Inherited Diabetes Mellitus Research Articles

Maternally inherited diabetes mellitus and deafness (MIDD): A case report and review of literature

Abstract Maternally inherited diabetes and deafness (MIDD) is a rare subtype of diabetes with a prevalence of up to 1% globally but often missed if not suspected. We present a case of MIDD and a thorough review of the literature related to it. The phenotypic presentation of diabetes depends on heteroplasmy levels of m.3243A>G mutation of the individual patient. Patients with MIDD may have involvement of other organs such as eye, muscles, kidney, and heart. In our patient, along with diabetes and deafness, there was also an associated vision loss with a strong maternal inheritance of diabetes. A young male who presented with diabetic ketoacidosis (DKA) and hearing and vision impairment and on further diagnostic work up turned out to be a case of genetically confirmed (m.3243A>G mutation) MIDD. To the best of our knowledge, this should be the first case of MIDD presenting as DKA being reported from India.

A mitochondrial origin for inherited diabetes mellitus.

A mitochondrial origin for inherited diabetes mellitus.

Proteomic Analysis of m.8296A>G Variation in the Mitochondrial tRNALys Gene

Variation in the mitochondrial tRNA^Lys gene at position 8296 was previously found to be associated with maternally inherited diabetes mellitus and deafness, hypertrophic cardiomyopathy, myoclonic epilepsy with ragged-red fibers and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The pathogenicity of the m.8296A>G variation is unclear. In this study, we aimed to analyze the mitochondrial proteome in a patient with m.8296A>G variation to elucidate the effects of this mutation at the protein level. Whole-exome sequencing and mitochondrial genome analysis were performed in a patient with sensorineural hearing impairment, cognitive impairment, leukodystrophy, migraine-like headaches, and gastrointestinal dysmotility. Mitochondrial genome analysis identified a homoplasmic m.8296A>G variation in the mitochondrial tRNA^Lys gene in the proband and unaffected mother. Global mitochondrial proteome analysis was carried out in the muscle mitochondria of the index patient and a control subject. Comparative muscle mitochondrial proteome analysis revealed a total of 13 nuclear-encoded mitochondrial proteins differently expressed with respect to the control. Ten of the 13 proteins were downregulated. Most of the proteins were involved in ATP synthesis and Krebs cycle and have strong interactions with each other. We considered the m.8296A>G variation to be pathogenic with variable penetrance for our patient’s phenotype, and this variation led to different expressions of nuclear-encoded proteins involved in energy metabolism.

Maternally Inherited Diabetes Mellitus Associated with a Novel m.15897G>A Mutation in Mitochondrial tRNAThr Gene.

We report here the clinical, genetic, and molecular characteristics of type 2 diabetes in a Chinese family. There are differences in the severity and age of onset in diabetes among these families. By molecular analysis of the complete mitochondrial genome in this family, we identified the homoplasmic m.15897G>A mutation underwent sequence analysis of whole mitochondrial DNA genome, which localized at conventional position ten of tRNAThr, and distinct sets of mtDNA polymorphisms belonging to haplogroup D4b1. This mutation has been implicated to be important for tRNA identity and stability. Using cybrid cell models, the decreased efficiency of mitochondrial tRNAThr levels caused by the m.15897G>A mutation results in respiratory deficiency, protein synthesis and assembly, mitochondrial ATP synthesis, and mitochondrial membrane potential. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cell lines. These data provide a direct evidence that a novel tRNA mutation was associated with T2DM. Thus, our findings provide a new insight into the understanding of pathophysiology of maternally inherited diabetes.

