Treatment challenges in type 1 diabetes after roux-en-Y gastric bypass.

Bariatric surgery is an effective treatment of type 2 diabetes in obese patients. The obesity epidemic does not spare patients with type 1 diabetes mellitus (T1DM), but there is no consensus regarding the role of surgery in the management of obese T1DM patients. Published data consistently report significant weight loss after surgery in obese T1DM patients, but long-term glycaemic control remains difficult to achieve. Here we present our experience with a challenging patient and a review of the literature. Our patient successfully underwent a roux-en-Y gastric bypass (RYGB) when she was 28 years old. Five years after surgery, she was diagnosed with latent autoimmune diabetes of adults and insulin therapy was initiated. Insulin therapy proved very difficult to adjust, with frequent episodes of postprandial hyperglycaemia. These difficulties could only be overcome by the initiation of a subcutaneous insulin infusion using a sensor-augmented insulin pump with automated suspension. This change allowed better glycaemic control. Despite considerable weight loss with a concomitant decrease in insulin requirement, glycaemic control remained difficult after surgery. Due to their different impacts on glucose kinetics, the type of surgical operation should be part of the assessment. These patients might benefit from sensor-augmented insulin pump therapy with automated insulin suspension after bariatric surgery. The decision for surgical intervention in these patients should be carefully weighed against the difficulties in achieving adequate glycaemic control

Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals

Aims/hypothesis: Glitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes. Their use is, however, associated with fluid retention and an increased risk of congestive heart failure. We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers. This study examines the effects of pioglitazone on renal sodium handling in individuals prone to insulin resistance, i.e. those with diabetes and/or hypertension. Methods: In this double-blind randomised placebo-controlled four-way crossover study, we examined the effects of pioglitazone (45mg daily during 6weeks) or placebo on renal, systemic and hormonal responses to changes in sodium intake in 16 individuals, eight with type 2 diabetes and eight with hypertension. Results: Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption, without any change in renal haemodynamics or in the modulation of the renin-angiotensin aldosterone system to changes in salt intake. A compensatory increase in brain natriuretic peptide levels was observed. In spite of sodium retention, pioglitazone dissociated the blood-pressure response to salt and abolished salt sensitivity in salt-sensitive individuals. Conclusions/interpretation: Pioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals. These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones. Trial registration:: ClinicalTrial.gov NCT01090752 Funding:: Hypertension Research Foundation Lausann

Canakinumab in patients with COVID-19 and type 2 diabetes - A multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Patients with type 2 diabetes and obesity have chronic activation of the innate immune system possibly contributing to the higher risk of hyperinflammatory response to SARS-CoV2 and severe COVID-19 observed in this population. We tested whether interleukin-1β (IL-1β) blockade using canakinumab improves clinical outcome. METHODS: CanCovDia was a multicenter, randomised, double-blind, placebo-controlled trial to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in patients with type 2 diabetes and a BMI > 25 kg/m$^{2}$ hospitalised with SARS-CoV2 infection in seven tertiary-hospitals in Switzerland. Patients were randomly assigned 1:1 to a single intravenous dose of canakinumab (body weight adapted dose of 450-750 mg) or placebo. Canakinumab and placebo were compared based on an unmatched win-ratio approach based on length of survival, ventilation, ICU stay and hospitalization at day 29. This study is registered with ClinicalTrials.gov, NCT04510493. FINDINGS: Between October 17, 2020, and May 12, 2021, 116 patients were randomly assigned with 58 in each group. One participant dropped out in each group for the primary analysis. At the time of randomization, 85 patients (74·6 %) were treated with dexamethasone. The win-ratio of canakinumab vs placebo was 1·08 (95 % CI 0·69-1·69; p = 0·72). During four weeks, in the canakinumab vs placebo group 4 (7·0%) vs 7 (12·3%) participants died, 11 (20·0 %) vs 16 (28·1%) patients were on ICU, 12 (23·5 %) vs 11 (21·6%) were hospitalised for more than 3 weeks, respectively. Median ventilation time at four weeks in the canakinumab vs placebo group was 10 [IQR 6.0, 16.5] and 16 days [IQR 14.0, 23.0], respectively. There was no statistically significant difference in HbA1c after four weeks despite a lower number of anti-diabetes drug administered in patients treated with canakinumab. Finally, high-sensitive CRP and IL-6 was lowered by canakinumab. Serious adverse events were reported in 13 patients (11·4%) in each group. INTERPRETATION: In patients with type 2 diabetes who were hospitalised with COVID-19, treatment with canakinumab in addition to standard-of-care did not result in a statistically significant improvement of the primary composite outcome. Patients treated with canakinumab required significantly less anti-diabetes drugs to achieve similar glycaemic control. Canakinumab was associated with a prolonged reduction of systemic inflammation. FUNDING: Swiss National Science Foundation grant #198415 and University of Basel. Novartis supplied study medication

