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Aims: This study aims to describe the prevalence of monogenic diabetes in an Australian referral cohort, in relation to Exeter maturity-onset diabetes of the young (MODY) probability calculator (EMPC) scores and next-generation sequencing with updated testing where relevant. Methods: State-wide 5-year retrospective cohort study of individuals referred for monogenic diabetes genetic testing. Results: After excluding individuals who had cascade testing for a familial variant (21) or declined research involvement (1), the final cohort comprised 40 probands. Incorporating updated testing, the final genetic result was positive (likely pathogenic/pathogenic variant) in 11/40 (27.5%), uncertain (variant of uncertain significance) in 8/40 (20%) and negative in 21/40 (52.5%) participants. Causative variants were found in GCK, HNF1A, MT-TL1 and HNF4A. Variants of uncertain significance included a novel multi-exonic GCK duplication. Amongst participants with EMPC scores ≥ 25%, a causative variant was identified in 37%. Cascade testing was positive in 9/10 tested relatives with diabetes and 0/6 tested relatives with no history of diabetes. Conclusions: Contemporary genetic testing produces a high yield of positive results in individuals with clinically suspected monogenic diabetes and their relatives with diabetes, highlighting the value of genetic testing for this condition. An EMPC score cutoff of ≥ 25% correctly yielded a positive predictive value of ≥ 25% in this multiethnic demographic. This is the first Australian study to describe EMPC scores in the Australian clinic setting, albeit a biased referral cohort. Larger studies may help characterise EMPC performance between ethnic subsets, noting differences in the expected probability of monogenic diabetes relative to type 2 diabetes. [ABSTRACT FROM AUTHOR]

Monogenic diabetes, including mitochondrial diabetes, constitutes 1% to 3% of all diabetes. Although there is an increased interest in understanding the mechanisms of bone fragility in people with diabetes, skeletal research is mostly focused on type 1 and type 2 diabetes. Little is known on skeletal health among people with mitochondrial diabetes. In this single‐center study, we presented clinical characteristics of individuals with mitochondrial diabetes and clinical diagnosis of osteoporosis. Of 10 patients with mitochondrial diabetes, 4 (40%) had a clinical diagnosis of osteoporosis. Patients with osteoporosis were older, had lower body mass index, longer diabetes duration, lower fasting C‐peptide, and presence of multiple comorbidities compared with patients without osteoporosis. In addition to our cases, we also systematically reviewed literature on skeletal health in people with mitochondrial diabetes and provided an overview of potential factors affecting skeletal health and future clinical and research directions to improve the care of people with mitochondrial disease. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

ABSTRACT Monogenic diabetes, including mitochondrial diabetes, constitutes 1% to 3% of all diabetes. Although there is an increased interest in understanding the mechanisms of bone fragility in people with diabetes, skeletal research is mostly focused on type 1 and type 2 diabetes. Little is known on skeletal health among people with mitochondrial diabetes. In this single‐center study, we presented clinical characteristics of individuals with mitochondrial diabetes and clinical diagnosis of osteoporosis. Of 10 patients with mitochondrial diabetes, 4 (40%) had a clinical diagnosis of osteoporosis. Patients with osteoporosis were older, had lower body mass index, longer diabetes duration, lower fasting C‐peptide, and presence of multiple comorbidities compared with patients without osteoporosis. In addition to our cases, we also systematically reviewed literature on skeletal health in people with mitochondrial diabetes and provided an overview of potential factors affecting skeletal health and future clinical and research directions to improve the care of people with mitochondrial disease. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature of MD. As mitochondrial dysfunction is one of the important factors causing IR, we need to focus on IR as another pathophysiology of MD. In this special issue, we first briefly summarized the insulin signaling and molecular mechanisms of IR. Second, we overviewed currently confirmed pathogenic mitochondrial DNA (mtDNA) mutations from the MITOMAP database. The variants causing diabetes were mostly point mutations in the transfer RNA (tRNA) of the mitochondrial genome. Third, we focused on these variants leading to the recently described "tRNA modopathies" and reviewed the clinical features of patients with diabetes. Finally, we discussed the pathophysiology of MD caused by mtDNA mutations and explored the possible mechanism underlying the development of IR. This review should be beneficial to all clinicians involved in diagnostics and therapeutics related to diabetes and mitochondrial diseases. [ABSTRACT FROM AUTHOR]

