Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile.

AIMS: Change in weight, HbA1c , lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression. METHODS: We involved people with type 2 diabetes from two UK-based cohorts: 11,914 individuals with GP follow-up data from the UK Biobank and 723 from Salford. We generated a 'favourable adiposity' genetic score and conducted cross-sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow-up time points with 1-year intervals. RESULTS: The 'favourable adiposity' genetic score was cross-sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m2 [0.19,0.40]), but higher high-density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (-0.04 mmol/L [-0.07, -0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow-up. There was a trend for participants with higher 'favourable adiposity' genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid-lowering (0.91 [0.86, 0.97]) and anti-hypertensive medication (0.95 [0.91, 0.99]). CONCLUSIONS: In individuals with type 2 diabetes, having more 'favourable adiposity' alleles is associated with a marginally better lipid profile long-term and having lower odds of requiring lipid-lowering or anti-hypertensive medication in spite of relatively higher adiposity.

Assessment of global long interspersed nucleotide element-1 (LINE-1) DNA methylation in a longitudinal cohort of type 2 diabetes mellitus (T2DM) individuals.

INTRODUCTION: Recent studies have indicated that methylation of the LINE-1 elements is associated with an increased risk of worsening carbohydrate metabolism. It has been shown that overall DNA methylation of LINE-1 elements could be considered as a risk factor for T2DM and its complications, independent of other established risk factors. METHODS: A total of 794 T2DM individuals from Salford, UK were included in this study (60% men n = 470). All patients had clinical and metabolic variables measured in 2002 (baseline outcomes) and annually through to 2016. Global LINE-1 DNA methylation was measured at four CpG sites. The QIAGEN PyroMark Q96 MD pyrosequencer was used to quantify methylation. RESULTS: The overall mean ± SD global LINE-1 methylation was 75.81 ± 3.25%. Cross-sectional linear regression analysis at baseline year 2002 showed that LINE-1 methylation was a significant predictor of diastolic BP (adjusted beta coefficient ß = -0.25), estimated glomerular filtration rate (eGFR) (ß = -0.48) and cholesterol HDL ratio (ß = -0.04). A 10% increase in LINE-1 methylation was associated with a lower diastolic BP by 2.5 mm Hg, a lower eGFR by 4.8 ml/min/1.73 m2 and decreased cholesterol/HDL ratio by 0.4 mmol/L. Longitudinal analysis over the 14-year-follow-up periods showed that global LINE-1 methylation at baseline was associated with lower BMI in women [ß = -0.25] and lower cholesterol: HDL ratio [ß = -0.07]. A 10% increase in LINE-1 methylation was associated with reduction in BMI by 2.5 kg/m2 in women and reduction in cholesterol:HDL ratio by 0.7 mmol/L. CONCLUSION: In a 14-year longitudinal cohort of T2DM individuals, relations between global LINE-1 DNA methylation status and specific metabolic markers were seen. Also, a higher degree of DNA methylation was predictive of less weight gain over time in women.

Improving outcomes in diabetes in pregnancy.

One in 250 pregnancies in the UK involves diabetes. The majority of cases (87.5%) are gestational diabetes, 7.5% are type 1 and 5% are type 2 diabetes. Diabetes in pregnancy is associated with a five fold increase in risk of stillbirth and a two-fold increased risk of congenital defects compared with the general maternity population. Fasting blood glucose levels above 5.3 mmol/L can directly affect organogenesis, particularly of the fetal heart and spine. Hyperglycaemia can cause placental failure and stillbirth and for this reason early delivery is recommended. For women with pre-existing diabetes good blood glucose control prior to conception can minimise pregnancy risks towards levels approaching that of women without diabetes. The recommended glycated haemoglobin (HbA(1c)) target in preparation for pregnancy is 48 mmol/mol (6.5%) if this can be safely achieved. Women with an HbA(1c) 86 mmol/mol should be strongly advised against pregnancy. In normal pregnancy, the increased insulin resistance mediated by placental hormone secretion is compensated by increased maternal insulin secretion to maintain euglycaemia. Gestational diabetes arises from an inability to meet these increased insulin requirements adequately. Lifestyle modification with input from a specialist diabetes dietician is key to the management of gestational diabetes. Women with gestational diabetes have a significant lifetime risk of developing type 2 diabetes, hence diabetes screening must be undertaken on an annual basis in primary care.

