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Aims: Advances in type 1 diabetes management are enabling more to reach older ages. Frailty is known to complicate type 2 diabetes. However, frailty in people with type 1 diabetes has not been extensively researched. This review summarises the available evidence on frailty in those with type 1 diabetes., Methods: A systematic search strategy was applied to multiple databases (Medline, Embase, CINAHL and Cochrane) including grey literature (Scopus, OAIster, OpenGrey, dissertation and thesis database). All evidence types were considered. English articles published after 2001 were eligible. For inclusion, participants must have been over 55 with type 1 diabetes. Frailty must have been clearly defined or assessed. The results were synthesised into a descriptive format to identify key themes., Results: Of 233 papers subject to full-text review, 23 were included. Older adult diabetes research frequently does not specify the type of diabetes; 100 articles were excluded for this reason. No articles were found specifically researching frailty in older adults with type 1 diabetes. Fourteen different definitions and nine assessments of frailty were outlined. Generally, the papers supported relaxation of glucose targets and greater adoption of diabetes technology., Conclusions: This review highlights the paucity of evidence in older adults with type 1 diabetes and frailty. Consensus on standardised definitions and assessments of frailty would aid future research, which is urgently needed as more people with type 1 diabetes reach older ages. Identifying and addressing the key issues in this population is vital to support individuals through the challenges of ageing., (© 2024 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Introduction: Diabetes is widely reported to be more common in people living with HIV (PLWH). Much of the data supporting this originated during the earlier HIV era. The perceived increased risk of type 2 diabetes is reflected in HIV clinical guidelines that recommend screening for diabetes in PLWH on anti-retroviral therapy (ART). However, international HIV clinical guidelines do not agree on the best marker of glycaemia to screen for diabetes. This stems from studies that suggest HbA1c underestimates glycaemia in PLWH., Methods: Within this review we summarise the literature surrounding the association of HIV and type 2 diabetes and how this has changed over time. We also present the evidence on HbA1c discrepancy in PLWH., Conclusion: We suggest there is no basis to any international guidelines to restrict HbA1c based on HIV serostatus. We recommend, using the current evidence, that PLWH should be screened annually for diabetes in keeping with country specific guidance. Finally, we suggest future work to elucidate phenotype and natural history of type 2 diabetes in PLWH across all populations., (© 2023 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Aims/hypothesis: In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management., Methods: We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021., Results: In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3-8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18-24), with 23/25 (92%) reported before 28 weeks., Conclusions/interpretation: Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies., (© 2023. The Author(s).)

Monogenic diabetes occurs in up to 3% of people with diabetes. Mutations in over 40 different genes are responsible. The most common genes affected are HNF1A, HNF4A, GCK, and HNF1B. Additionally, other types of diabetes with a genetic aetiology include neonatal diabetes and diabetes plus syndrome. Each of these genetic subtypes has a different phenotype and requires distinctive treatments. Due to the overlap of monogenic diabetes with type 1 and 2 diabetes and even gestational diabetes, they can often be misdiagnosed. During pregnancy, individual subtypes require treatment that is different from standard diabetes care, so recognition and prompt diagnosis of monogenic diabetes are important to avoid inadequate treatment. We describe the management of monogenic diabetes for the most significant subtypes, focussing on the impact on and management in pregnancy. A genetic diagnosis of diabetes can alter long-term treatment in those with diabetes. In pregnancy and the postnatal period, this can involve specific management changes determined by the gene affected and whether there is a fetal inheritance of the gene. Where inheritance of the genotype influences the outcomes, cell-free fetal testing will hopefully soon become a diagnostic tool for early recognition of fetal mutations., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aims: HbA 1c is reported to underestimate glycaemia in people living with HIV (PLHIV). There is not an internationally agreed screening method for diabetes. The primary aim was to identify which tests are performed to diagnose and monitor diabetes in PLHIV. Secondary aims were to identify whether prevalence or incidence of diabetes differs according to marker of glycaemia and how figures compare in PLHIV compared to people without., Methods: Electronic databases were searched for studies investigating diabetes in PLHIV, not pregnant, aged ≥18 years. Narrative analysis and descriptive statistics were used to describe which markers of glycaemia, and their frequency, were employed in the diagnosis and monitoring of diabetes in PLHIV. Diagnostic studies provided prevalence or incidence of diabetes., Results: In all, 45 of 1028 studies were included. Oral glucose tolerance test (OGTT), fasting glucose (FG), HbA 1c and Fructosamine were used to investigate diabetes. In total, 27 studies described diagnosing diabetes, 14 using OGTT, 12 FG and 7 HbA1c. All 18 studies monitoring diabetes used HbA1c. Prevalence ranged from 1.3% to 26% and incidence 2.9% to 12.8%. Studies using glucose and HbA 1c reported HbA 1c to diagnose fewer people with diabetes, monitoring studies found HbA 1c to underestimate glycaemia levels. Controlled studies demonstrate diabetes was more common in PLHIV., Conclusion: OGTT was used most frequently to diagnose diabetes, and HbA 1c to monitor known diabetes. Prevalence and incidence varied depending on marker of glycaemia used. Studies reported a discrepancy in accuracy of HbA 1c in PLHIV, to address this, well-designed, prospective studies, providing individual-level data on HbA 1c levels and an additional marker of glycaemia in PLHIV are needed., (© 2020 Diabetes UK.)