Objectives: Mitochondrial DNA (mtDNA) plays an important role in the pathogenesis of diabetes. Variants in mtDNA have been reported in diabetes, but studies on the whole mtDNA variants were limited. Our study aims to explore the association of whole mtDNA variants with diabetes and diabetic kidney disease (DKD). Methods: The whole mitochondrial genome was screened by next-generation sequencing in cohort 1 consisting of 50 early-onset diabetes (EOD) patients with a maternally inherited diabetes (MID) family history. A total of 42 variants possibly associated with mitochondrial diseases were identified according to the filtering strategy. These variants were sequenced in cohort 2 consisting of 90 EOD patients with MID. The association between the clinical phenotype and these variants was analyzed. Then, these variants were genotyped in cohort 3 consisting of 1,571 type 2 diabetes mellitus patients and 496 subjects with normal glucose tolerance (NGT) to analyze the association between variants with diabetes and DKD. Results: Patients with variants in the non-coding region had a higher percentage of obesity and levels of fasting insulin (62.1% vs. 24.6%, P = 0.001; 80.0% vs. 26.5% P < 0.001). The patients with the variants in rRNA had a higher prevalence of obesity (71.4% vs. 30.3%, P = 0.007), and the patients with the variants in mitochondrial complex I had a higher percentage of the upper tertile of FINS (64.3% vs. 34.3%, P = 0.049). Among 20 homogeneous variants successfully captured, two known variants (m.A3943G, m.A10005G) associated with other mitochondrial diseases were only in the diabetic group, but not in the NGT group, which perhaps indicated its possible association with diabetes. The prevalence of DKD was significantly higher in the group with the 20 variants than those without these variants (18.7% vs. 14.6%, P = 0.049) in the participants with diabetes of cohort 3. Conclusion: MtDNA variants are associated with MID and DKD, and our findings advance our understanding of mtDNA in diabetes and DKD. Itwill have important implications for the individual therapy of mitochondrial diabetes. [ABSTRACT FROM AUTHOR]

It is estimated that between 0.5% to 2.8% of patients with diabetes have maternally inherited diabetes and deafness (MIDD), which is caused by a mutation at position 3243 of the mitochondrial DNA. The result of this mutation is reduced functional capacity of the respiratory enzyme complexes in mitochondria leading to reduced ATP generation. In the pancreatic beta cell, the altered ATP generation is thought to result in insulin deficiency, leading to diabetes. The diagnosis of MIDD is suspected based on the presence of one or more of 1) maternal heritability of diabetes or impaired glucose tolerance with a normal BMI, 2) hearing impairment and 3) maculopathy. Recognition is important as it allows tailored treatment and early detection, prevention and management of associated disorders in both the patient and their maternal relatives. We present two cases of MIDD and a review of the pathogenesis, clinical characteristics and management of this uncommon but under-recognised, monogenic form of diabetes.

