Type 1 diabetes and frailty: A scoping review.

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.

What Is the Influence of HIV Serostatus on HbA1c? A Prospective Analysis Using Continuous Glucose Monitoring.

OBJECTIVE: Type 2 diabetes (T2D) is reported to be more common in people living with HIV (PLWH). Clinical guidelines recommend screening for diabetes in PLWH, but there is no agreed method due to studies reporting HbA1c is falsely low in PLWH. These studies were performed in the early HIV era when participants were taking older preparations of antiretroviral therapy that are rarely used today. We aimed to investigate whether HIV serostatus influences HbA1c. RESEARCH DESIGNS AND METHODS: We conducted a prospective cohort study of PLWH and age- and sex-matched HIV-negative participants who were purposely recruited from clinics in Brighton, U.K. Each participant wore a Dexcom G6 continuous glucose monitor (CGM) for up to 10 days, had glucose measured during an oral glucose tolerance test, and fructosamine and paired HbA1c were measured. We performed regression analysis to assess the influence of HIV on HbA1c and used a separate model for CGM glucose, venous glucose, and fructosamine. In addition, we included predictor variables used in previous studies that explored HbA1c discrepancy. RESULTS: We recruited 60 PLWH (90% men, 50% with T2D, mean ± SD age 57 ± 10.7 years, 100% undetectable viral load) and 48 people without HIV (92% men, 30% with T2D, mean age 57.7 ± 8.9 years). We found that HIV serostatus did not have a significant influence on HbA1c within the regression models. CONCLUSIONS: We performed a comprehensive assessment of glycemia to assess whether HIV serostatus influences HbA1c. We did not find any strong evidence that HIV serostatus influenced HbA1c. The results of our study support incorporating HbA1c into routine clinical blood work in PLWH.

Two cases of linagliptin-associated bullous pemphigoid resulting in sepsis and endocarditis.

We describe two patients, in their 70s, each presenting to the emergency department, with 6-week histories of progressively developing pruritic bullae. Both individuals had multiple comorbidities, including type 2 diabetes-for which they took linagliptin, chronic kidney disease, hypertension and prosthetic heart valves. Owing to systemic illness and endocarditis secondary to superadded bacterial infections, they both required intensive treatment and prolonged hospital admissions.Despite the beneficial effect of linagliptin on glycaemic control and its reported cardiovascular and renal safety profiles, we add our cases as evidence of the significant risk of developing bullous pemphigoid while taking this medication. Secondary infection of bullous pemphigoid increased the risk of developing endocarditis, particularly among individuals with a medical history of valve replacement surgery. Considering this, we advocate caution when prescribing this medication.

HIV and type 2 diabetes: An evolving story.

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.

Lithium Monotherapy in Graves Thyrotoxicosis.

Lithium is not commonly used to treat thyrotoxicosis, and there are few reports in the literature of its use as initial therapy in thyrotoxicosis. We describe the case of a patient with Graves thyrotoxicosis and ophthalmopathy, on a background of autoimmune neutropenia, treated successfully with relatively long-term lithium monotherapy. Lithium was used at a lower dose and longer duration than previously reported on, to good effect. We demonstrate that lithium is an important and useful option for those who are unable to tolerate thionamide therapy.

Bringing precision medicine to the management of pregnancy in women with glucokinase-MODY: a study of diagnostic accuracy and feasibility of non-invasive prenatal testing.

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.

Hybrid Closed-Loop Therapy in Adults With Type 1 Diabetes and Above-Target HbA1c: A Real-world Observational Study.