MON-122 Familial Clinical Heterogeneity Manifested by the Presence of Either Diabetes or Deafness in a Pedigree of a Patient with Maternally Inherited Diabetes Mellitus and Deafness and Mitochondrial DNA M.3243a>G Mutation

Introduction: Mitochondrial DNA mutation is a rare cause for diabetes mellitus (DM) and deafness that is often misdiagnosed as type 1 or type 2 DM. Unique management issues, associated comorbidities and fertility plans require proper diagnosis. Proband: a 25 year-old female presented with a fasting glucose 205 mg/dl, Hb A1c 8.5% with intolerance to metformin. She has been previously diagnosed with sensorineural hearing loss. Her physical examination was unremarkable, except for a BMI of 20kg/m2 and a short stature. Her parents were not blood-related. The family history was notable for several relatives with either diabetes or deafness. Her twin sister had prediabetes, her older sister had deafness, her brother had muscle cramps and her mother had both DM and hearing loss, and was also diagnosed with "fibromyalgia". From the mother side; her grandmother had DM, her aunt had deafness and her daughter had DM, 2 uncles had DM. GAD antibodies, Islet cell antibodies and Zinc transporter 8 antibodies were negative. Renal function was normal. She responded well to basal insulin treatment, with an achieved Hb A1c of 7%. Her genetic workup identified a mutation in the mitochondrial DNA m.3243A>G which is associated with MIDD (maternally inherited diabetes and deafness) and MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like episodes). The following specific recommendations were made, which differ from the standard practice and guidelines in the care of classical type 1 or type 2 diabetes: 1) avoid metformin; 2) rigidly maintain adequate carbohydrate consumption when ill, as stroke- like episodes have been described in this condition during acute illness when carbohydrate supply was inadequate; 3) use Coenzyme Q10 which might enhance insulin secretion and potentially improve symptoms of myopathy. 4) attempt not to postpone fertility due to the risk of premature ovarian failure; 5) for pregnancy planning, consider "three parent IVF" with mitochondria and cytoplasm from a donated ovum, thus potentially avoiding transmitting the defect. Conclusion: Diagnosis of MIDD should be considered in subjects with family history of premature deafness and diabetes, not necessarily in the same subjects. The correct diagnosis may offer multiple therapeutic advantages. With accurate genetic diagnose, appropriate therapy, family screening, genetic counseling and surveillance for existing and future complications can be applied.

SUN-LB033 New Onset Diabetes in a Post-Renal Transplant Pediatric Patient with a Mutation of the Hepatocyte Nuclear Factor-1β Gene

Background: Maturity onset diabetes of the young (MODY) 5 is a rare type of dominantly inherited diabetes mellitus (DM). It is caused by mutations of the hepatocyte nuclear factor-1beta (HNF-1 beta) gene. Most are missense mutations that produce truncated proteins resulting in a variable clinical spectrum that may include kidney, genital and pancreatic abnormalities. We describe a case of a young patient diagnosed with DM after renal transplant; also, his diagnosis disclosed extensive family history of DM. Case: Six-year-old African-American patient with history of end stage renal disease due to bilateral cystic dysplasia presented with significant hyperglycemia three days after renal transplant. Polycystic kidney disease observed in prenatal ultrasound led to genetic testing. He was found to have a 1.0-1.8Mb deletion on chromosome microarray at 17q12 that included TCF2/HNF1B genes. His HbA1C was 5.8% at time of endocrine evaluation. He received one time high dose steroids in operating room and was started on tacrolimus after transplant. Pancreatic ultrasound showed normal pancreatic head, body not visualized. He was sent home with intensive insulin management on day 20 after renal transplant. Patient’s family history revealed mother with diagnosis of type 2 diabetes mellitus (T2DM) at age 19, maternal grandmother and great-grandmother diagnosed at early age with T2DM as well. Discussion: HNF-1 beta gene encodes a transcription factor that regulates nephron and embryonic pancreas development. MODY 5 is clinically heterogeneous disorder and the degree of insulin deficiency is variable, some family members who carry the gene remain free of diabetes into later adult life. The mean age of diagnosis of DM is 26 years with a range of 10–61 years. Our patient is only six years old and he may have presented earlier due post-transplant status, high dose steroids and tacrolimus use, all factors known to be triggers for hyperglycemia but the persistence of insulin requirement and levels of HbA1C being on pre-diabetes range at time of evaluation might be a sign of early deterioration of pancreatic function. Diagnosis of MODY5 has important implications for treatment, prognosis, and genetic counseling. Diabetes in these patients requires early use of insulin. Patient’s family members were advised to undergo genetic testing and screening for renal abnormalities and DM. Further studies on the correlation of phenotypes and genotypes will help delineate the clinical course of MODY 5. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SUN-130 A Not-So-Simple Work-Up of Diabetes: A Case of MODY 5

