Hypoglycaemia in type 1 diabetes: risk factors, symptoms and recovery

Hypoglycaemia is the commonest side-effect of insulin treatment for diabetes mellitus. Appreciation of the risk factors for hypoglycaemia and early recognition of its symptoms can help the affected individual with prompt self-treatment of hypoglycaemia, preventing progression to severe hypoglycaemia. The proposed MD project will consist of three major studies to investigate the risks for, symptoms of, and rate of recovery from, hypoglycaemia.STUDY ONE: This study will examine the alleged association between severe hypoglycaemia and serum angiotensin converting enzyme (ACE) levels. While many patients rarely experience severe hypoglycaemia, a small subgroup experiences recurrent episodes. These are very disruptive to daily life and may be dangerous, for example if they occur when the individual is driving. It is therefore of clinical importance to identify risk factors for severe hypoglycaemia.Scandinavian studies have reported an association between elevated serum ACE activity and an increased risk of severe hypoglycaemia in type 1 diabetes. A hypothetical explanation for these findings is that lower ACE activity confers increased ability for cerebral function to be maintained despite metabolic substrate deprivation. It is possible that in diabetes, this could manifest as greater impairment of mental ability during hypoglycaemia in people with high ACE activity. This would explain their increased risk of severe hypoglycaemia for a given level of blood glucose as they would be more incapacitated, and therefore less able to self-treat. However these studies have methodological limitations and these findings have not yet been reproduced outside Scandinavia.In this study, it is proposed to examine the relationship between serum ACE levels and the incidence of severe hypoglycaemia. Blood will be sampled for serum ACE activity and the self-estimated frequency of severe hypoglycaemia will be recorded in 300 people with type 1 diabetes attending diabetes clinics at the Royal Infirmary of Edinburgh.STUDY TWO: This study will examine the variability of hypoglycaemia symptom reporting. It is known that the symptoms of hypoglycaemia are idiosyncratic and age-specific. However, no studies have assessed the extent of any intra-individual variability in symptom reporting.A cohort of 350 people with type 1 and type 2 diabetes, with different disease durations and varying treatment modalities, will be recruited and the symptoms associated with each hypoglycaemic episode will be recorded prospectively over a 12 month period. The reported symptom clusters will be analysed to assess the consistency of symptom reporting for each individual. Regression analysis will be used to assess whether an individual's consistency coefficient is related to any other factors such as disease duration or treatment modality. The ability to predict which individuals will report a consistent group of symptoms and which individuals will experience an erratic pattern of symptoms would assist patient education and allow clinicians to inform patients about how to anticipate and recognise hypoglycaemia.STUDY THREE: This study will examine the time taken for full cognitive recovery from hypoglycaemia and the possible effect of the clinical syndrome of impaired awareness of hypoglycaemia on this process. The effects of acute insulin-induced hypoglycaemia on cognitive function have been investigated extensively but the recovery period after hypoglycaemia has not been rigorously assessed. Previous studies examining recovery have had multiple limitations.The objective of this third study is to measure the recovery time for various domains of cognitive function in a large group of patients with type 1 diabetes who have either normal (n=20) or impaired (n=l 6) awareness of hypoglycaemia. A hyperinsulinaemic glucose clamp technique will be used to induce controlled hypoglycaemia and a battery of cognitive tests will be applied at baseline, at the beginning and end of a one hour period of hypoglycaemia, then at ten minute intervals during a 90 minute recovery period. Each subject will act as their own control by undergoing a euglycaemic clamp on a separate occasion. Test scores will be compared using general linear modelling with awareness of hypoglycaemia as a betweensubjects factor. The findings of this study will have important clinical implications and help to advise patients how long to wait after restoration of euglycaemia before resuming activities such as driving

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

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 &amp;lt; 0.001) and hypoglycemia symptom scores were significantly higher (P &amp;lt; 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. </jats:sec

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) (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; eta(2) = 0.37; Cohen d = 0.65) and a fall in correct responses (P = 0.005; eta(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; eta(2) = 0.11; Cohen d = 0.25). For the reading of the next fragment, hypoglycemia affected the healthy volunteer groupmore than the adults with type 1 diabetes (P = 0.03; eta(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; eta(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

Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement

Persistent symptoms in patients treated for hypothyroidism are common. Despite more than 20 years of debate, the use of liothyronine for this indication remains controversial, as numerous randomised trials have failed to show a benefit of treatment regimens that combine liothyronine (T3) with levothyroxine over levothyroxine monotherapy. This consensus statement attempts to provide practical guidance to clinicians faced with patients who have persistent symptoms during thyroid hormone replacement therapy. It applies to non‐pregnant adults and is focussed on care delivered within the UK National Health Service, although it may be relevant in other healthcare environments. The statement emphasises several key clinical practice points for patients dissatisfied with treatment for hypothyroidism. Firstly, it is important to establish a diagnosis of overt hypothyroidism; patients with persistent symptoms during thyroid hormone replacement but with no clear biochemical evidence of overt hypothyroidism should first have a trial without thyroid hormone replacement. In those with established overt hypothyroidism, levothyroxine doses should be optimised aiming for a TSH in the 0.3–2.0 mU/L range for 3 to 6 months before a therapeutic response can be assessed. In some patients, it may be acceptable to have serum TSH below reference range (e.g. 0.1–0.3 mU/L), but not fully suppressed in the long term. We suggest that for some patients with confirmed overt hypothyroidism and persistent symptoms who have had adequate treatment with levothyroxine and in whom other comorbidities have been excluded, a trial of liothyronine/levothyroxine combined therapy may be warranted. The decision to start treatment with liothyronine should be a shared decision between patient and clinician. However, individual clinicians should not feel obliged to start liothyronine or to continue liothyronine medication provided by other health care practitioners or accessed without medical advice, if they judge this not to be in the patient's best interest

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 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 sub-optimal 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 Type 2 diabetes 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 Type 2 diabetes (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 one and association with incident disease 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 ≥50μg/L) to FIB-4 (cut-point ≥1.3) maintained a false negative rate ≤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 Type 2 diabetes. These findings require validation in independent cohorts

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course