Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

BACKGROUND: Type 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk-stratification tools are suboptimal and perform worse in people with diabetes. AIMS: To determine whether the addition of complementary biomarker(s) to current NAFLD risk-stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC. METHODS: The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D (n = 1066, age 60-75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow-up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression. RESULTS: Of existing risk-stratification scores tested, the Fibrosis-4 (FIB-4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut-point ≥ 50  µ  g/L) to FIB-4 (cut-point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as "high risk" for incident disease by ∼50%. CONCLUSIONS: The addition of hyaluronic acid to FIB-4 reduced the proportion of people inappropriately identified as "high risk" for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.

HbA1c response and hospital admissions following commencement of flash glucose monitoring in adults with type 1 diabetes.

INTRODUCTION: Our aim was to assess the effect of introducing flash monitoring in adults with type 1 diabetes with respect to change in hemoglobin A1c (HbA1c) and frequency of hospital admissions. RESEARCH DESIGN AND METHODS: Prospective observational study of adults with type 1 diabetes in our center, in whom a prescription for a flash monitoring sensor was collected. Primary outcome was change in HbA1c between 2016 and after flash monitoring. Rates of hospital admission were compared between the first year after flash monitoring and the corresponding 12-month period 2 years earlier. RESULTS: Approximately half of all adults with type 1 diabetes, attending our center, collected prescriptions for flash monitoring sensors (n=2216). Median fall in HbA1c was -1 (-0.1) mmol/mol (%) (p<0.001) and was greatest in those with baseline HbA1c >75 (9.0) mmol/mol (%): -10 (-0.9) mmol/mol (%), p<0.001. 43% of those with a baseline HbA1c >53 mmol/mol (7%) experienced a ≥5 mmol/mol (0.5%) fall in HbA1c. In addition to higher HbA1c, early commencement within 1 month of NHS-funded flash monitoring (p<0.001), and male gender (p=0.013) were associated with a fall in HbA1c of ≥5 (0.5) mmol/mol (%). Socioeconomic deprivation (p=0.009) and collecting fewer than 2 sensors per month (p=0.002) were associated with lack of response. Overall, hospital admissions did not change but an increase in admissions for hypoglycemia was observed (1.1% vs 0.3%, p=0.026). CONCLUSIONS: Flash monitoring is associated with reduction in HbA1c in individuals with HbA1c >58 mmol/mol. Numerous clinical features are independently associated with HbA1c response. An increase in hypoglycemia admissions occurred following flash monitoring.

Non-invasive risk scores do not reliably identify future cirrhosis or hepatocellular carcinoma in Type 2 diabetes: The Edinburgh type 2 diabetes study.

BACKGROUND: The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non-alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non-invasive markers of fibrosis for risk-stratification and guiding onward referral. AIMS: To test the ability of individual fibrosis scores and the European screening algorithm to predict 11-year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes. METHODS: The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60-75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow-up, cases of cirrhosis and HCC were identified. RESULTS: Forty-three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk-stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low-positive predictive values (5-46%) and high false-negative and -positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation. CONCLUSIONS: In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.

Marked improvement in HbA1c following commencement of flash glucose monitoring in people with type 1 diabetes.

