>G mutation. In addition, diabetic subjects demonstrated insulin resistance and relative insulin deficiency, resulting in an inability to increase glucose oxidation which can explain the development of DM in those subjects. Non-diabetic subjects showed normal insulin sensitivity; and therefore, they were able to increase their glucose oxidation rate. The ability to increase glucose utilization can act as a compensatory mechanism that explains why these subjects do not have DM despite the higher rate of glucose production. These results suggest that increased gluconeogenesis is not enough to cause DM and the occurrence of combined insulin resistance and relative insulin deficiency are needed to develop DM in individuals with the m.3243A>G mutation. Therefore, multiple defects in insulin and glucose metabolism are required for DM to occur in individuals with mitochondrial diseases. The results of this study uncovers previously undocumented alterations in glucose metabolism in individuals with the m.3243A>G mutation that contribute significantly to our understanding of the pathogenesis of mitochondrial DM and can have significant implications for its management.
"In human cells, mitochondria are the only organelles that contain extrachromosomal DNA. Mitochondria are essential organelles that primarily function to support aerobic respiration and to provide energy substrates, and their function is intimately related to insulin secretion and possibly insulin action (Gerbitz et al 1995, Velho et al 1996, Lee et al 2005, Ritz and Berrut 2005). "
[Show abstract][Hide abstract] ABSTRACT: Aim: Mitochondrial DNA (mtDNA) content is essential for maintaining normal mitochondrial function, and the mitochondrial function is critical for the production and the release of insulin in type 2 diabetes mellitus. We investigated whether peripheral blood mtDNA content was reduced in type 2 diabetes. Methods: Fifteen Egyptian Type 2 diabetes (T2DM) and twelve normal subjects were enrolled in this study. The quantity of relative mtDNA content was measured by a real-time PCR and corrected by simultaneous measurement of the nuclear DNA. An assay based on real-time quantitative PCR was used for both nuclear DNA (nDNA) and mtDNA quantification using SYBR green as a fluorescent dye (Invitrogen, Buenos Aires, Argentina). The copy number of mtDNA and nDNA was calculated from the CT number and by use of the standard curve Plasma glucose was analysed using automated autoanalyzer. Results: A significant difference in the mtDNA/nDNA ratio among the control subjects and patients was reported; since results from this study detected reduced mtDNA content in type 2 diabetes patients (13.36 +/- 6.13) compared to healthy individuals (109.15 +/- 49.4). Conclusion: Our results demonstrated that lower peripheral blood mtDNA content is associated with type 2 diabetes.
"The most common form of maternally inherited diabetes and deafness (MIDD) is associated with the m.3243A>G mutation in mitochondrial DNA (mtDNA), which is located in the tRNALeu gene (1). The mutation that affects up to 1% of diabetic patients leads to both impaired glucose-induced insulin secretion (2) and progressive β-cell loss (3). However, in some rare cases characterized by a highly suggestive phenotype but without m.3243A>G "
[Show abstract][Hide abstract] ABSTRACT: The m.3243A>G mutation in mitochondrial DNA (mtDNA) is responsible for maternally inherited diabetes and deafness (MIDD). Other mtDNA mutations are extremely rare.
We studied a patient presenting with diabetes and deafness who does not carry the m.3243A>G mutation.
We identified a deficiency of respiratory chain complex I in the patient's fibroblasts. mtDNA sequencing revealed a novel mutation that corresponds to an insertion of one or two cytosine residues in the coding region of the MT-ND6 gene (m.14535_14536insC or CC), leading to premature stop codons. This heteroplasmic mutation is unstable in the patient's somatic tissues.
We describe for the first time an unstable mutation in a mitochondrial gene coding for a complex I subunit, which is responsible for the MIDD phenotype. This mutation is likely favored by the m.14530T>C polymorphism, which is homoplasmic and leads to the formation of an 8-bp polyC tract responsible for genetic instability.
Diabetes care 12/2011; 34(12):2591-3. DOI:10.2337/dc11-1012 · 8.42 Impact Factor
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