Introduction: Maturity-onset diabetes of the young 5 (MODY-5) is a rare type of inherited diabetes mellitus. It is an autosomal dominant disease, manifesting as a clinically heterogeneous disorder with a lack of autoantibodies. On the molecular level, MODY 5 is due to defects of hepatocyte nuclear factors 1B (HNF1B), which not only cause structural abnormalities, but also intrinsic organ dysfunction in the kidneys, liver, and pancreas as well. Case: This is a 33 year old female presented for diabetes type 2 management. Her past medical history originated at the age of 7, diagnosed with short ureters with reflux leading to frequent pyelonephritis, requiring reconstructive surgery. At 15, found to have high liver enzymes, which have had variable and persistent elevation; she had 4 liver biopsies, which were pathologically unremarkable and no cause found. At 27, diagnosed with type 2 DM based on her HbA1c being >7 and initiated on metformin. Recently was also diagnosed with PCOS after a first trimester missed abortion and subsequent infertility. Abdominal US subsequently revealed bilateral renal cysts. Family history was remarkable for type 1 diabetes in her father, type 2 diabetes in her sister and maternal uncle, and renal dysfunction in her niece. Physical exam was unremarkable, and BMI was 19.53 kg/m2. Laboratory workup revealed elevated liver enzymes (Alkaline Phosphatase: 445 U/l; Bilirubin: 1.7 mg/dl, ASL: 106 U/L, ALT 248 U/L). A1C was 5.3% at that time. Based off the presentation and exam, it was felt that her disease process did not fit the classic paradigm of type 2 diabetes mellitus, no obesity, no hypertension and no dyslipidemia. This prompted autoimmune diabetes screening which was negative. A MODY Sequencing Panel was then performed, which was positive for MODY type 5; she was found to be heterozygous in the HNF1B gene, c.544+1G>A variant. Given her diagnosis, an insulin regimen was initiated but due to allergic reaction, she was then converted to glipizide orally. She is now following with medical genetics. Conclusion: MODY is not commonly seen in the diabetes population, where prevalence accounts for 2 to 5 % of known diabetics. MODY-5 is a more uncommon subset in the population with MODY, manifesting as 5-10% of such cases. As such, many MODY patients are often misclassified has having either type 1 or type 2 diabetes. Given other organ dysfunctions affected by MODY-5, a lack of diagnosis of this condition can delay monitoring and treatment of the disease. As such, recognition of MODY should be increased, as is need for early screening for patients if the disease is suspected. Citation: Dubois-Laforgue, D,. et al. (2017). Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B ( HNF1B ) Molecular Defects. Diabetes Care, 40(11), 1436-1443. doi:10.2337/dc16-2462. PMID: 28420700

Novel mutation in the hepatocyte nuclear factor 1B/maturity – onset diabetes of the young type 5 gene – unreported Vietnamese case

Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1 (HNF-1β) gene, mostly generating truncated protein. Various phenotypes are related to HNF-1β mutations. Our aim to describe clinical and genetic findings in the unreported Vietnamese case identified with HNF-1β mutations. The proband with kidney failure from 7.5 years of age and diabetes diagnosed at 13.5 years of age who were described. Case report included information: characteristics of diabetes, renal function and structure, pancreas structure. Genomic DNA were extracted from WBC of whole blood and HNF-1β mutation was performed using PCR and direct sequencing. The proband is heterozygous for a novel HNF1B missense mutation (c.505T>C; p.Y169H). This mutation results in the substitution of the amino acid histidine (charged polar) for tyrosine (uncharged polar) at codon 169. The tyrosine residue is conserved across species and it is therefore likely that the p.Y169H mutation is pathogenic. This result is consistent with a diagnosis of renal cysts and diabetes syndrome (RCAD). Testing was done for proband's parents and no mutation was found in HNF1B. It is therefore likely that the p.Y169H mutation has arisen de novo. Kidney MRI showed right kidney atrophy and pancreas MRI showed only tissue of head of pancreas. Investigations at 14.5 years of age – diagnosed diabetes showed: plasma urea 10.1 mmol/l; creatinine 250 micrommol/l; HbA1C 13.6%. He was given insulin of 0.8 UI/Kg/day and HbA1C was 6.8% after one year of treatment with insulin injection. Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1β is warranted, even without a family history of diabetes, in non obese patients with diabetes and slowly progressive non diabetic nephropathy, particularly when pancreatic atrophy. Written informed consent was obtained from the patient for publication of this Case report (and any accompanying images). A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Dominantly inherited diabetes mellitus caused by GATA6 haploinsufficiency: variable intrafamilial presentation

GATA6 haploinsufficiency has recently been reported as the most frequent cause of neonatal diabetes with pancreatic agenesis. Although all previously reported cases represented a de novo mutation with complete agenesis...

Mitochondrial tRNALeu(UUR) gene mutation and maternally inherited diabetes mellitus in Pakistani population

Background and objectivesMaternally Inherited Diabetes Mellitus and Deafness (MIDD) occurs due to the mutations in mitochondrial DNA (mtDNA). The most common heteroplasmic point mutation reported, is in the tRNALeu(UUR) gene, i.e., A3243G, accompanied with deafness. The objectives of the present study were to determine whether the cause of MIDD in selected Pakistani population, is also the mutation of A3243G in mitochondrial tRNALeu(UUR) gene or not, and is there any genotype–phenotype correlation for the MIDD in this population. Subjects and methodsThe present study was conducted in the Department of Biochemistry and Molecular Biology, Army Medical College, Rawalpindi, Pakistan, during the period November 2005 to November 2007. The patients and control subjects were randomly selected from the two cities; Rawalpindi and Multan (both rural and urban areas) and were divided into three groups. (1) Fifty patients with T2DM and maternal history with feature(s) of MIDD. (2) Fifty non-diabetic first-degree relatives of patients with T2DM. (3) Fifty non-diabetic controls with no maternal history of T2DM. The patients and control subjects were scanned for the detection of potential mutations in mitochondrial DNA tRNALeu(UUR) gene (np 3035–3456, 422 bp fragment). ResultsOn the basis of a polymerase chain reaction, electrophoresis and mtDNA sequencing along with insulin dependence, degree of deafness in patients and subjects, it is proved that there is no A-to-G mutation at np 3243 of mitochondrial leucine tRNA gene in any of the groups studied. ConclusionIt is concluded that in the Pakistani population, selected for the present study, the MIDD is not due to A3243G mutation in mitochondrial tRNALeu(UUR) gene.

Maternally inherited diabetes mellitus, deafness, chronic progressive external ophthalmoplegia and myopathy as the result of A3243G mutation of mtDNA

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome are caused mainly by the A3243G mutation of the mitochondrial genome. The A3243G substitution of mitochondrial DNA (mtDNA) is also responsible for various, other clinical phenotypes and syndromes. Here we report the case of a 33-year-old woman, with childhood onset ophthalmoplegia externa, progressive, generalised exercise intolerability, muscle weakness, hypacusis and diabetes mellitus as the symptoms of mitochondrial disease. Genetic analysis of the mitochondrial DNA revealed a heteroplasmic A to G substitution at position 3243 in the tRNS Leu(UUR) gene. In our case the classical MELAS phenotype has not yet appeared, however, some examples show in the literature that maternally inherited diabetes mellitus, progressive hypacusis, progressive ophthalmoplegia externa, exercise intolerance, and myopathy are often linked to as isolated symptoms of A3243G mutation. The phenotype in the family is consistent, the proband's daughter has ptosis, exercise intolerance, and myopathy, too. A brief summary of the different clinical phenotypes associated with A3243G mutation, and of the different mtDNA mutations which can cause chronic progressive ophthalmoplegia externa (CPEO) will also be reviewed in this case report.

Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation

Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (K(ATP)) channel, cause both permanent and transient neonatal diabetes. Identification of KCNJ11 mutations has important therapeutic implications, as many patients can replace insulin injections with sulphonylurea tablets. The aim was to determine if a KCNJ11 mutation was responsible for a dominantly inherited form of diabetes mellitus, showing variability in age at diagnosis, in an Italian family. We sequenced KCNJ11 in members of a three-generation family with variable phenotypes of dominantly inherited diabetes mellitus. One had transient early-onset diabetes, one had impaired glucose tolerance during the second pregnancy, and two had young-onset diabetes. None of the subjects showed permanent neonatal diabetes or neurological symptoms. A novel heterozygous mutation (c. 679C-->G and c. 680A-->T) was identified, resulting in a GAG-->CTG (E227L) substitution in KCNJ11. Functional studies of recombinant heterozygous K(ATP) channels revealed a small reduction in channel inhibition by ATP (IC(50) of 15 micromol/l and 38 micromol/l for wild-type and heterozygous channels, respectively) and an increase in the resting K(ATP) current. This would be expected to impair insulin secretion. The results are in agreement with the mild phenotype of the patients. Our results broaden the spectrum of diabetes phenotypes resulting from KCNJ11 mutations. They indicate testing for KCNJ11 mutations should be considered not only for neonatal diabetes but also for other forms of dominantly inherited diabetes with later onset, especially where these are associated with a low body mass index and low birth weight.

Autosomal dominant transmission of diabetes and congenital hearing impairment secondary to a missense mutation in the WFS1 gene

Mutations of the WFS1 gene have been implicated in autosomal dominant diseases, such as low-frequency sensorineural hearing impairment (LFSNHI) and/or diabetes mellitus and/or optic atrophy. The aim was to investigate WFS1 gene sequences in a family with diabetes mellitus and hearing impairment. Three members of a family with a maternally inherited combination of diabetes mellitus and hearing impairment, but no specific mutations in its mitochondrial genome, were investigated for mutations in the WFS1 gene. This pedigree, in which the proband had non-insulin-dependent diabetes mellitus and congenital hearing impairment and his mother a triple combination of diabetes mellitus, hearing impairment and optic atrophy, was found to be associated with autosomal dominant transmission of the E864K mutation of the WFS1 gene. In the light of this confirmatory study, we recommend the systematic analysis of WFS1 gene sequences in patients with parentally inherited diabetes mellitus and deafness (+/- optic atrophy), in particular when diabetogenic mtDNA mutations have been excluded.

Progressive Sensorineural Hearing Impairment in Maternally Inherited Diabetes Mellitus and Deafness (MIDD)

To study the progression of hearing impairment (HI) and audiological features in patients with the mitochondrial A to G mutation in the tRNA(LEU(RUU)) gene at position 3,243 associated with maternally inherited diabetes and deafness. Retrospective phenotype genotype family study. Tertiary referral center. Six adult family members with the mitochondrial tRNA(LEU(RUU)) gene mutation at location 3,243. Data were obtained on medical history, otological examination, and pure tone and speech audiometry. Peripheral leukocytes were analyzed for the presence of the mutation, and heteroplasmy levels were determined. Selected patients underwent vestibular testing, brainstem-evoked response audiometry and neurological examination. One patient showed relatively normal hearing, whereas in the others, HI had started at 27 to 79 years of age. All the patients showed progression in HI of approximately 1.4 dB/yr on average at 0.25 and 8 kHz. In the frequency range 0.5 to 2 kHz, progression was approximately 2 dB/yr; at 4 kHz, progression was 2.4 dB/yr. Vestibular and brainstem-evoked response audiometry test results were normal. All the patients achieved the maximum speech recognition score, as was expected based on their pure-tone average at 1, 2, and 4 kHz. Our six adult patients with the mitochondrial tRNA(LEU(RUU)) gene mutation at location 3,243 showed almost normal to severe HI which was progressive beyond presbyacusis. Data from the literature and our findings suggest a cochlear localization of the HI.

