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Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

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.

Maternally inherited diabetes and deafness (MIDD) syndrome refers to a rarely diagnosed disorder caused by pathogenic variants in mtDNA. It was first identified in 1992 and, to date, is considered underdiagnosed because of misclassification to type 1 or type 2 diabetes mellitus. MIDD reflects a multisystem metabolic syndrome commonly resulting in insulin-requiring diabetes and sensorineural deafness but can also lead to a broad range of other manifestations. The spectrum of pathology differs among individuals, likely because of varied degrees of heteroplasmy associated with mtDNA. Heteroplasmy also creates diagnostic difficulties, with a high index of suspicion required to diagnose MIDD in some cases. Here, we review a patient with MIDD who presented with an atypical clinical diabetes picture, additionally documenting his pedigree. To our knowledge, this is the first Cypriot reported with MIDD. [ABSTRACT FROM AUTHOR]

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]

Purposeof Review: This review aims to provide an update on the etiologies of diabetes that are due to genetic disorders and that co-occur with impaired hearing or vision and to compare them. The potential mechanisms, including novel treatments, will be detailed. Recent Findings: Wolfram syndrome, Kearns–Sayre syndrome, thiamine-responsive megaloblastic anemia, and maternally inherited diabetes and deafness are genetic disorders characterized by diabetes, impaired hearing, and vision. They differ in mode of inheritance, age at presentation, and the involvement of other organs; they are often misdiagnosed as type 1 or type 2 diabetes. Summary: Suspicion of a genetic diabetes syndrome should be raised when pancreatic autoantibodies are negative, other organs are involved, and family history includes diabetes. Correct diagnosis of the various syndromes is important for tailoring the most advanced treatment, preventing disease progression, and enabling proper genetic counseling. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to analyze the clinical characteristics and the pattern of long-term changes of fasting plasma C-peptide in patients with mitochondrial diabetes (MD), and to provide guidance for the diagnosis and treatment of MD. Methods: We retrieved MD patients with long-term follow-up at Peking Union Medical College Hospital from January 2005 to July 2021 through the medical record retrieval system and retrospectively analyzed their clinical data, biochemical parameters, fasting plasma C-peptide, glycosylated hemoglobin and treatment regimens. Non-parametric receiver operating characteristic (ROC) curves were used to assess the relationship between exercise test-related plasma lactate levels and suffering from MD. Results: A total of 12 MD patients were included, with clinical characteristics of early-onset, normal or low body weight, hearing loss, maternal inheritance, and negative islet-related autoantibodies. In addition, patients with MD exhibited significantly higher mean plasma lactate levels immediately after exercise compared to patients with type 1 diabetes mellitus (T1DM) (8.39 ± 2.75 vs. 3.53 ± 1.47 mmol/L, p=0.003) and delayed recovery time after exercise (6.02 ± 2.65 vs. 2.17 ± 1.27 mmol/L, p=0.011). The optimal cut-off points identified were 5.5 and 3.4 mmol/L for plasma lactate levels immediately after and 30 minutes after exercise, respectively. The fasting plasma C-peptide levels decreased as a negative exponential function with disease progression (Y= 1.343*e-0.07776X, R2 = 0.4154). Treatment regimens in MD patients were varied, with no metformin users and a weak correlation between insulin dosage and body weight. Conclusions: The increased level of plasma lactate during exercise or its delayed recovery after exercise would contribute to the diagnosis of MD. Changes of fasting plasma C-peptide in MD patients over the course of the disease indicated a rapid decline in the early stages, followed by a gradual slowing rate of decline. [ABSTRACT FROM AUTHOR]

