Diabetes mellitus carrying a mutation in the mitochondrial tRNALeu(UUR) gene

Abstract

SummaryWe screened 214 Japanese NIDDM (noninsulin-dependent) diabetic patients with a family history of diabetes for mutations in the mitochondrial tRNA ~u(v~JR) gene using polymerase chain reactionrestriction fragment length polymorphism and direct sequencing. Six patients were identified as having an A to G transition at position 3243 (3243 mutation), but no patients were detected with a T to C transition at position 3271, in the mitochondrial tRNA Leu(uum gene. These two mutations were not present in 85 healthy control subjects. It was disclosed that the patients' mothers were also affected by diabetes mellitus in five of the six cases. In these six affected patients, the 3243 mutation shows variable phenotypes, such as the degree of multiple organ involvement, intrafamilial and interfamilial differences in disease characteristics, and the degree of the involvement of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) phenotype. Endocrinological examinations revealed that those diabetic patients with the 3243 mutation show not only beta-cell dysfunction, but also a defect in alphacell function, which is considered characteristic of diabetes with the 3243 mutation. When compared with 50 selected diabetic control subjects without the 3243 mutation, whose mothers, but not fathers, were found to have diabetes, it was established statistically that those with the 3243 mutation possess the following clinical characteristics; 1) the age of diabetes onset is lower, 2) they have lean body constitutions, and 3) they are more likely to be treated with insulin than control subjects. We suggest that diabetes with the 3243 mutation possesses phenotypes distinct from those in common forms of diabetes. [Diabetologia (1995) 38: 193-200]

Insulin secretion and insulin sensitivity are normal in non‐diabetic subjects from maternal inheritance diabetes and deafness families

“…In our study and others [3,9,29], islet cell and anti‐GAD antibodies were not elevated. Kobayashi et al [30] have identified positive islet cell antibodies in 13 of 31 and GAD antibodies in two of 31 MIDD subjects using similarly sensitive assay techniques.…”

“…The most common mitochondrial mutation, resulting in the syndrome maternal inheritance diabetes and deafness (MIDD), is the A‐G mutation at position 3243 of tRNA LEU(UUR) of mitochondrial DNA [1,2] (the 3243 mtDNA mutation). There is evidence to support both reduced insulin secretion [3–13] and insulin resistance [1,14–18] as a cause of diabetes in those with this mutation, with some authors suggesting that both are instrumental [15,16,19]. Differences observed may relate to differing levels of mutant mtDNA in the relevant tissues to glucose tolerance, that is muscle for insulin sensitivity and the β‐cell for insulin secretion.…”

Multiple Endocrine Involvement in Two Pediatric Patients with Kearns-Sayre Syndrome

“…Diabetes mellitus is an expression of mtDNA mutations or deletions and impaired oxidative phosphorylation with diminished ATP synthesis [2]. In such cases, diabetes mellitus is noninsulin-dependent in its origin, but the patients progressively become insulin-deficient and finally, almost all need insulin for their metabolic control [15, 16]. Case 1 had type II diabetes mellitus, with normal pancreatic reserve but unresponsive to hypoglycemic oral agents, who required insulin therapy 2 months after the onset of the diabetes.…”

Age of onset possibly associated with the degree of heteroplasmy in two male siblings with diabetes mellitus having an A to G transition at 3243 of mitochondrial DNA

“…Recent studies have revealed that a mitochondrial gene mutation at 3243 is associated with diabetes and deafness, and accounts for up to 0.5% of diabetic patients [8,9]. Diabetic patients with the mitochondrial gene mutation at 3243 possess the following clinical characteristics: (i) a lower age of onset of diabetes; (ii) lean body constitution; (iii) increased likelihood of insulin treatment; (iv) transmission of diabetes maternally; and (v) high likelihood of hearing loss [10,11].…”

“…Some reports have examined the relationship between the degree of heteroplasmy in the peripheral blood and clinical features such as the age of onset, current treatment, body mass index, glucose tolerance, and insulin‐secretory capacity [11–13]. They have failed to find a positive relationship between the extent of heteroplasmy in the peripheral blood and disease stage.…”