OBJECTIVE: We explored longitudinal changes associated with switching to hybrid closed-loop (HCL) insulin delivery systems in adults with type 1 diabetes and elevated HbA1c levels despite the use of intermittently scanned continuous glucose monitoring (isCGM) and insulin pump therapy. RESEARCH DESIGN AND METHODS: We undertook a pragmatic, preplanned observational study of participants included in the National Health Service England closed-loop pilot. Adults using isCGM and insulin pump across 31 diabetes centers in England with an HbA1c ≥8.5% who were willing to commence HCL therapy were included. Outcomes included change in HbA1c, sensor glucometrics, diabetes distress score, Gold score (hypoglycemia awareness), acute event rates, and user opinion of HCL. RESULTS: In total, 570 HCL users were included (median age 40 [IQR 29-50] years, 67% female, and 85% White). Mean baseline HbA1c was 9.4 ± 0.9% (78.9 ± 9.1 mmol/mol) with a median follow-up of 5.1 (IQR 3.9-6.6) months. Of 520 users continuing HCL at follow-up, mean adjusted HbA1c reduced by 1.7% (95% CI 1.5, 1.8; P < 0.0001) (18.1 mmol/mol [95% CI 16.6, 19.6]; P < 0.0001). Time in range (70-180 mg/dL) increased from 34.2 to 61.9% (P < 0.001). Individuals with HbA1c of ≤58 mmol/mol rose from 0 to 39.4% (P < 0.0001), and those achieving ≥70% glucose time in range and <4% time below range increased from 0.8 to 28.2% (P < 0.0001). Almost all participants rated HCL therapy as having a positive impact on quality of life (94.7% [540 of 570]). CONCLUSIONS: Use of HCL is associated with improvements in HbA1c, time in range, hypoglycemia, and diabetes-related distress and quality of life in people with type 1 diabetes in the real world.

Diagnosis and Management of Monogenic Diabetes in Pregnancy.

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.

A Retrospective Study Assessing the Effect of Diabetes on Mortality in Patients With COVID-19 at a Teaching Hospital in the United Kingdom.

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.

The investigation of diabetes in people living with HIV: A systematic review.

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.

Images of the month: An incidental finding of spontaneous pneumomediastinum (Hamman's syndrome) secondary to diabetic ketoacidosis during the coronavirus pandemic.

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.

Noninvasive Fetal Genotyping by Droplet Digital PCR to Identify Maternally Inherited Monogenic Diabetes Variants.

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.

Cognitive, Neurological, and Behavioral Features in Adults With KCNJ11 Neonatal Diabetes.

OBJECTIVE: Central nervous system (CNS) features in children with permanent neonatal diabetes (PNDM) due to KCNJ11 mutations have a major impact on affected families. Sulfonylurea therapy achieves outstanding metabolic control but only partial improvement in CNS features. The effects of KCNJ11 mutations on the adult brain and their functional impact are not well understood. We aimed to characterize the CNS features in adults with KCNJ11 PNDM compared with adults with INS PNDM. RESEARCH DESIGN AND METHODS: Adults with PNDM due to KCNJ11 mutations (n = 8) or INS mutations (n = 4) underwent a neurological examination and completed standardized neuropsychological tests/questionnaires about development/behavior. Four individuals in each group underwent a brain MRI scan. Test scores were converted to Z scores using normative data, and outcomes were compared between groups. RESULTS: In individuals with KCNJ11 mutations, neurological examination was abnormal in seven of eight; predominant features were subtle deficits in coordination/motor sequencing. All had delayed developmental milestones and/or required learning support/special schooling. Half had features and/or a clinical diagnosis of autism spectrum disorder. KCNJ11 mutations were also associated with impaired attention, working memory, and perceptual reasoning and reduced intelligence quotient (IQ) (median IQ KCNJ11 vs. INS mutations 76 vs. 111, respectively; P = 0.02). However, no structural brain abnormalities were noted on MRI. The severity of these features was related to the specific mutation, and they were absent in individuals with INS mutations. CONCLUSIONS: KCNJ11 PNDM is associated with specific CNS features that are not due to long-standing diabetes, persist into adulthood despite sulfonylurea therapy, and represent the major burden from KCNJ11 mutations.

Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.

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 ß-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 ß-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 ß-cells. For epinephrine, we found increased responses in GCK-MODY patients, in ß-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 ß-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.

Current laboratory requirements for adrenocorticotropic hormone and renin/aldosterone sample handling are unnecessarily restrictive.

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.

Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes.

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.

Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation.

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.

When to suspect 'funny' diabetes.

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.

Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.

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.

A diagnostic approach for defining idiopathic remitting diabetes: a retrospective cohort study.

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.