ObjectiveThe aim of this study was to analyze the clinical characteristics and the pattern of long-term changes of fasting plasma C-peptide in patients with mitochondrial diabetes (MD), and to provide guidance for the diagnosis and treatment of MD.MethodsWe retrieved MD patients with long-term follow-up at Peking Union Medical College Hospital from January 2005 to July 2021 through the medical record retrieval system and retrospectively analyzed their clinical data, biochemical parameters, fasting plasma C-peptide, glycosylated hemoglobin and treatment regimens. Non-parametric receiver operating characteristic (ROC) curves were used to assess the relationship between exercise test-related plasma lactate levels and suffering from MD.ResultsA total of 12 MD patients were included, with clinical characteristics of early-onset, normal or low body weight, hearing loss, maternal inheritance, and negative islet-related autoantibodies. In addition, patients with MD exhibited significantly higher mean plasma lactate levels immediately after exercise compared to patients with type 1 diabetes mellitus (T1DM) (8.39 ± 2.75 vs. 3.53 ± 1.47 mmol/L, p=0.003) and delayed recovery time after exercise (6.02 ± 2.65 vs. 2.17 ± 1.27 mmol/L, p=0.011). The optimal cut-off points identified were 5.5 and 3.4 mmol/L for plasma lactate levels immediately after and 30 minutes after exercise, respectively. The fasting plasma C-peptide levels decreased as a negative exponential function with disease progression (Y= 1.343*e-0.07776X, R2 = 0.4154). Treatment regimens in MD patients were varied, with no metformin users and a weak correlation between insulin dosage and body weight.ConclusionsThe increased level of plasma lactate during exercise or its delayed recovery after exercise would contribute to the diagnosis of MD. Changes of fasting plasma C-peptide in MD patients over the course of the disease indicated a rapid decline in the early stages, followed by a gradual slowing rate of decline.

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.

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.

Abstract 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 Background In mitochondrial diabetes, apoptosis of β-cells caused by mitochondrial stress plays an important role in impaired insulin secretion. Several studies have reported that coenzyme Q10 (CoQ10) has therapeutic effects on mitochondrial diabetes, but no reports have examined the fundamental effectiveness or mechanism of CoQ10 in mitochondrial diabetes. We previously reported in a Japanese article that CoQ10 has protective effects on pancreatic β-cells against mitochondrial stress using mouse pancreatic β-cell line MIN6 and staurosporine (STS). Here, we report that CoQ10 protects MIN6 cells against apoptosis caused by STS and describe the more detailed apoptotic cascade. Methods Apoptosis of MIN6 cells was induced by 0.5 µM STS treatment for specific periods with or without 30 μM CoQ10. The apoptosis cascade in MIN6 cells was then investigated using WST-8 assays, annexin-V staining, western blotting, and DNA degradation analysis. Results Sixteen hours of 0.5 μM STS treatment led to 47% cell viability, but pretreatment with 30 μM CoQ10 resulted in significantly higher viability of 76% (P

Maternally-inherited diabetes with deafness (MIDD) is a rare form of monogenic diabetes that results, in most cases, from an A-to-g transition at position 3243 of mitochondrial DNA (m.3243A>g). The clinical presentation of m.3243A>g mutation is variable, ranging from mild to severe phenotypes. Diabetes is often accompanied by sensorineural deafness, cardiomyopathy, neuromuscular, psychiatric disorders, macular dystrophy and renal failure (kidney manifestations in adults presenting with this mutation remain poorly defined). The study presents a case of a 40-years-old woman with a history of bilateral sensorineural deafness, renal failure and diabetes that was diagnosed due to increasing muscle weakness during exercise. MIDD was diagnosed based on the clinical picture and the results of laboratory studies including genetic testing. As far as we know, glomerulopathy with incomplete distal renal tubular acidosis has never been described before as a cause of renal failure in MIDD patients. [ABSTRACT FROM AUTHOR]

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]

