c-peptide and Deafness

The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q10 (CoQ10) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ10-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ10 for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ10-DM group was significantly higher than that in the control-DM group. CoQ10 therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ10 treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ10 treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ10 on MIDD.

Topics: Adult; C-Peptide; Coenzymes; Deafness; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; DNA, Mitochondrial; Family Health; Female; Glucagon; Glucose Intolerance; Glucose Tolerance Test; Hearing; Humans; Lactic Acid; Male; Middle Aged; Mothers; Point Mutation; Time Factors; Treatment Outcome; Ubiquinone

This article presents a clinically characterization of the mitochondrial DNA mutation (A3243G) associated with maternally inherited diabetes and deafness (MIDD) syndrome in two families.. Six patients with MIDD and one mutation-positive relative with normal glucose tolerance (NGT) were examined. Fasting serum C-peptide was measured in all subjects and compared with controls having NGT (n = 14). C-peptide response to an intravenous glucose tolerance test (IVGTT) was investigated in the diabetic patients not treated with insulin (n = 3) and in the mutation-positive healthy individual and compared with the controls.. The A3243G heteroplasmy value varied between 5 and 30%. All A3243G carriers had HLA-DR1-DQ5 haplotype, and either the -DQ5 or the -DQ6 allele. The fasting and the serum C-peptide levels at 120 min during the IVGTT did not differ between the A3243G carriers and the controls. A missing first phase and a decreased total C-peptide response was detected in the mutation-positive diabetics compared with controls (p < 0.0001). The same abnormality was found in the A3243G carrier with NGT. Circulating islet cell antibody (ICA) was present in three patients with MIDD. Glutamic acid decarboxylase (GAD), tyrosine phosphatase-like protein IA-2 (IA-2) and mitochondrial antibodies were missing. The diagnosis of MIDD was delayed in each case.. A missing first phase and a decreased total C-peptide response during an IVGTT was characteristic for the A3243G mutation. The fasting C-peptide level of the carriers did not differ from the controls. Circulating ICA was present in some patients, but GAD, IA-2 and mitochondrial antibodies were absent. All subjects had HLA-DR1-DQ5 haplotype, and either -DQ5 or -DQ6 alleles.

Topics: Adult; C-Peptide; Deafness; Diabetes Complications; Diabetes Mellitus; DNA Primers; DNA, Mitochondrial; Family; Female; Glucose Tolerance Test; HLA-DQ Antigens; HLA-DR Antigens; Humans; Male; Middle Aged; Mothers; Pedigree; Polymerase Chain Reaction; Polymorphism, Single Nucleotide

The effects of glucose, arginine, and glucagon on beta-cell function as well as alpha-cell response to arginine were studied in a family with mitochondrial diabetes.. The function of alpha- and beta-cells was assessed in all five siblings carrying the mitochondrial tRNA Leu(UUR) gene mutation at position 3243 and compared with six sex-, age-, and weight-matched control subjects. Insulin and C-peptide responses were evaluated by intravenous glucagon application, intravenous arginine stimulation test, and intravenous glucose tolerance test. Glucagon secretion was assessed during the arginine stimulation test.. The glucose disappearance constant (K(g)) value (mean +/- SEM 0.61 +/- 0.04 vs. 1.1 +/- 0.04, P = 0.0002) as well as the acute insulin response to glucose (area under the curve [AUC] 0-10 min, 77.7 +/- 50.7 vs. 1,352.3 +/- 191.5 pmol/l, P = 0.0004) were decreased in all patients. Similarly, glucagon-stimulated C-peptide response was also impaired (728 +/- 111.4 vs. 1,526.7 +/- 157.7 pmol/l, P = 0.005), whereas the insulin response to arginine (AUC) was normal (1,346.9 +/- 710.8 vs. 1,083.2 +/- 132.5 pmol/l, P = 0.699). Acute glucagon response to arginine (AUC) was normal but tended to be higher in the patients than in the control subjects (181.7 +/- 47.5 vs. 90.0 +/- 21.1 pmol/l, P = 0.099).. This study shows impaired insulin and C-peptide secretion in response to a glucose challenge and to glucagon stimulation in diabetic patients with mitochondrial tRNA Leu(UUR) gene mutation, although insulin and glucagon secretory responses to arginine were normal.

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Deafness; Diabetes Complications; Diabetes Mellitus; DNA, Mitochondrial; Female; Genomic Imprinting; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Nuclear Family; Pedigree; Point Mutation; Reference Values; RNA; RNA, Mitochondrial; RNA, Transfer, Leu; Time Factors

The pathophysiological mechanism of diabetes mellitus in the presence of the 3243 A-G tRNALEU(UR) mitochondrial DNA mutation is thought to result from deficient insulin secretion. However, few subjects with normal glucose tolerance have been studied to determine the sequence of events resulting in the development of diabetes mellitus.. To determine whether abnormalities of insulin sensitivity, insulin secretion or glucose effectiveness are present in non-diabetic subjects with the 3243 A-G tRNALEU(UUR) mitochondrial DNA mutation.. Twelve non-diabetic subjects with the mutation were compared with 12 controls, matched for age and anthropometric parameters, using both oral and intravenous glucose tolerance tests, the latter with Minimal Model analysis.. Following an oral glucose load we found significantly higher blood glucose levels at 90 min and 120 min and significantly higher insulin levels at 120 min and 180 min in non-diabetic subjects with the mutation but no difference in the insulinogenic indices at 30 min and 180 min. From the intravenous glucose tolerance test there was no difference in overall glucose tolerance, insulin sensitivity, first- or second-phase insulin secretion, proinsulin secretion or glucose effectiveness. Insulin-independent glucose disposal was increased in subjects with lower insulin sensitivity and declined with increasing age in subjects with the mutation but not in controls.. While there appear to be subtle defects of glucose handling in non-diabetic subjects with the 3243 mutation, these could not be explained by differences in insulin sensitivity or secretion.

Topics: Autoantibodies; Blood Glucose; C-Peptide; Cholesterol; Deafness; DNA, Mitochondrial; Fasting; Female; Genomic Imprinting; Glucose Tolerance Test; Glutamate Decarboxylase; Humans; Insulin; Insulin Secretion; Lipoproteins, HDL; Lipoproteins, LDL; Male; Mutation; Pedigree; Proinsulin; Reference Values; RNA, Transfer, Leu; Triglycerides

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Deafness; Diabetes Complications; Diabetes Mellitus; DNA, Mitochondrial; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Japan; Middle Aged; Point Mutation; RNA, Transfer, Lys

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

Topics: Adenine; Adolescent; Adult; Aged; Arginine; Blood Glucose; Body Mass Index; C-Peptide; Child; Child, Preschool; Deafness; Diabetes Mellitus, Type 2; Female; Genomic Imprinting; Glucose Tolerance Test; Glycated Hemoglobin; Guanine; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Pedigree; Periodicity; Phenotype; Point Mutation; Reference Values; RNA, Transfer, Leu; Sex Characteristics

Topics: Blood Glucose; C-Peptide; Carnitine; Coenzymes; Deafness; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Insulin; Magnetic Resonance Spectroscopy; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Point Mutation; Retinitis; RNA, Transfer, Leu; Ubiquinone