Background: Mitochondrial diabetes (MD) is a rare monogenic form of diabetes and divided into type l and type 2. It is characterized by a strong familial clustering of diabetes with the presence of maternal transmission in conjunction with bilateral hearing impairment in most of the carriers. The most common form of MD is associated with the m.3243A>G mutation in the mitochondrial MT‐TL1, but there are also association with a range of other point mutations, deletion, and depletion in mtDNA. Methods: The mitochondrial genome anomalies were investigated in a family with clinical features of MD, which includes a proband presenting severe MD conditions including cardiomyopathy, retinopathy, and psychomotor retardation. Results: By investigating the patient's blood leukocytes and skeletal muscle, we identified the m.3243A>G mutation in heteroplasmic state. This mutation was absent in the rest of the family members. In addition, our analysis revealed in the proband a large mtDNA heteroplasmic deletion (~1 kb) and a reduction in mtDNA copy number. Conclusion: Our study points out, for the first time, a severe phenotypic expression of the m.3243A>G point mutation in association with mtDNA deletion and depletion in MD. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial diabetes is a kind of rare diabetes caused by monogenic mutation in mitochondia. The study aimed to summarize the clinical phenotype profiles in mitochondrial diabetes withm.3243A>G mitochondrial DNA mutation and to investigate the mechanism in this kind of diabetes by analyzing the relationship among clinical phenotypes and peripheral leukocyte DNA telomere length. Methods: Fifteen patients with maternally inherited diabetes in five families were confirmed as carrying the m.3243A>G mitochondrial DNA mutation. One hundred patients with type 2 diabetes and one hundred healthy control subjects were recruited to participate in the study. Sanger sequencing was used to detect the m.3243A>G mitochondrial DNA mutation. The peak height G/A ratio in the sequence diagram was calculated. Real-time polymerase chain reaction (PCR) was used to measure telomere length. Results: The patients with mitochondrial diabetes all had definite maternally inherited history, normal BMI (19.5 ± 2.36 kg/m2), early onset of diabetes (35.0 ± 14.6 years) and deafness. The peak height G/A ratio correlated significantly and negatively with the age at onset of diabetes (≦25 years, 61.6 ± 20.17 %; 25-45 years, 16.59 ± 8.64 %; >45 years, 6.37 ± 0.59 %; p = 0.000). Telomere length was significantly shorter among patients with mitochondrial diabetes and type 2 diabetes than in the control group (1.28 ± 0.54 vs. 1.14 ± 0.43 vs. 1.63 ± 0.61; p = 0.000). However, there was no significant difference between patients with mitochondrial diabetes and those with type 2 diabetes. There was no correlation between telomere length and the peak height G/A ratio. Conclusion: Deafness with definite maternal inheritance and normal BMI, associated with elevated blood lactic acid and encephalomyopathy, for the most part, suggest the diagnosis of mitochondrial diabetes . The peak height G/A ratio could reflect the spectrum of age at onset of the disease. Telomere length was shorter in patients with mitochondrial diabetes and those with type 2 diabetes, which suggests that the shorter telomere length is likely involved in the pathogenesis of diabetes but is not specific for this kind of diabetes. [ABSTRACT FROM AUTHOR]

Monogenic diabetes is frequently mistakenly diagnosed as either type 1 or type 2 diabetes, yet accounts for approximately 1–2% of diabetes. Identifying monogenic forms of diabetes has practical implications for specific therapy, screening of family members and genetic counselling. The most common forms of monogenic diabetes are due to glucokinase (GCK), hepatocyte nuclear factor (HNF)-1A and HNF-4A, HNF-1B, m.3243A>G gene defects. Practical aspects of their recognition, diagnosis and management are outlined, particularly as they relate to pregnancy. This knowledge is important for all physicians managing diabetes in pregnancy, given this is a time when previously unrecognised monogenic diabetes may be uncovered with careful attention to atypical features of diabetes misclassified as type 1, type 2, or gestational diabetes. [ABSTRACT FROM AUTHOR]