Mitochondrial diabetes is a rare form of diabetes caused by mutations in mitochondrial DNA. Clinically, mitochondrial diabetes often remains unrecognized. Most patients are diagnosed between age of 35 and 40 years, and previously treated as type 2 diabetes mellitus. The most common mutation of mitochondrial DNA associated with mitochondrial diabetes is A3243G, but some other mutations of mitochondrial DNA associated with various syndromes (MELAS, MIDD, Kearns-Sayre syndrome, etc.) can as well lead to diabetes mellitus. Diabetes mellitus is more commonly found in various syndromes that are the result of chromosomal aberrations such as Down's syndrome (type 1 diabetes), Turner's syndrome (type 1 and type 2 diabetes), and Klinefelter's syndrome (type 2 diabetes). Also, some genetic disorders are associated with a higher frequency of diabetes mellitus, and most commonly referred are: Prader-Willi syndrome, Wolfram syndrome, Wolcott-Ralisson's syndrome, Rabson-Mendenhall's syndrome and leprechaunism. Although rare, these forms of diabetes mellitus should be considered in patients with atypical clinical picture of the disease. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a heterogeneous group of conditions defined by resultant chronic hyperglycemia. Given the increasing prevalence of diabetes mellitus and the increasing understanding of genetic etiologies, we present a broad review of rare genetic forms of diabetes that have differing diagnostic and/or treatment implications from type 1 and type 2 diabetes. Advances in understanding the genotype-phenotype associations in these rare forms of diabetes offer clinically available examples of evolving precision medicine where defining the correct genetic etiology can radically alter treatment approaches. In this review, we focus on forms of monogenic diabetes, mitochondrial diabetes, and syndromic diabetes. [ABSTRACT FROM AUTHOR]

Mitochondrial diabetes (MD) is a heterogeneous disorder characterized by a chronic hyperglycemia and is maternally transmitted. Syndromic MD is a subgroup of MD including diabetic microangiopathy and macroangiopathy, in addition to extrapancreatic disorder. MD is caused by genetic mutations and deletions affecting mitochondrial DNA. This mitochondrial damage initiates apoptosis. In this study, we hypothesized that functional polymorphisms in genes involved in apoptotic pathway could be associated with the development of apoptosis in MD disease and increased its risk. Detection of apoptosis was confirmed on muscle biopsies taken from MD patients using the TUNEL method and the Cytochrome c protein expression level. We genotyped then 11 published SNPs from intrinsic and extrinsic apoptotic pathway and assessed the signification of these polymorphisms in 43 MD patients and 100 healthy controls. We found 10 selected polymorphisms ( p53 (rs1042522 and rs17878362), BCL2 (rs2279115), BAX (rs1805419), BAK1 (rs210132 and rs2227925), CASP3 (rs1405937), CASP7 (rs2227310), CASP8 (rs1045485) and CASP10 (rs13006529)) with a potential apoptosis effect in MD patients compared to control population. Specifically, SNPs involved in the intrinsic pathway ( p53 , BCL2 , BAK1 and CASP3 ) presented the highest risk of apoptosis. Our result proved that apoptosis initiated by mtDNA mutations, can be emphasized by a functional apoptotic polymorphisms associated with high expression of cytochrome c protein and more myofibers with apoptosis in syndromic MD subgroup compared with non-syndromic MD subgroup. [ABSTRACT FROM AUTHOR]

Introduction. Considering the urgent need to optimize the methods for preventing diabetes mellitus, it is important to find the methods of early diagnosis of carbohydrate metabolism disorders that precede the manifestation of type 2 diabetes mellitus and to promote the method of self-monitoring of carbohydrate metabolism available in Ukraine and abroad for each family. In connection with the peculiarities of energy metabolism, the expediency of studying the pyruvate dehydrogenase activity of blood for the purpose of early diagnosis of diabetes mellitus is obvious. Aim. To identify the persons with a hereditary predisposition to type 2 diabetes mellitus (with mitochondrial diabetes) in the population of the Prykarpattya region using the assessment of carbohydrate metabolism. To recommend the use of a bloodless visual method of studying the total content of α-ketoacids in the urine. Materials and methods. Into the study there were involved 292 practically healthy residents of the Prykarpattya region (166 men and 126 women aged 6 to 80 years) in which the blood glucose level did not exceed 5.6 mmol (100.8 mg%). The state of carbohydrate metabolism was evaluated using pyruvate dehydrogenase and α-ketoglutarate dehydrogenase tests. The monitoring was performed by indicators of pyruvate dehydrogenase activity in blood of healthy persons in the range of 8.01-16.30 μcat/l, as well as the 2-hour α-ketoneuria (6.4-11.4 mg, p