Aim The aim of the study was to compare the clinical characteristics and outcomes (mortality, intensive care admission, mechanical ventilation, and length of stay, LoS) of patients with and without diabetes with confirmed COVID-19.  Methods This retrospective study evaluated clinical and laboratory variables in adult inpatients from Brighton and Sussex University Hospitals NHS Trust with laboratory-confirmed COVID-19 between March 10, 2020, and June 30, 2020. Univariate and multivariate analyses were performed to compare the outcomes of patients with and without diabetes.  Results Over 457 patients were included in this study (140 with diabetes and 317 without diabetes), of which 143 (31.9%) died. The median age was 80 years and were predominantly males (59.1%). Baseline characteristics at the time of COVID-19 diagnosis demonstrated that the patients with diabetes were younger than those without diabetes (p=0.008). Mortality increased with age. There was no difference in adverse outcomes in those with and without diabetes. However, subgroup analysis of patients aged ≤60 years demonstrated a significantly increased mortality in those with diabetes (p=0.016). Patients with diabetes had an increased length-of-stay compared to those without diabetes, which was more evident in those aged ≤60 years. Conclusion Age is the most important predictor of mortality. Patients with diabetes did not have increased mortality from COVID-19, which is likely due to their younger age in our cohort. More patients with diabetes stayed in the hospital longer than seven days than those without diabetes., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ahmed et al.)

Hamman's syndrome is a spontaneous pneumomediastinum and is described as a rare complication of diabetic ketoacidosis (DKA). It typically follows a self-limiting course after successful treatment of the underlying DKA. We describe a case of a 28-year-old woman with type 1 diabetes presenting with facial pain, vomiting and abdominal pain. She also complained of dyspnoea and chest pain. She was diagnosed and treated for DKA triggered by a dental abscess. Given the presentation during the coronavirus pandemic, a computed tomography pulmonary angiography was performed in line with the diagnostic pathway for COVID-19, which incidentally showed a significant pneumomediastinum and pneumopericardium. The patient was initially investigated for oesophageal rupture secondary to vomiting (Boerhaave's syndrome), however, remained clinically stable throughout. Follow-up computed tomography showed near-complete resolution of pneumomediastinum with no intervention other than treatment of DKA. This therefore confirmed Hamman's syndrome.We propose that given the benign nature of the condition and the incidental finding in this report, as well as poor identification of mediastinal gas on chest X-ray, Hamman's syndrome is more common than reported., (© Royal College of Physicians 2020. All rights reserved.)