Mitochondrial diabetes (MD) is a heterogeneous disorder characterized by a chronic hyperglycemia, maternal transmission and its association with a bilateral hearing impairment. Several studies reported mutations in mitochondrial genes as potentially pathogenic for diabetes, since mitochondrial oxidative phosphorylation plays an important role in glucose-stimulated insulin secretion from beta cells. In the present report, we studied a Tunisian family with mitochondrial diabetes (MD) and deafness associated with nephropathy. The mutational analysis screening revealed the presence of a novel heteroplasmic mutation m.9276G>C in the mitochondrial COIII gene, detected in mtDNA extracted from leukocytes of a mother and her two daughters indicating that this mutation is maternally transmitted and suggest its implication in the observed phenotype. Bioinformatic tools showed that m.9267G>C mutation (p.A21P) is « deleterious » and it can modify the function and the stability of the MT-COIII protein by affecting the assembly of mitochondrial COX subunits and the translocation of protons then reducing the activity of the respective OXPHOS complexes of ATP synthesis. The nonsynonymous mutation (p.A21P) has not been reported before, it is the first mutation described in the COXIII gene which is related to insulin dependent mitochondrial diabetes and deafness and could be specific to the Tunisian population. The m.9267G>C mutation was present with a nonsynonymous inherited mitochondrial homoplasmic variation MT-COI m.5913 G>A (D4N) responsible of high blood pressure, a clinical feature detected in all explored patients. [ABSTRACT FROM AUTHOR]

However, very few reports described the impact of treatment with GLP-1 RA in patients with mitochondrial diabetes. Keywords: Glucagon-like peptide-1 receptor agonists; GLP1-RA; Dulaglutide; Mitochondrial diabetes; Maternally inherited diabetes and deafness (MIDD); MT-TL1 gene EN Glucagon-like peptide-1 receptor agonists GLP1-RA Dulaglutide Mitochondrial diabetes Maternally inherited diabetes and deafness (MIDD) MT-TL1 gene 1281 1282 2 07/30/21 20210901 NES 210901 Manuscript It has been estimated that one in 5000 adults may be affected by mitochondrial diseases, diabetes being the most common endocrine feature of these syndromes [[1]]. Glucagon-like peptide-1 receptor agonists, Dulaglutide, Mitochondrial diabetes, Maternally inherited diabetes and deafness (MIDD), MT-TL1 gene, GLP1-RA. [Extracted from the article]

Abstract: Background: The purpose was to characterize the clinical, biochemical, and immunological features of newly diagnosed adult-onset nonobese diabetic patients in China. Methods: Newly diagnosed diabetic patients aged 18–45 years with body mass index<23 kg/m2 were included. Excluding one mitochondrial diabetes patient, there were 102 diabetic patients enrolled in this study. Clinical and biochemical data were collected and analyzed. Radioimmunoassay was used to detect islet autoantibodies. Results: Among the 102 study participants, 68.6% had type 1 diabetes (T1DM), 20.6% had type 2 diabetes (T2DM), and 10.8% had latent autoimmune diabetes in adults (LADA). About 92% of the T1DM patients presented hyperglycemic symptoms. The corresponding number in T2DM and LADA patients was 13% and 38%, respectively (P<.01). C-peptide in T2DM patients (1.4±0.7 ng/ml) was significantly higher than that in T1DM (0.4±0.3 ng/ml) and LADA (0.4±0.2 ng/ml) patients (P<.01). The prevalence of glutamic acid decarboxylase antibody (GADA) (64.3%) in T1DM patients was higher than that of insulin autoantibody (17.1%) (P<.05). GADA and islet cell antibody (ICA) combination was positive in 75.7% of T1DM patients. Conclusion: T1DM patients accounted for majority of the study sample. In addition, the clinical symptoms of T1DM patients were more severe compared with T2DM patients. GADA is the most sensitive autoantibody marker for adult-onset T1DM and LADA. GADA and ICA are the best test combination for adult-onset autoimmune diabetes. Specific types of diabetes should be in mind when diabetes presents itself with special transmission mode or with other extrapancreatic manifestations. [Copyright &y& Elsevier]

The article presents a study which examined the clinicopathologic characterization of diabetes mellitus in vervet monkeys which include hyperglycemia, hypertriglyceridemia and islet amyloidosis. It states that pedigree analysis is consistent with either an autosomal dominant or mitochondrial inheritance pattern. The calculation of the blood glucose reference range for vervet monkeys is explained.