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]

Mitochondrial diabetes originates mainly from mutations located in maternally transmitted, mitochondrial tRNA-coding genes. In a genetic screening program of type 2 diabetes conducted with a Chinese Han population, we found one family with suggestive maternally transmitted diabetes. The proband's mitochondrial genome was analyzed using DNA sequencing. Total 42 known nucleoside changes and 1 novel variant were identified, and the entire mitochondrial DNA sequence was assigned to haplogroup M11b. Phylogenetic analysis showed that a homoplasmic mutation, 10003T>C transition, occurred at the highly conserved site in the gene encoding tRNA. Using a transmitochondrial cybrid cell line harboring this mutation, we observed that the steady-state level of tRNA significantly affected and the amount of tRNA decreased by 97 %, production of reactive oxygen species was enhanced, and mitochondrial membrane potential, mtDNA copy number and cellular oxygen consumption rate were remarkably decreased compared with wild-type cybrid cells. The homoplasmic 10003T>C mutation in the mitochondrial tRNA gene suggested to be as a pathogenesis-related mutation which might contribute to the maternal inherited diabetes in the Han Chinese family. [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]

A 25 years female diagnosed and confirmed mitochondrial by gene analysis mutation DNA 3243(A-G). CQ10 was useful for the resolution of clinical symptoms, and metformin should be avoided in mito-chondrial diabetes. [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. It will have important implications for the individual therapy of mitochondrial diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Gong, Han, Zhou, Zhang, Ren, Cai, Luo, Liu, Zhu, Zhou, Li and Ji.)

Monogenic forms of diabetes mellitus cover a heterogeneous group of diabetes which are uniformly caused by a single gene mutation and are characterised by impaired insulin secretion of the pancreatic beta cell. It is estimated that they account for up to 5% of all cases of diabetes mellitus, which are often not diagnosed or are misclassified as type 1 or 2 diabetes. However, accurate diagnosis is important because of the special implications for treatment, prognosis and family risk. The knowledge of typical clinical features such as mode of inheritance, age at diagnosis and impaired insulin secretion, as well as genetic testing establishes the diagnosis of MODY, mitochondrial diabetes and neonatal diabetes.

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]

Abstract: The BHE/cdb rat has a mutation in adenosine triphosphate (ATP) synthase that impairs insulin secretion. However, male BHE/cdb rats have normal circulating glucose and enhanced glucose tolerance. The aim of the current study was to identify mechanisms of enhanced glucose tolerance. The respiratory exchange ratio was increased, indicating increased oxidation of carbohydrate in BHE/cdb rats, consistent with increases in liver pyruvate dehydrogenase activity and muscle citrate synthase activity. Liver also exhibited diminished phosphoenol pyruvate carboxykinase content, which correlated with a decreased counter-regulatory response in the insulin tolerance test. Signaling via Akt or AMP-dependent kinase pathways in the liver could not account for lower blood glucose. We conclude that chronically low insulin secretion leads to adaption in glucose metabolism primarily in liver to maintain euglycemia. [Copyright &y& Elsevier]

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.

Abstract: Mitochondrial diabetes affects up to 1% of patients with diabetes and is often unrecognised by the physicians. Maternally inherited diabetes and deafness (MIDD) resulting from the mutation 3243A>G of the mitochondrial DNA is the most frequent mutation associated with mitochondrial diabetes. This review summarizes the range of clinical phenotypes associated with MIDD and outlines the advances in genetic diagnosis, pathogenesis and management of these patients. [Copyright &y& Elsevier]

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]

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.