Liza K. Phillips

Gastric emptying and glycaemia in health and diabetes mellitus

The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia—gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.

Effect of itopride on gastric emptying in longstanding diabetes mellitus

Abstract  Delayed gastric emptying (GE) occurs in 30–50% of patients with longstanding type 1 or 2 diabetes, and represents a major cause of morbidity. Current therapeutic options are limited. We aimed at evaluating the effects of itopride on GE in patients with longstanding diabetes. Twenty‐five patients (20 type 1, 5 type 2; 10 males, 15 females; mean age 45.2 ± 2.7 years; body mass index 27.5 ± 0.9 kg m−2; duration of diabetes 20.2 ± 2.4 years) were enrolled in a double‐blind, placebo‐controlled, randomized, crossover trial. Subjects received both itopride (200 mg) and placebo t.i.d. for 7 days, with a washout of 7–14 days. GE (scintigraphy), blood glucose (glucometer) and upper gastrointestinal (GI) symptoms (questionnaire) were measured following each treatment period. The test meal comprised 100 g ground beef (99mTc‐sulphur colloid) and 150 mL of 10% dextrose [67Ga‐ethylenediaminetetraacetic acid (EDTA)]. There was a slight trend for itopride to accelerate both solid (P = 0.09) and liquid (P = 0.09) GE. With itopride treatment, the emptying of both solids and liquids tended to be more accelerated, as the emptying with placebo was slower (solids: r = 0.39, P = 0.057; liquids: r = 0.44, P < 0.03). Twelve (48%) patients had delayed solid and/or liquid GE on placebo and in this group, itopride modestly accelerated liquid (P < 0.05), but not solid (P = 0.39), emptying. Itopride had no effect on mean blood glucose during the GE measurement (placebo: 9.8 ± 0.6 mmol L−1vs itopride: 9.6 ±0.6 mmol L−1), or GI symptoms (placebo: 1.4 ± 0.4 vs itopride: 1.8 ± 0.5). Itopride, in a dose of 200 mg t.i.d. for 7 days, tends to accelerate GE of liquids and solids in longstanding diabetes. The magnitude of this effect appears to be modest and possibly dependent on the rate of GE without itopride.

Nutrient stimulation of mesenteric blood flow - implications for older critically ill patients

Nutrient ingestion induces a substantial increase in mesenteric blood flow. In older persons (aged ≥ 65 years), particularly those with chronic medical conditions, the cardiovascular compensatory response may be inadequate to maintain systemic blood pressure during mesenteric blood pooling, leading to postprandial hypotension. In older ambulatory persons, postprandial hypotension is an important pathophysiological condition associated with an increased propensity for syncope, falls, coronary vascular events, stroke and death. In older critically ill patients, the administration of enteral nutrition acutely increases mesenteric blood flow, but whether this pathophysiological response is protective, or precipitates mesenteric ischaemia, is unknown. There are an increasing number of older patients surviving admission to intensive care units, who are likely to be at increased risk of postprandial hypotension, both during, and after, their stay in hospital. In this review, we describe the prevalence, impact and mechanisms of postprandial hypotension in older people and provide an overview of the impact of postprandial hypotension on feeding prescriptions in older critically ill patients. Finally, we provide evidence that postprandial hypotension is likely to be an unrecognised problem in older survivors of critical illness and discuss potential options for management.

Severe hypoglycaemic unawareness in a patient with insulinoma

A 21-year-old man presented after a witnessed, generalized tonic-clonic seizure.Hehadbeen seen some3 months earlier following an unwitnessed, unconscious collapse. Physical examination, routine plasma biochemical screens (without glucosemeasurement) andamagnetic resonance imaging of the brain carried out at that time were normal. Following his initial presentation, he had experienced three episodes of ‘lightheadedness’ and perioral paraesthesiaewhichoccurred after exercise andwhenamealwas delayed.Medical historywas otherwiseunremarkable –he was not taking any medications, was a non-smoker and had minimal alcohol intake. Twohours following the seizure, thevenous glucosewas 2.4 mmol/L on routine biochemistry; he was asymptomatic at the time. Four hours into a 48-h fast, the plasma glucose was 1.7 mmol/L and he was again asymptomatic. Letters to the Editor

Trends in surgery, hospital admissions and imaging for pituitary adenomas in Australia.