Background: Babies of women with heterozygous pathogenic glucokinase (GCK) variants causing mild fasting hyperglycemia are at risk of macrosomia if they do not inherit the variant. Conversely, babies who inherit a pathogenic hepatocyte nuclear factor 4α (HNF4A) diabetes variant are at increased risk of high birth weight. Noninvasive fetal genotyping for maternal pathogenic variants would inform pregnancy management., Methods: Droplet digital PCR was used to quantify reference and variant alleles in cell-free DNA extracted from blood from 38 pregnant women heterozygous for a GCK or HNF4A variant and to determine fetal fraction by measurement of informative maternal and paternal variants. Droplet numbers positive for the reference/alternate allele together with the fetal fraction were used in a Bayesian analysis to derive probability for the fetal genotype. The babies' genotypes were ascertained postnatally by Sanger sequencing., Results: Droplet digital PCR assays for GCK or HNF4A variants were validated for testing in all 38 pregnancies. Fetal fraction of ≥2% was demonstrated in at least 1 cell-free DNA sample from 33 pregnancies. A threshold of ≥0.95 for calling homozygous reference genotypes and ≤0.05 for heterozygous fetal genotypes allowed correct genotype calls for all 33 pregnancies with no false-positive results. In 30 of 33 pregnancies, a result was obtained from a single blood sample., Conclusions: This assay can be used to identify pregnancies at risk of macrosomia due to maternal monogenic diabetes variants., (© American Association for Clinical Chemistry 2020.)

Objective: Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses., Methods: Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase., Results: GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated β-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in β-cells. For epinephrine, we found increased responses in GCK-MODY patients, in β-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release., Conclusions: Our data suggest that glucokinase in brain and other non β-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Samples for adrenocorticotropic hormone (ACTH) and aldosterone/renin analysis usually require rapid transport to the receiving laboratory for immediate separation and freezing. In practice, this means assessment is limited to hospital settings and many samples are rejected. We examined whether these requirements are necessary by assessing the stability of ACTH, aldosterone and renin over 48 hours in whole blood collected in serum gel and EDTA plasma from 31 participants. Our results show that ACTH collected into EDTA plasma is stable at room temperature for at least 6 hours, mean change at 6 hours -2.6% (95% CI -9.7 to 4.5). Both aldosterone and renin were stable collected on serum gel at room temperature for at least 6 hours: mean change aldosterone +0.2% (95% CI -3.6 to 4.0), renin -1.9% (95% CI -7.0 to3.2). Therefore, by using appropriate preservatives, ACTH and aldosterone/renin can be measured on samples collected at room temperature and processed within 6 hours. This would facilitate outpatient and emergency room assessment of these analytes., (© Royal College of Physicians 2017. All rights reserved.)

Aims/hypothesis: The finding that patients with diabetes due to potassium channel mutations can transfer from insulin to sulfonylureas has revolutionised the management of patients with permanent neonatal diabetes. The extent to which the in vitro characteristics of the mutation can predict a successful transfer is not known. Our aim was to identify factors associated with successful transfer from insulin to sulfonylureas in patients with permanent neonatal diabetes due to mutations in KCNJ11 (which encodes the inwardly rectifying potassium channel Kir6.2)., Methods: We retrospectively analysed clinical data on 127 patients with neonatal diabetes due to KCNJ11 mutations who attempted to transfer to sulfonylureas. We considered transfer successful when patients completely discontinued insulin whilst on sulfonylureas. All unsuccessful transfers received ≥0.8 mg kg(-1) day(-1) glibenclamide (or the equivalent) for >4 weeks. The in vitro response of mutant Kir6.2/SUR1 channels to tolbutamide was assessed in Xenopus oocytes. For some specific mutations, not all individuals carrying the mutation were able to transfer successfully; we therefore investigated which clinical features could predict a successful transfer., Results: In all, 112 out of 127 (88%) patients successfully transferred to sulfonylureas from insulin with an improvement in HbA1c from 8.2% (66 mmol/mol) on insulin, to 5.9% (41 mmol/mol) on sulphonylureas (p = 0.001). The in vitro response of the mutation to tolbutamide determined the likelihood of transfer: the extent of tolbutamide block was <63% for the p.C166Y, p.I296L, p.L164P or p.T293N mutations, and no patients with these mutations successfully transferred. However, most individuals with mutations for which tolbutamide block was >73% did transfer successfully. The few patients with these mutations who could not transfer had a longer duration of diabetes than those who transferred successfully (18.2 vs 3.4 years, p = 0.032). There was no difference in pre-transfer HbA1c (p = 0.87), weight-for-age z scores (SD score; p = 0.12) or sex (p = 0.17)., Conclusions/interpretation: Transfer from insulin is successful for most KCNJ11 patients and is best predicted by the in vitro response of the specific mutation and the duration of diabetes. Knowledge of the specific mutation and of diabetes duration can help predict whether successful transfer to sulfonylureas is likely. This result supports the early genetic testing and early treatment of patients with neonatal diabetes aged under 6 months.