Maternally inherited diabetes and deafness (MIDD) and myoencephalopathy, lactic acidosis, stroke-like episodes (MELAS) syndromes are characterized by the same A3243G mutation of mitochondrial DNA (mtDNA). Should there be a link between these two clinical entities, one could expect to observe minor signs of MELAS in MIDD patients. To examine this issue, extensive evaluations of brain function and imaging in patients with mitochondrial diabetes and in age-matched type 1 diabetic patients were conducted and compared. MIDD patients (nine A3243G, two T14709G) and nine age-matched type 1 diabetic patients (T1D) were submitted for evaluation of cognitive functions, brain magnetic resonance (MR) imaging, and 1H-MR spectroscopy. Three MIDD patients exhibited cerebellar ataxia. The MIDD group exhibited poorer performances in sustained attention, verbal memory working, and abstract reasoning procedures, in comparison with the T1D group. MR imaging showed cerebellar atrophy in seven out of ten MIDD patients (versus 3 mild/8 in T1D controls) and basal ganglia calcifications in one MIDD patient. No evidence of (sub)acute stroke was detected. White-matter anomalies were observed in both groups (50%). 1H-MR spectroscopy revealed a significant decrease of N-acetyl aspartate only in vermis in the MIDD group, suggesting functional defect and/or neuronal loss. Lactate was detected in cerebrospinal fluid (CSF) in two MIDD and one T1D patient. Typical manifestations of MELAS are rare in MIDD syndrome, suggesting two different clinical entities. However, cerebellum involvement as assessed by imaging and 1H-MR spectroscopy is shared by both phenotypes. [ABSTRACT FROM AUTHOR]

Aims: Friedreich's Ataxia (FRDA) is a progressive neuromuscular disorder typically caused by GAA triplet repeat expansions in both frataxin gene alleles. FRDA can be complicated by diabetes mellitus (DM). The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related DM.Methods: FACOMS, a prospective, multi-site natural history study, includes 1,104 individuals. Extracted data included the presence of DM and other co-morbidities, genetic diagnosis, and markers of disease severity. We performed detailed medical record review and a survey for the subset of individuals with FRDA-related DM followed at one FACOMS site, Children's Hospital of Philadelphia.Results: FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common and newer glucose-lowering agents were used rarely.Conclusions: Clinical factors identify individuals at increased risk for FRDA-related DM. Future studies should test strategies for FRDA-related DM screening and management, in particular the potential role for novel glucose-lowering therapies in preventing or delaying FRDA-related cardiac disease. [ABSTRACT FROM AUTHOR]

Introduction: m.3243A>G-related disease has multi-systemic manifestations including diabetes mellitus. It is uncertain whether metformin would trigger neurological manifestations of this disease. This study aims to review the diagnosis and management of m.3243A>G-related diabetes genetically confirmed by our laboratory and to evaluate the risk of metformin use triggering neurological manifestations.Methods: Cases with m.3243A>G detected between 2009 and 2020 were reviewed. Cases with diabetes mellitus were included. Cases with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) before diabetes onset were excluded. Odds ratio was calculated for association between metformin use and newly developed neurological manifestations.Results: Sixteen patients were identified. Odds ratio for metformin use was 3.50 [0.37-33.0; p = 0.3287]. One illustrative case with clear causal relationship between metformin use and neurological manifestations was described in detail.Conclusion: m.3243A>G-related diabetes mellitus is underdiagnosed. Red flags including positive family history, short stature, low body weight and hearing loss are often overlooked. Early diagnosis allows regular systemic assessment. In the era of precision medicine and novel therapies, it is prudent to avoid metformin as it could trigger neurological manifestations in this condition. Coenzyme Q10, DPP-IV inhibitors, SGLT2 inhibitors and GLP-1 receptor agonists may be considered. [ABSTRACT FROM AUTHOR]

The article provides clues for considering monogenic diabetes mellitus (DM) and genetic testing whenever facing a child with DM. DM is a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genes play an important role in the development of DM. Type 1 DM accounts for more than 95% of childhood and adolescence diabetes in most Western countries. Type 2 DM is considered a polygenic disorder with multiple genes located on different chromosomes. Meanwhile, monogenic DM results from the presence of one or more mutations in a single gene. Almost all cases of monogenic DM result from mutations in genes causing Β-cell loss or Β-cell dysfunction.