PurposeThere is a paucity of epidemiological information on treatment and imaging of pituitary adenomas in Australia.MethodsAustralian data on pituitary surgery, hospital admissions for pituitary adenomas, and pituitary imaging on patients 15 years and over were obtained from administrative databases between 2000/2001 and 2014/2015. Changes over time and by age and sex were assessed.ResultsIn 2014/15 there were 37.7 pituitary procedures/million population, corresponding to a 35.4% (p < 0.05) increase over the 2000/2001 rate. Overall, most (87.2%) procedures were partial excisions of pituitary gland via transsphenoidal surgery (TSS). Admissions for acromegaly increased from 7.1/million in 2000/2001 to 17.2/million in 2003/2004 and then decreased to 6.5/million in 2014/2015. The average age-adjusted rate of pituitary imaging over the study period was 689.6/million/year, which increased significantly (p < 0.05). There was a significant increase in pituitary MRIs (p < 0.05) and a significant decline in pituitary CTs (p < 0.05). Surgical procedure rates were correlated with the pituitary imaging rates (r = 0.62, p < 0.05).ConclusionPituitary surgery rates increased between 2000/2001 and 2014/2015. The most common procedure was partial excision of the pituitary gland via TSS. Admissions for pituitary neoplasms increased over the study while admissions for acromegaly rose to their highest rate in 2003/2004 and then decreased. There was a substantial increase in the rate of pituitary imaging, which may have resulted in increased detection of pituitary incidentalomas. The underlying reasons for the increased rate of pituitary surgery, and the non-sustained increased rate of admissions for acromegaly are unclear and warrant further investigation.

Stress induced hyperglycemia and the subsequent risk of type 2 diabetes in survivors of critical illness

Objective Stress induced hyperglycemia occurs in critically ill patients who have normal glucose tolerance following resolution of their acute illness. The objective was to evaluate the association between stress induced hyperglycemia and incident diabetes in survivors of critical illness. Design Retrospective cohort study. Setting All adult patients surviving admission to a public hospital intensive care unit (ICU) in South Australia between 2004 and 2011. Patients Stress induced hyperglycemia was defined as a blood glucose ≥ 11.1 mmol/L (200 mg/dL) within 24 hours of ICU admission. Prevalent diabetes was identified through ICD-10 coding or prior registration with the Australian National Diabetes Service Scheme (NDSS). Incident diabetes was identified as NDSS registration beyond 30 days after hospital discharge until July 2015. The predicted risk of developing diabetes was described as sub-hazard ratios using competing risk regression. Survival was assessed using Cox proportional hazards regression. Main Results Stress induced hyperglycemia was identified in 2,883 (17%) of 17,074 patients without diabetes. The incidence of type 2 diabetes following critical illness was 4.8% (821 of 17,074). The risk of diabetes in patients with stress induced hyperglycemia was approximately double that of those without (HR 1.91 (95% CI 1.62, 2.26), p<0.001) and was sustained regardless of age or severity of illness. Conclusions Stress induced hyperglycemia identifies patients at subsequent risk of incident diabetes.

Postprandial hypotension in older survivors of critical illness

Purpose: In older people postprandial hypotension occurs frequently; and is an independent risk factor for falls, cardiovascular events, stroke and death. The primary aim of this pilot study was to estimate the frequency of postprandial hypotension and evaluate the mechanisms underlying this condition in older survivors of an Intensive Care Unit (ICU). Materials and methods: Thirty‐five older (>65years) survivors were studied 3months after discharge. After an overnight fast, participants consumed a 300mL drink containing 75g glucose, labelled with 20MBq 99mTc‐calcium phytate. Patients had concurrent measurements of blood pressure, heart rate, blood glucose and gastric emptying following drink ingestion. Proportion of participants is presented as percent (95% CI) and continuous variables as mean (SD). Results: Postprandial hypotension was evident in 10 (29%; 95% CI 14–44), orthostatic hypotension in 2 (6%; 95% CI 0–13) and cardiovascular autonomic dysfunction in 2 (6%; 95% CI 0–13) participants. The maximal postprandial nadir for systolic blood pressure and diastolic blood pressures were −29 (14) mmHg and −18 (7) mmHg. Conclusions: In this cohort of older survivors of ICU postprandial hypotension occurred frequently. This suggests that postprandial hypotension is an unrecognised issue in older ICU survivors. HIGHLIGHTSPostprandial hypotension is prevalent in older survivors of critical illness.Postprandial hypotension occurred more frequently than orthostatic hypotension.Symptoms of postprandial hypotension were rarely reported by patients.Postprandial hypotension may be an unrecognised problem in older ICU survivors.