AIMS/HYPOTHESIS: Minimal evidence supports the efficacy of flash monitoring in lowering HbA1c. We sought to assess the impact of introducing flash monitoring in our centre. METHODS: We undertook a prospective observational study to assess change in HbA1c in 900 individuals with type 1 diabetes following flash monitoring (comparator group of 518 with no flash monitoring). Secondary outcomes included changes in hypoglycaemia, quality of life, flash monitoring data and hospital admissions. RESULTS: Those with baseline HbA1c ≥58 mmol/mol (7.5%) achieved a median -7 mmol/mol (interquartile range [IQR] -13 to -1) (0.6% [-1.2 to -0.1]%) change in HbA1c (p < 0.001). The percentage achieving HbA1c <58 mmol/mol rose from 34.2% to 50.9% (p < 0.001). Median follow-up was 245 days (IQR 182 to 330). Individuals not using flash monitoring experienced no change in HbA1c across a similar timescale (p = 0.508). Higher HbA1c (p < 0.001), younger age at diagnosis (p = 0.003) and lower social deprivation (p = 0.024) were independently associated with an HbA1c fall of ≥5 mmol/mol (0.5%). More symptomatic (OR 1.9, p < 0.001) and asymptomatic (OR 1.4, p < 0.001) hypoglycaemia was reported after flash monitoring. Following flash monitoring, regimen-related and emotional components of the diabetes distress scale improved although the proportion with elevated anxiety (OR 1.2, p = 0.028) and depression (OR 2.0, p < 0.001) scores increased. Blood glucose test strip use fell from 3.8 to 0.6 per day (p < 0.001). Diabetic ketoacidosis admissions fell significantly following flash monitoring (p = 0.043). CONCLUSIONS/INTERPRETATION: Flash monitoring is associated with significant improvements in HbA1c and fewer diabetic ketoacidosis admissions. Higher rates of hypoglycaemia may relate to greater recognition of hitherto unrecognised events. Impact upon quality of life parameters was mixed but overall treatment satisfaction was overwhelmingly positive.

Predicting outcomes and complications following radioiodine therapy in Graves' thyrotoxicosis.

OBJECTIVE: Radioiodine (RAI) is an effective treatment for Graves' thyrotoxicosis but is associated with a failure rate of 15% and may be a risk factor for thyroid eye disease (TED) and weight gain. We sought to examine predictors of RAI failure, weight gain, TED and patient satisfaction. DESIGN: Retrospective cohort study. PATIENTS: A total of 655 episodes of RAI in Graves' thyrotoxicosis patients (2006-2015). MEASUREMENTS: Biochemical assessment, including TFTs and thyrotropin receptor antibodies (TRAb), clinical features (eg, TED, weight and thionamide use) and patient questionnaire. RESULTS: The treatment failure rate was 17%. Failure was greater with higher fT4 (P = 0.002) and higher TRAb (P = 0.004). Failure rate was 42.2% when TRAb >40 U/L. Median weight gain was 3.2 kg in those with normal fT4 prior to RAI and 5.8 kg when fT4 was elevated (P < 0.001). New TED developed in 7.6% but was not associated with post-RAI dysthyroidism. Treatment satisfaction was generally high (median response 8/10). CONCLUSIONS: Treatment failure after RAI occurs in predictable groups and this should be reflected in the information provided to patients. Weight gain is common and may not entirely be explained by a return to pre-thyrotoxic baseline. We were unable to detect any significant impact of post-RAI dysthyroidism on weight gain, TED or thyroid symptoms in this large cohort.

Thyrotropin Receptor Antibody Levels at Diagnosis and After Thionamide Course Predict Graves' Disease Relapse.

BACKGROUND: Thionamides are associated with a high risk of recurrence following cessation. Thyrotropin receptor-stimulating antibody (TRAb) levels at diagnosis and/or after thionamides may be biomarkers of this risk. This study assesses the natural history of Graves' thyrotoxicosis following thionamide withdrawal and factors that predict recurrence, particularly TRAb levels at diagnosis and cessation. METHODS: An observational study was conducted of patients with a first presentation of Graves' disease, who were prescribed (and completed) a course of primary thionamide treatment (n = 266) in a university teaching hospital endocrine clinic. Recurrence rates over four years and factors predictive of recurrent thyrotoxicosis were assessed. RESULTS: The relapse rate was 31% at one year and 70% at four years. Younger age (39 years [range 30-49 years] vs. 47 years [range 37-53 years]; p = 0.011), higher TRAb levels at diagnosis (8.8 IU/L [range 5.3-17.0 IU/L] vs. 5.7 IU/L [range 4.1-9.1 IU/L]; p = 0.003), and higher TRAb levels at cessation of therapy (1.2 IU/L [range 0-2.3 IU/L] vs. <0.9 IU/L [range 0-1.3 IU/L]; p = 0.003) were associated with a higher risk of relapse. By four years, cessation TRAb <0.9 IU/L was associated with a 58% risk of recurrence compared with 82% with TRAb >1.5 IU/L (p = 0.001). TRAb at diagnosis >12 IU/L was associated with an 84% risk of recurrence over four years compared with 57% with TRAbs <5 IU/L (p = 0.002). CONCLUSION: High TRAb at diagnosis and/or positive TRAb at cessation of therapy suggest a high likelihood of relapse, mostly within the first two years. They stratify patients likely to need definitive therapy (radioiodine or surgery).