A study to investigate genetic factors associated with weight gain in people with diabetes: analysis of polymorphisms in four relevant genes.

BACKGROUND: Weight change is often seen in people with diabetes. We investigated the effects of genes associated with weight change/glucose handling/insulin-signalling. MATERIALS/METHODS: DNA from diabetes individuals and non-diabetes individuals, plus clinical data, were available from the DARE study (n = 379 individuals: T1D n = 111; T2D n = 222; controls n = 46). Weight gain was assessed by temporal change of Body Mass Index (BMI). Genotyping was performed for CAV1rs926198, LEPRrs1137101, BDNFrs6265 and FTOrs9939609. RESULTS: No differences in genotype distributions were observed for the four SNPs in all groups un-stratified by weight gain. Following stratification differences in genotype distribution were observed. For those BMI relatively stable; controls showed a difference in genotype distributions versus T1D (CAV1rs926198, LEPRrs1137101). In T2D vs controls, significant differences were observed in genotype distribution for all four genes. For BMI increase, the only difference by category was LEPRrs1137101 (bothT1D/T2D vs controls). In BMI-stable groups, CAV1rs926198, T1D individuals showed lower T allele frequency (p=0.004) vs non-diabetes and for LEPRrs1137101 a higher G allele frequency versus controls (p=0.002). For T2D, CAV1rs926198, T allele frequency was lower in T2D than controls (p=0.005). For LEPR rs1137101, the G allele frequency was higher than in controls (p=0.004). In those with BMI increase, LEPRrs1137101 T1D individuals had higher G allele frequency versus controls (p=0.002) as did T2D vs controls (p=0.03). CONCLUSION: Differences in allele frequency were seen between diabetes individuals and non-diabetes diagnosed at baseline in relation to the likelihood of BMI increase of >10%. It is established that the G allele of LEPRrs1137101 is associated with weight gain/obesity. However, this is the first report of CAV1rs926198 polymorphism being associated with weight stability/gain in diabetes.

Changes in prescribing of psychotropic vs some physical health medication in primary care through the COVID-19 pandemic in England: a national-level survey.

INTRODUCTION: The COVID-19 pandemic globally impacted healthcare provision. Prescribing changes in common medications can be used as a marker for new diagnoses. We describe how the prescribing of specific psychotropics was impacted by the pandemic. METHODS: Primary Care Prescribing data for different classes of drugs from March 2017 to February 2022 were considered. To capture the impact during periods of restricted access to health services for new diagnoses/existing conditions, repeat prescriptions/episodic prescribing were included with account taken of historical trends. The pre-pandemic prescriptions issued each month from March 2018 to February 2020 were linearly extrapolated forward to give an expected annual growth (EAG). The monthly average expected prescriptions for the pandemic period (March 2020-February 2022) were compared. RESULTS: Physical health medications had lower monthly prescriptions during the pandemic, most markedly for antibiotics - 12.5% (EAG - 1.3%). Bronchodilator prescribing showed a marked increase in the early pandemic months from March 2020 of 5% (EAG 0.1%). Mental health medication prescribing increased above trend for hypnotics/anxiolytics by 0.2% (EAG - 2.3%), while antidepressants fell by - 0.2% (EAG 5.0%), with no net change for antipsychotics (EAG 2.8%), but a temporary increase in antipsychotic prescribing in the early pandemic period. For all the main antidepressants prescribed in England (Sertraline, Mirtazapine, Venlafaxine, Fluoxetine and Citalopram), prescribing actually decreased in the main pandemic period vs historical trend. CONCLUSIONS: The increase in anxiolytic/hypnotic prescribing above trend links to pandemic effects on anxiety/worry. If anything, there was a slight fall in prescribing of the main antidepressants prescribed, which given prevailing circumstances at the time, suggests that access to services may have restricted access to timely assessment.

A Longitudinal Clinical Trajectory Analysis Examining the Accumulation of Co-morbidity in People with Type 2 Diabetes (T2D) Compared with Non-T2D Individuals.