A whey/guar "preload" improves postprandial glycaemia and HbA(1c) in type 2 diabetes: a 12-week, single-blind, randomised and placebo controlled trial

Background and aims: Social jetlag is the discrepancy between our internal circadian clock and social clock and is a measure of circadian misalignment. Previous studies have shown that up to two thirds of the general population, aged 18-35y, suffer from social jetlag and its negative effects on metabolic parameters. As data from the general population over 40+y is missing, the aim of this study is to examine the prevalence of social jetlag and the association between social jetlag, the metabolic syndrome and type 2 diabetes in a 40+yearold, population-based cohort. Materials and methods: We used cross-sectional data from the New Hoorn study cohort, n=1734, 48% male, aged 45-73y. Social jetlag was measured using a questionnaire, calculated as the difference in mid-point sleep on week and weekend days and defined as 0-1h, 1-2h or >2h social jetlag.Metabolic syndrome was defined according to the Adult Treatment Panel III, including waist circumference, hypertension and levels of fasting plasma glucose, HDL-C and triglycerides. Pre-diabetes and Type 2 diabetes were defined according to the WHO guidelines; glucose levels > 6.1 mmol/l, HbA1c > 6% or use of diabetes medication. Results: In our 40+year-old population-based cohort, we observed that only 15% of the unemployed/retired participants had social jetlag of >1h and 65% of the employed participants. In the unemployed/retired group no significant associations were observed between social jetlag status, (parameters of) metabolic syndrome and (pre-)diabetes. However, in the employed group, logistic regression adjusted for age, sex and sleep duration showed a positive association between social jetlag, metabolic syndrome and (pre-)diabetes, with respectively OR 1.1 (95%CI 0.7-1.7) and OR 1.7 (95%CI 1.2-2.4) for participants with 1-2h social jetlag, as well as OR 2.1 (95%CI 1.2-3.6) and OR 2.3 (95%CI 1.5-3.8) for >2h of social jetlag, when compared to participants with 0-1h social jetlag. Conclusion: Social jetlag is associated with metabolic syndrome and (pre-)diabetes in working, 40+year-old participants.Abstracts of 52nd EASD Annual Meetings of 52nd EASD Annual Meeting OP 01 GLP-1 receptor agonists: combinations, type 1 diabetes and long-term use 1 Switching from sitagliptin to liraglutide in subjects with type 2 diabetes: analysis of composite endpoints from the LIRA-SWITCH randomised trial T. Bailey, R. Takács, F.J. Tinahones, P.V. Rao, G.M. Tsoukas, S.B. Christensen, M.S. Kaltoft, M. Maislos; AMCR Institute, Escondido, USA, University of Szeged, Szeged, Hungary, Hospital Universitario Virgen de la Victoria, Malaga, Spain, Ramdevrao Hospital, Hyderabad, India, McGill University, Montreal, Canada, Novo Nordisk A/S, Soeborg, Denmark, Soroka University Medical Centre, Beer Sheva, Israel. Background and aims: There is limited clinical evidence to guide treatment choices beyond the addition of another drug to achieve glycaemic target when second-line therapy is inadequate for patients with type 2 diabetes (T2D). The randomised, parallel-group, double-blind, doubledummy, active-controlled LIRA-SWITCH trial compared the efficacy and safety of switching from sitagliptin (sita) to liraglutide (lira) as addon to metformin (MET) in subjects with T2D not achieving adequate glycaemic control with