Effects of Sleep Deprivation on Hypoglycemia-Induced Cognitive Impairment and Recovery in Adults With Type 1 Diabetes.

OBJECTIVE: To ascertain whether hypoglycemia in association with sleep deprivation causes greater cognitive dysfunction than hypoglycemia alone and protracts cognitive recovery after normoglycemia is restored. RESEARCH DESIGN AND METHODS: Fourteen adults with type 1 diabetes underwent a hyperinsulinemic, hypoglycemic clamp on two separate occasions. Before one glucose clamp, the participants stayed awake overnight to induce sleep deprivation. Participants were randomized and counterbalanced to the experimental condition. Cognitive function tests were performed before and during hypoglycemia and for 90 min after restoration of normoglycemia. RESULTS: Cognitive impairment during hypoglycemia did not differ significantly between the sleep-deprived and non-sleep-deprived conditions. However, in the sleep-deprived state, digit symbol substitution scores and choice reaction times were significantly poorer during recovery (P < 0.001) and hypoglycemia symptom scores were significantly higher (P < 0.001), even when symptoms that may have been caused by sleep deprivation, such as tiredness, were removed. CONCLUSIONS: Hypoglycemia per se produced a significant decrement in cognitive function; coexisting sleep deprivation did not have an additive effect. However, after restoration of normoglycemia, preceding sleep deprivation was associated with persistence of hypoglycemic symptoms and greater and more prolonged cognitive dysfunction during the recovery period.

The prevalence of structural pituitary abnormalities by MRI scanning in men presenting with isolated hypogonadotrophic hypogonadism.

OBJECTIVE: Hypogonadotrophic hypogonadism (HH) is commonly associated with ageing, obesity and type 2 diabetes. The indications for pituitary imaging are controversial, and current guidelines are based on small case series. DESIGN: Retrospective case series from a secondary/tertiary endocrinology referral centre. PATIENTS: All men presenting to the Edinburgh Centre for Endocrinology and Diabetes with hypogonadotrophic hypogonadism (testosterone <10 nmol/l and normal prolactin) from 2006 to 2013, in whom pituitary MRI was performed (n = 281). All HH patients referred in 2011 (n = 86) were reviewed to assess differences between those selected for pituitary MRI and those who were not scanned. RESULTS: Pituitary MRI was normal in 235 men (83·6%), with 24 microadenomas (8·5%), 5 macroadenomas (1·8%) and 1 craniopharyngioma (0·4%) identified. The remaining 16 (5·7%) comprised a range of minor pituitary abnormalities including small cysts and empty sella. All men with abnormal imaging studies had otherwise normal pituitary function. Imaging abnormalities were associated with a significantly lower age at presentation (50 vs 54 years, P = 0·02), but no differences in testosterone or gonadotrophin levels were observed. Current Endocrine Society guidelines would have prompted imaging in only three of six patients with significant pituitary pathology. CONCLUSIONS: Structural pituitary disease is more common in isolated HH than in the general population, and current guidelines do not accurately identify 'at-risk' individuals. Full anterior pituitary function testing has a low yield in patients presenting with hypogonadism. The optimal strategy for determining the need for pituitary imaging remains uncertain.

