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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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, HbA
1c
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, HbA
1c
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 HbA
1c
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, HbA
1c
did not change. The mean change in HbA
1c
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. HbA
1c
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
HIV and type 2 diabetes: An evolving story Daultrey, Harriet; Levett, Tom; Oliver, Nick ...
HIV medicine,
April 2024, 2024-Apr, 2024-04-00, 20240401, Volume:
25, Issue:
4
Journal Article
Peer reviewed
Open access
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims
HbA1c 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), HbA1c 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 HbA1c reported HbA1c to diagnose fewer people with diabetes, monitoring studies found HbA1c to underestimate glycaemia levels. Controlled studies demonstrate diabetes was more common in PLHIV.
Conclusion
OGTT was used most frequently to diagnose diabetes, and HbA1c to monitor known diabetes. Prevalence and incidence varied depending on marker of glycaemia used. Studies reported a discrepancy in accuracy of HbA1c in PLHIV, to address this, well‐designed, prospective studies, providing individual‐level data on HbA1c levels and an additional marker of glycaemia in PLHIV are needed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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.
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.
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.
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.
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 HbA
1c
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 HbA
1c
(
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
Graphical Abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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