A cross-sectional questionnaire study: Impaired awareness of hypoglycaemia remains prevalent in adults with type 1 diabetes and is associated with the risk of severe hypoglycaemia.

OBJECTIVE: Impaired awareness of hypoglycaemia (IAH) is a risk factor for severe hypoglycaemia (SH) in type 1 diabetes (T1D). Much of the IAH prevalence data comes from older studies where participants did not have the benefit of the latest insulins and technologies. This study surveyed the prevalence of IAH and SH in a tertiary adult clinic population and investigated the associated factors. METHODS: Adults (≥18 years) attending a tertiary T1D clinic completed a questionnaire, including a Gold and Clarke score. Background information was collected from health records. RESULTS: 189 people (56.1% female) with T1D (median [IQR] disease duration 19.3 [11.5, 29.1] years and age of 41.0 [29.0, 52.0] years) participated. 17.5% had IAH and 16.0% reported ≥1 episode of SH in the previous 12 months. Those with IAH were more likely to report SH (37.5% versus 11.7%, p = 0.001) a greater number of SH episodes per person (median [IQR] 0 [0,2] versus 0 [0,0] P<0.001) and be female (72.7% versus 52.6%, p = 0.036). Socio-economic deprivation was associated with IAH (p = 0.032) and SH (p = 0.005). Use of technology was the same between IAH vs aware groups, however, participants reporting SH were more likely to use multiple daily injections (p = 0.026). Higher detectable C-peptide concentrations were associated with a reduced risk of SH (p = 0.04). CONCLUSION: Insulin pump and continuous glucose monitor use was comparable in IAH versus aware groups. Despite this, IAH remains a risk factor for SH and is prevalent in females and in older people. Socioeconomic deprivation was associated with IAH and SH, making this an important population to target for interventions.

Study protocol: a randomised controlled proof-of-concept real-world study - does maximising time in range using hybrid closed loop insulin delivery and a low carbohydrate diet restore the glucagon response to hypoglycaemia in adults with type 1 diabetes?

INTRODUCTION: People with type 1 diabetes (T1D) develop an impaired glucagon response to hypoglycaemia within 5 years of diagnosis, increasing their risk of severe hypoglycaemia. It is not known whether eliminating hypoglycaemia and hyperglycaemia allows recovery of this glucagon response. Hybrid closed loop (HCL) technologies improve glycaemic time in range (TIR). However, post-prandial glycaemic excursions are still evident. Consuming a low carbohydrate diet (LCD) may minimise these excursions. METHODS AND ANALYSIS: This feasibility study will assess if maximising TIR (glucose ≥3.9 mmol/L≤10 mmol/L) using HCL systems plus an LCD (defined here as <130 g carbohydrate/day) for >8 months, restores the glucagon response to insulin-induced hypoglycaemia. Adults (n=24) with T1D (C-peptide <200 pmol/L), naïve to continuous glucose monitoring (CGM) and HCL systems, will be recruited and randomised to: group 1 (non-HCL) to continue their standard diabetes care with intermittent blinded CGM; or group 2 (HCL-LCD) to use the HCL system and follow a LCD. Baseline data on diet and glycaemia will be collected from all participants. The HCL-LCD group will then enter a 2-week run-in to acclimatise to their devices. Throughout, the HCL-LCD group will have their glucose closely monitored and adjusted aiming for glycaemic TIR >70%. Participants will have their glucagon response to hypoglycaemia measured at the beginning and 8 months later at the study end using a stepped hyperinsulinaemic hypoglycaemic clamp, in combination with the stable isotopes 6,6-2H2-glucose (D2-glucose) and 1,1,2,3,3-2H5-glycerol (D5-glycerol) to assess glucose and glycerol kinetics. The impact of hypoglycaemia on symptoms and cognitive function will be assessed during each clamp study. The primary outcome is the difference in the glucagon response to hypoglycaemia between and within groups at baseline versus study end. ETHICS AND DISSEMINATION: Ethical (20/SS/0117)/institutional review board (2021/0001) approval has been obtained. The study will be disseminated by peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04614168.

Effects of islet transplantation on microvascular and macrovascular complications in type 1 diabetes.

Type 1 diabetes is associated with high morbidity and mortality from microvascular and macrovascular disease with considerable economic cost to society. Islet cell transplantation (ICT) is a treatment option recommended by National Institute for Health and Care Excellence (NICE) for people with debilitating hypoglycaemia due to type 1 diabetes, including those with renal failure where kidney transplantation may also be indicated. The primary aim of ICT is to improve glycaemic control, reduce severe hypoglycaemia, stabilise glycaemic variability and restore awareness of hypoglycaemia where this is compromised. Insulin independence, although not a primary aim, should also be considered a therapeutic goal. The impact ICT has on the progression of microvascular and macrovascular diabetes complications is derived from small studies and has not been examined in large clinical trials. Lifelong immunosuppression, which is necessary to avoid transplant rejection, has adverse effects on lipid metabolism, hypertension and renal function, which must also be considered. In this review, we discuss the role of ICT in type 1 diabetes management and the available evidence with respect to microvascular and macrovascular disease progression post-transplantation. We conclude that, following ICT, microvascular complications including retinopathy and neuropathy are stabilised or improved. Effects on nephropathy can be complicated by coexisting kidney transplantation and the impact of immunosuppression, the latter leading to an early decline in renal function; however, there is evidence to suggest stable renal outcomes in the long term. Short-term studies have demonstrated a positive impact of ICT on surrogate markers of macrovascular disease; however, long-term studies and trials in this area are lacking.

Non-genetic inheritance via the male germline in mammals.

Numerous studies in humans and in animal models have demonstrated that exposure to adverse environmental conditions in early life results in long-term structural and functional changes in an organism, increasing the risk of cardiometabolic, neurobehavioural and reproductive disorders in later life. Such effects are not limited to the first generation offspring but may be transmitted to a second or a number of subsequent generations, through non-genomic mechanisms. While the transmission of 'programmed' effects through the maternal line could occur as a consequence of multiple influences, for example, altered maternal physiology, the inheritance of effects through the male line is more difficult to explain and there is much interest in a potential role for transgenerational epigenetic inheritance. In this review, we will discuss the mechanisms by which induced effects may be transmitted through the paternal lineage, with a particular focus on the role of epigenetic inheritance. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.