Effects of acute hypoglycemia on working memory and language processing in adults with and without type 1 diabetes.

OBJECTIVE: To examine the effects of hypoglycemia on language processing in adults with and without type 1 diabetes. RESEARCH DESIGN AND METHODS: Forty adults were studied (20 with type 1 diabetes and 20 healthy volunteers) using a hyperinsulinemic glucose clamp to lower blood glucose to 2.5 mmol/L (45 mg/dL) (hypoglycemia) for 60 min, or to maintain blood glucose at 4.5 mmol/L (81 mg/dL) (euglycemia), on separate occasions. Language tests were applied to assess the effects of hypoglycemia on the relationship between working memory and language (reading span), grammatical decoding (self-paced reading), and grammatical encoding (subject-verb agreement). RESULTS: Hypoglycemia caused a significant deterioration in reading span (P < 0.001; η(2) = 0.37; Cohen d = 0.65) and a fall in correct responses (P = 0.005; η(2) = 0.19; Cohen d = 0.41). On the self-paced reading test, the reading time for the first sentence fragment increased during hypoglycemia (P = 0.039; η(2) = 0.11; Cohen d = 0.25). For the reading of the next fragment, hypoglycemia affected the healthy volunteer group more than the adults with type 1 diabetes (P = 0.03; η(2) = 0.12; Cohen d = 0.25). However, hypoglycemia did not significantly affect the number of errors in sentence comprehension or the time taken to answer questions. Hypoglycemia caused a deterioration of subject-verb agreement (correct responses: P = 0.011; η(2) = 0.159; Cohen d = 0.31). CONCLUSIONS: Hypoglycemia caused a significant deterioration in reading span and in the accuracy of subject-verb agreement, both of which are practical aspects of language involved in its everyday use. Language processing is therefore impaired during moderate hypoglycemia.

Optimal glycaemic control in elderly people with type 2 diabetes: what does the evidence say?

The global prevalence of type 2 diabetes mellitus (T2DM) is rising in an ageing population through a combination of lifestyle changes and greater longevity. However, by excluding participants aged over 70 years, most major interventional trials on which current diabetes therapeutic guidelines are based have failed to provide specific evidence to support the prescribed management of diabetes in elderly people. While diabetes per se has a significant impact on the elderly person, the side effects of medications, particularly hypoglycaemia, prevent optimisation of diabetes treatment. Hypoglycaemia is associated with significant morbidity, to which elderly people are often more vulnerable because of factors such as the effects of ageing, progressive renal impairment, frailty, polypharmacy and cognitive decline. T2DM is associated with accelerated cognitive decline in some individuals, and recurrent severe hypoglycaemia has been implicated as a potential contributory factor. Although the evidence for selection of appropriate glycaemic targets in elderly patients is sparse, it is now acknowledged that prevention of hypoglycaemia must influence individualisation of treatment goals in this vulnerable group. This should also be reflected by the choice of anti-diabetes agents that are initiated when diet and lifestyle advice is ineffective. Recently developed international guidelines, which have specifically addressed the management of diabetes in elderly people, highlight the importance of a pragmatic management approach rather than attempting to achieve a generic glycated haemoglobin goal and are summarised in this article.

Drug-induced hypoglycaemia in type 2 diabetes.