sita + MET. The aim of this analysis was to compare the proportion of subjects meeting four composite endpoints at 26 weeks, relating to glycaemia, body weight, systolic blood pressure (SBP) and hypoglycaemia outcomes. Materials and methods: Eligible subjects (≥18 years, HbA1c 7.5-9.5% [58-80 mmol/mol], BMI ≥20 kg/m), previously treated with stable doses of sita (100 mg/day) and MET (≥1500 mg/day or maximum tolerated dose ≥1000 mg/day) for ≥90 days, were randomised 1:1 to switch to lira 1.8 mg or continue sita 100 mg once daily, both + MET. A series of composite endpoints at week 26 were pre-defined: HbA1c <7.0% (53 mmol/mol) with no weight gain; HbA1c <7.0%, with no weight gain and SBP <140 mmHg; and HbA1c reduction ≥1.0% with no weight gain. In addition, a post hoc analysis of a further endpoint was conducted: HbA1c <7.0%, with no weight gain and no confirmed hypoglycaemic episodes. These dichotomous endpoints were analysed by logistic regression. Results: In total, 407 subjects (male 60%,mean age 56 years, BMI 32 kg/ m, HbA1c 8.3% [67 mmol/mol], T2D duration 8 years) were randomised (lira: 203; sita: 204). At week 26, more subjects achieved each of the four composite endpoints by switching from sita to lira compared with continued sita. HbA1c <7.0% with no weight gain: 48.3% vs. 24.2% (lira and sita, respectively), OR 3.40, 95% CI 2.11; 5.49, p<0.0001. HbA1c <7.0%, with no weight gain and SBP <140 mmHg: 44.9% vs. 19.2%, OR 3.88, 95% CI 2.36; 6.39, p<0.0001. HbA1c reduction ≥1.0% with no weight gain: 52.8% vs. 29.1%, OR 2.85, 95% CI 1.82; 4.47, p<0.0001. HbA1c <7.0%, with no weight gain and no confirmed hypoglycaemic episodes: 48.3% vs. 24.2%, OR 3.40, 95% CI 2.11; 5.49, p<0.0001 (Figure). Conclusion: Switching to lira resulted in more subjects achieving each of the composite endpoints analysed, compared with continued sita treatment. By switching from lira to sita, patients insufficiently controlled on sita and MET have higher probabilities of meeting clinically relevant composite endpoints relating to glycaemia, body weight, SBP and hypoglycaemia. Clinical Trial Registration Number: NCT01907854 Supported by: Novo Nordisk Disclosure: T. Bailey: Employment/Consultancy; AstraZeneca, Bayer, Becton Dickinson, Eli Lilly & Co, Medtronic, Novo Nordisk, Sanofi. Grants; Abbott, ACON, Bayer, Bristol-Myers Squibb, Dexcom, GlaxoSmithKline, Insulet, Janssen, Lexicon, Lifescan, Eli Lilly & Co, Medtronic, Merck, Novo Nordisk, Sanofi. Lecture/other fees; Abbott, Insulet, Novo Nordisk, Sanofi. 2 Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes, the ADJUNCT ONETM treat-to-target randomised trial B. Zinman, B. Bode, J.U. Hemmingson, V. Woo, P. Colman, E. Christiansen, M. Linder, C. Mathieu; Medicine, Mt Sinai Hospital, Toronto, Canada, Atlanta Diabetes Associates, USA, Capio St Gorans Hospital and Karolinska Institute, Stockholm, Sweden, Health Sciences Centre Winnipeg, Canada, Royal Melbourne Hospital, Melbourne, Australia, Novo Nordisk A/S, Bagsværd, Denmark, Katholieke Universiteit, Leuven, Belgium. Backgroundand aims:To investigate if adjunct treatment with liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces insulin requirements and body weight in type 1 diabetes (T1D). Materials and methods: A 52-week double-blinded multinational treatto-target (TTT) trial in adults with T1D in suboptimal glycaemic control DOI 10.1007/s00125-016-4046-9 Diabetologia (2016) 59 (Suppl 1):S1–S581