The C42R Mutation in the Kir6.2 (KCNJ11) Gene as a Cause of Transient Neonatal Diabetes, Childhood Diabetes, or Later-Onset, Apparently Type 2 Diabetes Mellitus

Known genes in maturity-onset diabetes of the young account for only a fraction of families with dominantly inherited diabetes in Japan. There should be as-yet-unidentified genes that account for the rest of the patients. To identify and characterize the mutation responsible for a Japanese family with dominantly inherited diabetes mellitus. Members of a four-generation family with dominantly inherited diabetes mellitus observed in three generations. None of the patients in this family had permanent neonatal diabetes. One had transient neonatal diabetes, one had childhood diabetes, and the others had adult-onset diabetes without autoantibodies or insulin resistance. Screening of the chromosomal location of the gene by a genome-wide linkage analysis followed by candidate gene sequencing. Confirmation of the functional significance of the identified mutation by the population survey and the physiological analysis. We identified a novel mutation (C42R) in the KCNJ11 gene coding for the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channel. The patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of our patients. These results broaden the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggest that mutations in this gene should be taken into consideration for not only permanent neonatal diabetes but also other forms of diabetes with milder phenotypes and later onset.

Clinical Spectrum Associated with Hepatocyte Nuclear Factor-1β Mutations

Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations. To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations. Multicenter, descriptive study. 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology. 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring. Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results. All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients. Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations. Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.

Pelvic lymphocyst infection associated with maternally inherited diabetes mellitus

A 45-year-old woman with 20-year history of diabetes mellitus was admitted to our hospital because of high fever and abdominal pain. Radical hysterectomy and bilateral pelvic lymphadenectomy had been performed 4 months before admission for invasive cervical cancer. On admission, elastic hard tumors were palpable in the lower abdomen. Laboratory examination showed positive C-reactive protein (CRP), anemia and renal dysfunction. Computed tomography (CT) revealed several lymphocysts in the pelvis. She was diagnosed with infection of pelvic lymphocysts. Since her mother also had diabetes associated with deafness, we examined mitochondrial DNA in leukocytes and detected an A to G transition at the nucleotide position of 3243 (A3243G mutation). She was diagnosed as maternally inherited diabetes mellitus and deafness (MIDD). Puncture of the cysts followed by administration of antibiotics resulted in marked improvement of symptoms and laboratory findings. This is a rare case of pelvic lymphocyst infection in a patient with a mitochondrial disorder. Although the exact mechanism of infection is not clear, MIDD may represent an unusual risk factor for infection, and further investigation is necessary to assess the influence of mitochondrial dysfunction on the immune system. Pelvic lymphocyst infection should be considered in the differential diagnosis of abdominal pain and fever in patients with MIDD after abdominal surgery.

Estudio de las mutaciones A3243G, C3256T y deleciones mitocondriales en 41 pacientes diabéticos

Mutations or deletions of mitochondrial DNA (mtDNA) define a new diabetes subtype. The A3243G and C3256T mutations and mtDNA deletions were studied in 41 diabetic patients with maternally inherited diabetes mellitus or deafness. The A3243G mutation was found in one out of forty-one diabetic patients (2.4%). Neither the C3256T mutation nor mtDNA deletions were detected. The search of A3243G mutation has to be considered in a diabetic patient with deafness and/or maternal history of diabetes.

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes.

Insulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca2+ influx, which raises cytosolic Ca2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca2+ concentration in the mitochondrial matrix activating Ca(2+)-sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca(2+)-stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca(2+)-induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1 alpha (HNF-1 alpha) also displayed deletion of glucose-induced but not Ca(2+)-induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease.

Lack of association between mitochondrial DNA mutation np3243 and maternally inherited diabetes mellitus

Lack of association between mitochondrial DNA mutation np3243 and maternally inherited diabetes mellitus