Glucokinase-maturity-onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. GCK gene mutations are present in ∼1 in 1,000 of the population, but most are not diagnosed. They are common causes of MODY (10-60%): persistent incidental childhood hyperglycemia (10-60%) and gestational diabetes mellitus (1-2%). GCK-MODY has a unique pathophysiology and clinical characteristics, so it is best considered as a discrete genetic subgroup. People with GCK-MODY have a defect in glucose sensing; hence, glucose homeostasis is maintained at a higher set point resulting in mild, asymptomatic fasting hyperglycemia (5.4-8.3 mmol/L, HbA1c range 5.8-7.6% [40-60 mmol/mol]), which is present from birth and shows slight deterioration with age. Even after 50 years of mild hyperglycemia, people with GCK-MODY do not develop significant microvascular complications, and the prevalence of macrovascular complications is probably similar to that in the general population. Treatment is not recommended outside pregnancy because glucose-lowering therapy is ineffective in people with GCK-MODY and there is a lack of long-term complications. In pregnancy, fetal growth is primarily determined by whether the fetus inherits the GCK gene mutation from their mother. Insulin treatment of the mother is only appropriate when increased fetal abdominal growth on scanning suggests the fetus is unaffected. The impact on outcome of maternal insulin treatment is limited owing to the difficulty in altering maternal glycemia in these patients. Making the diagnosis of GCK-MODY through genetic testing is essential to avoid unnecessary treatment and investigations, especially when patients are misdiagnosed with type 1 or type 2 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity., (© The Author 2014. Published by Oxford University Press.)

Diabetes comes in many shapes and forms. It is important for the general physician to recognise when clinical characteristics, response to treatment and associated features suggest an alternative variety of diabetes, over and above the traditional type 1 and type 2 forms which are far more common. Key to these suspicions are taking a clear history of the development of the diabetes and being aware of the family history., (© 2014 Royal College of Physicians.)

Background: 11 patients were referred to our Molecular Genetics Department at the Royal Devon and Exeter Hospital between 2000-2012 with a physician's diagnosis of remitting diabetes. Our aim was to identify patients with remitting diabetes whose clinical presentation is not explained by any known aetiology of diabetes., Methods: We obtained longitudinal clinical data on all 11 patients from the hospital records. All patients were aged between 0.5 and 35 years at diagnosis. We applied clinical criteria derived from the literature to establish 1) definite diabetes, 2) diabetes initially severe-requiring treatment with insulin, 3) remission of diabetes, and 4) exclusion of known causes of remitting diabetes., Results: 10 out of 11 patients had an alternative explanation for their remission or a clear diagnosis was not identified. We identified a single patient with idiopathic remitting diabetes using these criteria. The patient was a white Caucasian female diagnosed aged 15 with symptoms of diabetes, laboratory glucose of 21.2 mmol/L and HbA1c 134 mmol/mol. Her BMI was 23.6 kg/m2. She was treated with basal bolus insulin but discontinued two years after diagnosis due to hypoglycaemia. 13 years post diagnosis, she had a normal oral glucose tolerance test during pregnancy (fasting glucose 4.5 mmol/L, 2 hr glucose 4.8 mmol/L) and an HbA1c of 30 mmol/mol. This patient does not appear to have Type 1 or Type 2 diabetes, and furthermore does not fit into current classifications of diabetes., Conclusions: Idiopathic remitting diabetes is rare but does exist. Strict clinical criteria are important to ensure patients have a robust clinical diagnosis. Identification of more patients with idiopathic remitting diabetes will enable further study of the clinical course of this syndrome. Applying these strict criteria will allow the identification of patients with remitting diabetes to assess its aetiology.