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Mitochondria provide cells with most of the energy in the form of adenosine triphosphate (ATP). Mitochondria are complex organelles encoded both by nuclear and mtDNA. Only a few mitochondrial components are encoded by mtDNA, most of the mt-proteins are nuclear DNA encoded. Remarkably, the majority of the known mutations leading to a mitochondrial disease have been identified in mtDNA rather than in nuclear DNA. In general, the idea is that these pathogenic mutations in mtDNA affect energy supply leading to a disease state. Remarkably, different mtDNA mutations can associate with distinct disease states, a situation that is difficult to reconcile with the idea that a reduced ATP production is the sole pathogenic factor. This review deals with emerging insight into the mechanism by which the A3243G mutation in the mitochondrial tRNA (Leu, UUR) gene associates with diabetes as major clinical expression. A decrease in glucose-induced insulin secretion by pancreatic beta-cells and a premature aging of these cells seem to be the main process by which this mutation causes diabetes. The underlying mechanisms and variability in clinical presentation are discussed. [ABSTRACT FROM AUTHOR]

We report a patient with mitochondrial diabetes mellitus associated with the A3243G mutation (MDM3243). The patient is a 77-year man with diabetes. At age 68, he noticed diplopia, due to superior rectus muscle palsy of the right eye. At age 70, he noticed lipoma on the right arm. The pathology of his muscle revealed some ragged-red fibers, and focal cytochrome c oxidase deficiency. Hence, he may have a pathogenetic mechanism in common with CPEO (chronic progressive external ophthalmoplegia) or mitochondria-related autoimmune disorder associated with mononeuropathy.He had the rate of 0.102% for heteroplasmy of 3243 mitochondrial DNA mutation in leukocytes. This case’s heteroplasmy level is the smallest among the reported cases of MDM3243 in the literature. 3243 mitochondrial DNA mutation is known to induce a lack of uridine-modification in tRNALeu(UUR) at the first letter of the anticodon, with which the third letter of the codon pairs, and decline of the pairing of the anticodon of tRNA with the codon of mRNA, suggesting the termination of polypeptide–elongation to generate premature proteins. Therefore, we speculate that these premature proteins may accumulate overtime, thereby affecting cells in target organs. [Copyright &y& Elsevier]

A heteroplasmic T to C transition at nucleotide position 14709 in the mitochondrial tRNA glutamic acid (tRNAGlu) gene has previously been associated with maternally inherited diabetes and deafness (MIDD). To investigate the pathogenic mechanism of the T14709C mutation, we have constructed transmitochondrial cell lines by transferring fibroblasts mitochondria from a patient with the mutation into human cells lacking mitochondrial DNA (mtDNA) (rho° cells). Clonal cybrid cell lines were obtained containing various levels of the heteroplasmic mutation, or exclusively mutated or wild-type mtDNA. Measurement of respiratory chain enzymatic activities failed to detect a difference between the homoplasmic mutant and homoplasmic wild-type cybrid cell lines. However, a subtle decrease in the steady-state levels of tRNAGlu transcripts in some mutant clones. Our studies suggest that the T14709C mutation is insufficient to lead impairment of mitochondrial function in homoplasmic osteosarcoma cybrid clones, and that we cannot exclude that the T14709C mutation affects mitochondrial function by a yet unidentified mechanism. [Copyright &y& Elsevier]