BACKGROUND: Type 2 diabetes mellitus (T2D) is commonly associated with an increasing complexity of multimorbidity. While some progress has been made in identifying genetic and non-genetic risk factors for T2D, understanding the longitudinal clinical history of individuals before/after T2D diagnosis may provide additional insights. METHODS: In this study, we utilised longitudinal data from the DARE (Diabetes Alliance for Research in England) study to examine the trajectory of clinical conditions in individuals with and without T2D. Data from 1932 individuals (T2D n = 1196 vs. matched non-T2D controls n = 736) were extracted and subjected to trajectory analysis over a period of up to 50 years (25 years pre-diagnosis/25 years post-diagnosis). We also analysed the cumulative proportion of people with diagnosed coronary artery disease (CAD) in their general practice (GP) record with an analysis of lower respiratory tract infection (RTI) as a comparator group. RESULTS: The mean age of diagnosis of T2D was 52.6 (95% confidence interval 52.0-53.4) years. In the years leading up to T2D diagnosis, individuals who eventually received a T2D diagnosis consistently exhibited a considerable increase in several clinical phenotypes. Additionally, immediately prior to T2D diagnosis, a significantly greater prevalence of hypertension (35%)/RTI (34%)/heart conditions (17%)/eye, nose, throat infection (19%) and asthma (12%) were observed. The corresponding trajectory of each of these conditions was much less dramatic in the matched controls. Post-T2D diagnosis, proportions of T2D individuals exhibiting hypertension/chronic kidney disease/retinopathy/infections climbed rapidly before plateauing. At the last follow-up by quintile of disadvantage, the proportion (%) of people with diagnosed CAD was 6.4% for quintile 1 (least disadvantaged) and 11% for quintile 5 (F = 3.4, p = 0.01 for the difference between quintiles). CONCLUSION: These findings provide novel insights into the onset/natural progression of T2D, suggesting an early phase of inflammation-related disease activity before any clinical diagnosis of T2D is made. Measures that reduce social inequality have the potential in the longer term to reduce the social gradient in health outcomes reported here.

Psychometric and biomedical outcomes of glycated haemoglobin target-setting in adults with type 1 and type 2 diabetes: Protocol for a mixed-methods parallel-group randomised feasibility study.

BACKGROUND: The disease burden of diabetes can have wide-ranging implications on patients' psychological well-being and health-related quality of life. Glycated haemoglobin targets are commonly used to guide patient management in diabetes to reduce the future risk of developing diabetes complications, but little is known of the psychological impact of glycated haemoglobin target-setting. This protocol describes a study to determine the feasibility of evaluating psychological outcomes when setting explicit glycated haemoglobin targets in people with diabetes. METHODS: This single-centre randomised feasibility study will follow a mixed-methods approach across four sub-studies. In sub-study A, eligible adults (aged 18 and over) with type 1 or type 2 diabetes will complete baseline validated psychometric questionnaires evaluating health-related quality of life (EuroQoL-5D-5L), diabetes-related distress (Problem Areas In Diabetes), self-care (Summary of Diabetes Self-Care Activities), well-being (Well-Being Quetionnaire-12) and diabetes-related psychosocial self-efficacy (Diabetes Empowerment Scale-Long Form). Participants will be randomised to receive explicit glycated haemoglobin intervention targets 5mmol/mol above or below current glycated haemoglobin readings. Rates of eligibility, recruitment, retention and questionnaire response rate will be measured. Psychometric outcomes will be re-evaluated 3-months post-intervention. Sub-studies B and C will use qualitative semi-structured interviews to evaluate experiences, views and opinions of diabetes patients and healthcare professionals in relation to the acceptability of study processes, the use of glycated haemoglobin targets, the impact of diabetes on psychological well-being and, in sub-study D, barriers to participation in diabetes research. DISCUSSION: This mixed-methods study aims to provide a novel insight into the psychological implications of glycated haemoglobin target-setting for people with diabetes in secondary care, alongside testing the feasibility of undertaking a larger project of this nature. TRIAL REGISTRATION: The study is registered with the ISRCTN (registration number: 12461724; date registered: 11th June 2021). Protocol version: 2.0.5, 26th February 2021.

The individualisation of glycaemic targets in response to patient characteristics in type 2 diabetes: a scoping review.