Aims/hypothesis: Heterozygous glucokinase (GCK) mutations cause mild, fasting hyperglycaemia from birth. Although patients are usually asymptomatic and have glycaemia within target ranges, some are put on pharmacological treatment. We aimed to investigate how many patients are on pharmacological treatment and the impact of treatment on glycaemic control., Methods: Treatment details were ascertained for 799 patients with heterozygous GCK mutations. In a separate, longitudinal study, HbA1c was obtained for 16 consecutive patients receiving insulin (n = 10) or oral hypoglycaemic agents (OHAs) (n = 6) whilst on treatment, and again having discontinued treatment following a genetic diagnosis of GCK-MODY. For comparison, HbA1c before and after genetic testing was studied in a control group (n = 18) not receiving pharmacological therapy., Results: At referral for genetic testing, 168/799 (21%) of patients were on pharmacological treatment (13.5% OHAs, 7.5% insulin). There was no difference in the HbA1c of these patients compared with those receiving no treatment(median [IQR]: 48 [43, 51] vs 46 [43, 50] mmol/mol, respectively; 6.5% [6.1%, 6.8%] vs 6.4% [6.1%, 6.7%]; p = 0.11). Following discontinuation of pharmacological treatment in 16 patients, HbA1c did not change. The mean change in HbA1c was -0.68 mmol/mol (95% CI: -2.97, 1.61) (-0.06% [95% CI: -0.27, 0.15])., Conclusions/interpretation: Prior to a genetic diagnosis, 21% of patients were on pharmacological treatment. HbA1c was no higher than in untreated patients and did not change when therapy was discontinued, suggesting no impact on glycaemia. The lack of response to pharmacological therapy is likely to reflect the regulated hyperglycaemia seen in these patients owing to their glucose sensing defect and is an example of pharmacogenetics.

Objective: Identifying glucokinase monogenic diabetes (GCK-MODY) in pregnancy is important, as management is different from management for other forms of gestational diabetes mellitus (GDM) and there is no increased maternal risk of type 2 diabetes. We calculated the population prevalence of GCK-MODY in pregnancy and determined the clinical characteristics that differentiate pregnant women with GCK-MODY from those with GDM., Research Design and Methods: We calculated the population prevalence of GCK-MODY in pregnancy by testing a subset of patients from the population-based Atlantic Diabetes in Pregnancy (Atlantic DIP) study (n = 5,500). We sequenced for GCK mutations in 247 women with a fasting glucose ≥5.1 mmol/L and 109 randomly selected control subjects with normal fasting glucose. Using data from the cases found and 40 previously identified GCK-MODY pregnancies, we analyzed whether clinical criteria could be used to differentiate GCK-MODY from GDM., Results: Four women with fasting glucose ≥5.1 mmol/L were diagnosed with GCK-MODY. No cases were identified with normal fasting glucose. The population prevalence of GCK-MODY is 1.1 in 1,000 (95% CI 0.3-2.9 in 1,000) and prevalence in GDM is 0.9% (95% CI 0.3-2.3). Fasting glucose and BMI significantly differentiate GCK-MODY from GDM (P < 0.0001). Combined criteria of BMI <25 kg/m(2) and fasting glucose ≥5.5 mmol/L has a sensitivity 68%, specificity 96%, and number needed to test of 2.7 women with GDM to find one case of GCK-MODY., Conclusions: Our large population cohort of pregnant women tested estimates the population prevalence of GCK-MODY of 1.1 in 1,000. We have shown routine clinical criteria that can identify which women should be tested for GCK-MODY in pregnancy.