A global research priority agenda to advance public health responses to fatty liver disease

Background & aims An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Methods Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. Results The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of ‘agree’ responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement (‘agree’ + ‘somewhat agree’); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% ‘agree’), 13 priorities had 90% combined agreement. Conclusions Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community’s efforts to advance and accelerate responses to this widespread and fast-growing public health threat. Impact and implications An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat

Can indirect calorimetry combined to analysis of expired 13CO2 predict insulin resistance ? A preliminary study in healthy children

Introduction: Insulin resistance is increasingly found in the paediatric age group, resulting from elevated endogenous glucose production (hepatic glycogenolysis and gluconeogenesis) and/or altered glucose utilization (glucose oxidation and glycogen synthesis). These variables can be computed from the simultaneous use of indirect calorimetry and breath 13CO2 measurement, both non invasive methods. Objective: Predicting insulin resistance in targeted subjects requires to establish first the normal developmental pattern of glucose oxidation and glycogen turnover in school-aged children. Patients/Material and Methods: A beverage containing naturally enriched 13C maize glucose was given every hour during four hours, at a rate of 3 mg/kg/min, to 47 lean healthy subjects of both sexes, aged 12.4 ± 2.6 yrs (mean ± SD) of whom 11 aged 7-9 yrs (group 1, G1), 20 aged 10-13 yrs (G2) and 16 aged 14-17 yrs (G3). Energy expenditure (EE) and total glucose oxidation (TGO) were measured during the last two hours by indirect calorimetry. Exogenous glucose oxidation (EGO) was determined by the analysis of 13CO2 production in expired air. Glycogen degradation (GD) (mostly hepatic in resting conditions) was calculated as [TGO - EGO], and total glycogen synthesis (TGS) (liver and skeletal muscle) was calculated as [glucose intake - EGO]. Results: EE correlated negatively with age (r = -0.76, p < 0.001) as well as TGO (r = -0.66, p < 0.001) and GD (r = -0.59, p < 0.001), whereas EGO and TGS did not change signficantly. When expressed as age groups, EE decreased from 0.025 (G1) to 0.017 kcal/kg/min (G3) (p < 0.001). TGO fell from 4.61 (G1) to 4.25 (G2) and 2.93 mg/kg/min (G3) (p < 0.001 vs G1 and G2). Values for GD was 2.58, 2.30 and 1.23 mg/kg/min respectively (p = 0.004 for G3 vs G1 and p = 0.003 for G3 vs G2). Conclusions: 1) Indirect calorimetry coupled with breath 13CO2 measurement after oral glucose intake can easily be used in school-aged children. 2) This original non invasive procedure allows to assess glycogen degradation and synthesis simultaneously and, consequently, to describe the developmental pattern of whole body glycogen turnover in health and disease. 3) This pilot study shows significant changes in EE, TGO and GD with age in healthy subjects. These new data provide standardized values to be used in the evaluation of subjects at risk to develop anomalies of glucose metabolism

Le diabétique en attitude: physiopathologie et conséquences pratiques. [The diabetic patient at altitude: pathophysiology and practical implications]

The prevalence of diabetes is constantly growing and an ever increasing number of diabetics travel to moderate (1500-2000 m, 5000-6500 ft.) or high altitude (>2500 m, >8000 ft) for recreational purposes. Stays at moderate altitude are very well tolerated for a majority of diabetics, but can be limited by hypoxia or equipment failure due to freezing temperatures, or by the occurence of altitude-specific pathologies, as acute mountain sickness, which can mimick hypoglycemia in the diabetic. Beyond 2500 m, freezing, remoteness, hypoxia-induced anorexia, side effects of medications and the higher incidence of mountain sickness can make diabetes control difficult. A well informed and prepared diabetic patient, with sufficient and adequatly kept equipment, and a reasonably good fitness level, can enjoy and master mountaineering