BACKGROUND: Evidence and guidelines increasingly support an individualised approach to care for people with type 2 diabetes and individualisation of glycaemic targets in response to patient factors. METHODS: We undertook a scoping review of the literature for evidence of factors impacting upon glycated haemoglobin target individualisation in adults with type 2 diabetes. Data were analysed thematically with the themes inductively derived from article review. FINDINGS: Evidence suggests that presence of cardiovascular disease, hypoglycaemia unawareness, severe hypoglycaemia, limited life expectancy, advanced age, long diabetes duration, frailty, cognitive impairment, disability, extensive comorbidity, diabetes distress and patient preference should inform the setting of glycaemic targets. CONCLUSION: The management of people with diabetes is complex. In clinical practice, many patients will have a variety of factors that should be considered when personalising their care. Approaches to personalised care and glycaemic treatment targets should be undertaken as part of a shared decision-making process between physician and patient. Use of electronic records might enable greater efficiency and more widespread use of personalised care plans for people with diabetes.

Androgen receptor-reduced sensitivity is associated with increased mortality and poorer glycaemia in men with type 2 diabetes mellitus: a prospective cohort study.

INTRODUCTION: Hypogonadism is associated with poorer glycaemic outcomes/increased all-cause and cardiovascular morbidity/mortality in type 2 diabetes mellitus (T2DM). Increasing CAG repeat number within exon-1 of the androgen receptor (AR) gene is associated with increased AR resistance/insulin resistance. METHODS: We determined in a long-term 14-year follow-up cohort of 423 T2DM Caucasian men, the association between baseline androgen status/CAG repeat number (by PCR then Sequenom sequencing) and metabolic/cardiovascular outcomes. RESULTS: Metabolic outcomes: Lower total testosterone was associated with higher BMI (kg/m2) at 14-year-follow-up: regression coefficient -0.30 (95% confidence interval -0.445 to -0.157), P = 0.0001. The range of CAG repeat number was 9-29 repeats. Higher CAG repeat number in exon-1 of the AR gene was associated with higher follow-up HbA1c2016 - each unit increase in CAG repeat-associated with an increment of 0.1% in HbA1C2016 (P = 0.04), independent of baseline testosterone. Cardiovascular outcomes and mortality: At an average of 14-year-follow-up, 55.8% of hypogonadal men had died vs 36.1% of eugonadal men (P = 0.001). There was a 'u' shaped relation between number of CAG repeats and mortality. Twenty-one CAG repeats were associated with an up to nearly 50% lower mortality rate than <21 CAG repeats and >21 CAG repeats - independent of baseline testosterone level. CONCLUSION: A higher number of CAG repeats at the AR gene associates with higher future HbA1c. There was a 'u' shaped relation between CAG repeat number and mortality rate. Determination of CAG repeat number may become part of assessment of androgen status/its consequences for men with T2DM.

Clinical Characteristics of COVID-19 Patients in a Regional Population With Diabetes Mellitus: The ACCREDIT Study.

Objective: To identify clinical and biochemical characteristics associated with 7- & 30-day mortality and intensive care admission amongst diabetes patients admitted with COVID-19. Research Design and Methods: We conducted a cohort study collecting data from medical notes of hospitalised people with diabetes and COVID-19 in 7 hospitals within the Mersey-Cheshire region from 1 January to 30 June 2020. We also explored the impact on inpatient diabetes team resources. Univariate and multivariate logistic regression analyses were performed and optimised by splitting the dataset into a training, test, and validation sets, developing a robust predictive model for the primary outcome. Results: We analyzed data from 1004 diabetes patients (mean age 74.1 (± 12.6) years, predominantly men 60.7%). 45% belonged to the most deprived population quintile in the UK. Median BMI was 27.6 (IQR 23.9-32.4) kg/m2. The primary outcome (7-day mortality) occurred in 24%, increasing to 33% by day 30. Approximately one in ten patients required insulin infusion (9.8%). In univariate analyses, patients with type 2 diabetes had a higher risk of 7-day mortality [p < 0.05, OR 2.52 (1.06, 5.98)]. Patients requiring insulin infusion had a lower risk of death [p = 0.02, OR 0.5 (0.28, 0.9)]. CKD in younger patients (<70 years) had a greater risk of death [OR 2.74 (1.31-5.76)]. BMI, microvascular and macrovascular complications, HbA1c, and random non-fasting blood glucose on admission were not associated with mortality. On multivariate analysis, CRP and age remained associated with the primary outcome [OR 3.44 (2.17, 5.44)] allowing for a validated predictive model for death by day 7. Conclusions: Higher CRP and advanced age were associated with and predictive of death by day 7. However, BMI, presence of diabetes complications, and glycaemic control were not. A high proportion of these patients required insulin infusion warranting increased input from the inpatient diabetes teams.