We describe a new syndrome of young onset diabetes, short stature and microcephaly with intellectual disability in a large consanguineous family with three affected children. Linkage analysis and whole exome sequencing were used to identify the causal nonsense mutation, which changed an arginine codon into a stop at position 127 of the tRNA methyltransferase homolog gene TRMT10A (also called RG9MTD2). TRMT10A mRNA and protein were absent in lymphoblasts from the affected siblings. TRMT10A is ubiquitously expressed but enriched in brain and pancreatic islets, consistent with the tissues affected in this syndrome. In situ hybridization studies showed that TRMT10A is expressed in human embryonic and fetal brain. TRMT10A is the mammalian ortholog of S. cerevisiae TRM10, previously shown to catalyze the methylation of guanine 9 (m(1)G9) in several tRNAs. Consistent with this putative function, in silico topology prediction indicated that TRMT10A has predominant nuclear localization, which we experimentally confirmed by immunofluorescence and confocal microscopy. TRMT10A localizes to the nucleolus of β- and non-β-cells, where tRNA modifications occur. TRMT10A silencing induces rat and human β-cell apoptosis. Taken together, we propose that TRMT10A deficiency negatively affects β-cell mass and the pool of neurons in the developing brain. This is the first study describing the impact of TRMT10A deficiency in mammals, highlighting a role in the pathogenesis of microcephaly and early onset diabetes. In light of the recent report that the type 2 diabetes candidate gene CDKAL1 is a tRNA methylthiotransferase, the findings in this family suggest broader relevance of tRNA methyltransferases in the pathogenesis of type 2 diabetes., Competing Interests: The authors have declared that no competing interests exist.

Objective: In women with hyperglycemia due to heterozygous glucokinase (GCK) mutations, the fetal genotype determines its growth. If the fetus inherits the mutation, birth weight is normal when maternal hyperglycemia is not treated, whereas intensive treatment may adversely reduce fetal growth. However, fetal genotype is not usually known antenatally, making treatment decisions difficult., History and Examination: We report two women with gestational diabetes mellitus resulting from GCK mutations with hyperglycemia sufficient to merit treatment., Investigation: In both women, DNA from chorionic villus sampling, performed after high-risk aneuploidy screening, showed the fetus had inherited the GCK mutation. Therefore, maternal hyperglycemia was not treated. Both offspring had a normal birth weight and no peripartum complications., Conclusions: In pregnancies where the mother has hyperglycemia due to a GCK mutation, knowing the fetal GCK genotype guides the management of maternal hyperglycemia. Fetal genotyping should be performed when fetal DNA is available from invasive prenatal diagnostic testing.

Primary hypothyroidism is the most common endocrine disease. Although the diagnosis and treatment of hypothyroidism is often considered simple, there are large numbers of people with this condition who are suboptimally treated. Even in those people with hypothyroidism who are biochemically euthyroid on levothyroxine replacement there is a significant proportion who report poorer quality of life. This review explores the historical and current treatment options for hypothyroidism, reasons for and potential solutions to suboptimal treatment, and future possibilities in the treatment of hypothyroidism.

Lipodystrophy is commonly reported in Africa after antiretroviral therapy (ART) is initiated, but few studies have objectively measured changes in body composition. Body composition was determined in 76 HIV-infected participants from Mbarara, Uganda after starting a thymidine-analog regimen, and annual change was determined using repeated measures analysis. We measured skinfolds (tricep, thigh, subscapular, and abdomen), circumferences (arm, hip, thigh, waist), and total lean and fat mass (using bioelectric impedance analysis). A cross-sectional sample of 49 HIV-uninfected participants was studied for comparison. At baseline, most body composition measures were lower in HIV-infected than uninfected participants, but waist circumference was similar. After 12 months on ART, there was little difference in body composition measures between HIV-infected and uninfected participants; median waist circumference appeared higher in HIV-infected participants (79 vs. 75 cm; p = 0.090). Among HIV-infected participants, increases were observed in total lean and fat mass, circumference, and skinfold measures; only the increase in tricep skinfold did not reach statistical significance (+1.05 mm; 95% confidence interval: -0.24, 2.34; p = 0.11). Regional anthropometry in peripheral and central body sites increased over 12 months after ART initiation in HIV-infected persons from southwestern Uganda, suggesting a restoration to health. Gains in the tricep skinfold, a reliable marker of subcutaneous fat, appeared blunted, which could indicate an inhibitory effect of zidovudine on peripheral subcutaneous fat recovery.

Addison disease is a rare but potentially fatal disorder of the adrenal glands. Its manifestations are often confused with many common disorders, and a high index of suspicion is required for the diagnosis. Optimum steroid replacement and patient education are vital for good quality of life and to prevent acute adrenal crisis in this condition., (Copyright 2010 Elsevier Inc. All rights reserved.)