INTRODUCTION: Hypoglycaemia is a side effect caused by some therapies for type 2 diabetes, which can cause physical, social and psychological harm. Hypoglycaemia also prevents attainment of treatment goals and satisfactory glycaemic control. AREAS COVERED: The risk of hypoglycaemia associated with commonly prescribed therapies, including metformin, sulphonylureas, dipeptidyl peptidase-4 enzyme (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists and thiazolidinediones, is reviewed in this paper (insulin-induced hypoglycaemia is not included). Other medications that are frequently co-prescribed in type 2 diabetes are also discussed, including anti-hypertensive drugs, antibiotics and fibrates, along with various important patient-related risk factors. EXPERT OPINION: Hypoglycaemia is a common and potentially dangerous side effect of some medications used for type 2 diabetes. The risk of hypoglycaemia should always be considered when selecting and implementing a therapy, with a focus on the individual. Future research into new therapies should measure the frequency of hypoglycaemia prospectively and accurately. Hypoglycaemia has been shown to be a potentially life-threatening metabolic stress; therefore therapies that effectively manage diabetes without the risk of hypoglycaemia are likely to be favoured in the future.

Modeling the consistency of hypoglycemic symptoms: high variability in diabetes.

BACKGROUND: The aim of the present study was to examine symptoms of hypoglycemia, to develop a method to quantify individual differences in the consistency of symptom reporting, and to investigate which factors affect these differences. METHODS: Participants recorded their symptoms with every episode of hypoglycemia over a 9-12-month period. A novel logistic-type latent variable model was developed to quantify the consistency of each individual's symptom complex and was used to analyze data from 59 subjects (median age, 57.5 years [range, 22-74 years], 65% male, 77% type 1 diabetes) who had experienced 19 or more hypoglycemic episodes. The association between the calculated consistency parameter and age, sex, type and duration of diabetes, and C-peptide and serum angiotensin converting enzyme concentration was examined using a generalized linear model. Analyses were performed under a Bayesian framework, using Markov chain Monte-Carlo methodology. RESULTS: Individuals exhibited substantial differences in between-episode consistency of their symptom reports, with only a small number of individuals exhibiting high levels of consistency. Men were more consistent than women. No other factors affected consistency in patients with normal hypoglycemia awareness. CONCLUSIONS: By using a novel stochastic model as a quantitative tool to compare the consistency of hypoglycemic symptom reporting, much greater intra-individual variability in symptom reporting was identified than has been recognized previously. This is relevant when instructing patients on identification of hypoglycemic symptoms and in interpreting symptomatic responses during experimentally induced hypoglycemia.

Delayed recovery of cognitive function following hypoglycemia in adults with type 1 diabetes: effect of impaired awareness of hypoglycemia.

OBJECTIVE: Recovery times of cognitive functions were examined after exposure to hypoglycemia in people with diabetes with and without impaired hypoglycemia awareness. RESEARCH DESIGN AND METHODS: A total of 36 subjects with type 1 diabetes were studied (20 with normal hypoglycemia awareness [NHA] and 16 with impaired hypoglycemia awareness [IHA]). A hyperinsulinemic glucose clamp was used to lower blood glucose to 2.5 mmol/l (45 mg/dl) (hypoglycemia) for 1 h or to maintain blood glucose at 4.5 mmol/l (81 mg/dl) (euglycemia) on separate occasions. Cognitive tests were applied during each experimental condition and were repeated at 10- to 15-min intervals for 90 min after euglycemia had been restored. RESULTS: In the NHA group, performance was impaired on all cognitive tasks during hypoglycemia and remained impaired for up to 75 min on the choice reaction time (CRT) task (P = 0.03, eta(2) = 0.237). In the IHA group, performance did not deteriorate significantly during hypoglycemia. When all subjects were analyzed within the same general linear model, performance was impaired during hypoglycemia on all tasks. Significant impairment during recovery persisted for up to 40 min on the CRT task (P = 0.04, eta(2) = 0.125) with a significant glycemia-awareness interaction for CRT after one hour of hypoglycemia (P = 0.045, eta(2) = 0.124). Performance on the trail-making B task was impaired for up to 10 min after euglycemia was restored (P = 0.024, eta(2) = 0.158). CONCLUSIONS: Following hypoglycemia, the recovery time for different cognitive tasks varied considerably. In the IHA group, performance was not significantly impaired during hypoglycemia. The state of awareness of hypoglycemia may influence cognitive function during and after hypoglycemia.