Etomidate in the management of severe Cushing's disease and MRSA bacteraemia in a district general hospital in the United Kingdom.

SUMMARY: We report our experience on managing a case of florid Cushing's disease with Methicillin-resistant Staphylococcus aureus (MRSA) sepsis using intravenous etomidate in the intensive care unit of a UK district general hospital. LEARNING POINTS: Severe Cushing's syndrome is associated with high morbidity and mortality. Etomidate is a safe and effective medical therapy to rapidly lower cortisol levels even in the context of severe sepsis and immunosuppression. Etomidate should ideally be administered in an intensive care unit but is still feasible in a district general hospital. During treatment with etomidate, accumulation of serum 11ß-deoxycortisol (11DOC) levels can cross-react with laboratory cortisol measurement leading to falsely elevated serum cortisol levels. For this reason, serum cortisol measurement using a mass spectrometry assay should ideally be used to guide etomidate prescription.

Pregnancy Following Bariatric Surgery-Medical Complications and Management.

Bariatric surgery is most commonly carried out in women of childbearing age. Whilst fertility rates are improved, pregnancy following bariatric surgery poses several challenges. Whilst rates of many adverse maternal and foetal outcomes in obese women are reduced after bariatric surgery, pregnancy is best avoided for 12-24 months to reduce the potential risk of intrauterine growth retardation. Dumping syndromes are common after bariatric surgery and can present diagnostic and therapeutic challenges in pregnancy. Early dumping occurs due to osmotic fluid shifts resulting from rapid gastrointestinal food transit, whilst late dumping is characterized by a hyperinsulinemic response to rapid absorption of simple carbohydrates. Dietary measures are the mainstay of management of dumping syndromes but pharmacotherapy may sometimes become necessary. Acarbose is the least hazardous pharmacological option for the management of postprandial hypoglycemia in pregnancy. Nutrient deficiencies may vary depending on the type of surgery; it is important to optimize the nutritional status of women prior to and during pregnancy. Dietary management should include adequate protein and calorie intake and supplementation of vitamins and micronutrients. A high clinical index of suspicion is required for early diagnosis of surgical complications of prior weight loss procedures during pregnancy, including small bowel obstruction, internal hernias, gastric band erosion or migration and cholelithiasis.

Screening for hypogonadism in diabetes 2008/9: results from the Cheshire Primary Care cohort.

AIM: There is increasing awareness of hypogonadism in men with type 2 diabetes but limited data from Primary Care. SUBJECTS AND METHODS: The anonymised records of 6457 male patients aged 18-80 years with diabetes were accessed. Within the last 2 years 391 men (6.0% of total) underwent measurement of serum testosterone. Data search was performed through the centralised data facility afforded by EMIS®, the majority GP systems provider in Cheshire. RESULTS: 4.4% of type 2 diabetes men screened were frankly hypogonadal with a serum total testosterone of less than 8.0 nmol/l. For borderline hypogonadism (serum total testosterone 8-11.99 nmol/l) the proportion of type 2 diabetes men rose to 32.1%. Age adjusted mean (geometric) testosterone was lower in men with type 2 diabetes (13.6 nmol/l 95%CI: 13.1-14.2) vs type 1 diabetes (17.9 nmol/l; 95%CI 15.2-21.0), F=10.3; p=0.0014. For those screened age adjusted body mass index (BMI) was greater in type 2 diabetes at 30.7 (30.1-31.3) vs 28.4 (26.1-30.6)kg/m(2) in type 1 diabetes (F=4.3; p=0.04). Multiple linear regression analysis indicated that there was a statistically significant interaction (P=0.014) between BMI and diabetes type in their relation with log testosterone. For persons with type 1 DM and type 2 DM, testosterone can be expected to decrease by 6% (P=0.002) and by 1% (P=0.002) respectively, for every one unit increment in BMI. CONCLUSIONS: There is manifestly a subset of men with diabetes and androgen deficiency who could benefit from testosterone replacement. BMI has an independent influence on androgen status.

Guillain-Barré Syndrome presenting with bilateral facial nerve paralysis: a case report.

Bilateral paralysis of the facial nerve is a relatively rare presentation and often indicates a serious underlying medical condition. Guillain-Barré syndrome needs to be considered, among others in the differential diagnoses of such presentation. We present here the case of a 35 year old female who presented with bilateral facial nerve paralysis due to the Guillain-Barré syndrome.