Recurrent Severe Hypoglycemia Research Articles

The impact of islet mass, number of transplants, and time between transplants on graft function in a national islet transplant program

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C‐peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3–8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C‐peptide at 12 months (p < .01). Despite 1.9‐fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291–15 417] vs. 6442 [5156–7639] IEQ/kg; p < .0001), stimulated C‐peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta −0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.

Insulin Receptor Autoantibody–mediated Hypoglycemia in a Woman With Mixed Connective Tissue Disease

Autoantibodies to the insulin receptor are rare and typically cause severe insulin resistance and hyperglycemia, a condition termed type B insulin resistance. Uncommonly, antibodies to the insulin receptor can cause hypoglycemia. We present the case of a woman who developed recurrent severe hypoglycemia and myopathy, was found to have insulin receptor autoantibodies and mixed connective tissue disease, and had resolution of hypoglycemia with immunosuppression. A 55-year-old woman with a history of obesity, hypertension, and prior hemorrhagic stroke presented with recurrent severe hypoglycemia. A diagnostic fast resulted in hypoinsulinemic hypoketotic hypoglycemia. Adrenal function was intact. Progressive myopathy had developed simultaneously with her hypoglycemia, and rheumatologic evaluation revealed mixed connective tissue disease. The plasma acylcarnitine profile was normal, extensive oncologic evaluation including insulin-like growth factor 2 measurement was unrevealing, and anti-insulin antibody testing was negative. Ultimately, anti-insulin receptor antibodies were found to be present. The patient was treated with glucocorticoids and rituximab. Eight weeks after initiation of immunosuppression, the insulin receptor antibody titer had decreased and hypoglycemia had resolved. Eight months after diagnosis, the patient remained free of severe hypoglycemia despite tapering of glucocorticoids to a near-physiologic dose. Though antibodies to the insulin receptor typically cause severe insulin resistance, this patient had no evidence of insulin resistance and instead presented with recurrent severe hypoglycemia, which responded to glucocorticoids and rituximab. The diagnosis of insulin receptor antibody–mediated hypoglycemia is rare but should be considered in patients with systemic autoimmune disease, including mixed connective tissue disease, in the appropriate clinical context.

Impaired Awareness of Hypoglycemia and Severe Hypoglycemia in Drivers With Diabetes: Insights From the Association of British Clinical Diabetologists Nationwide Audit

Hypoglycemia is an acute complication in people living with diabetes, with 83% of those with type 1 diabetes experiencing hypoglycemia at least once a month and even higher rates of 5 events per week recorded on continuous glucose monitoring (1). There are limited population-based data on the prevalence of impaired awareness of hypoglycemia (IAH) and severe hypoglycemia (SH) in drivers with diabetes in the U.K. and worldwide. The availability of these data can inform policy decisions and help optimize treatment options for people living with diabetes (2). To understand the prevalence of IAH and SH in drivers with diabetes, we obtained data from the nationwide audit of FreeStyle Libre (FSL), conducted by the Association of British Clinical Diabetologists (ABCD). Baseline pre-FSL data included demographics, HbA1c values from the previous 12 months, Gold score (3) (to assess hypoglycemia awareness), and SH. Rates of recurrent SH, defined as two or more episodes of hypoglycemia requiring third-party assistance in the 12 months prior to FSL initiation (4), were documented by clinicians. The study consisted of 13,127 adults (aged ≥17 years) with diabetes, and information about driving was available for 4,262 (96% type 1 diabetes) of those (3,210 drivers and 1,052 nondrivers). Of those with a driving license, 3,182 had a group 1 driving license (a license to drive a motor car and a motorcycle), 25 had a group 2 driving …

131-OR: ADA Presidents’ Select Abstract: Effect of Insulin Degludec vs. Insulin Glargine U100 on Occurrence of Nocturnal Hypoglycemia Assessed by Nocturnal Plasma Glucose Profiles in People with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycemia

Background and Aims: The risk of nocturnal hypoglycemia (NH) is a limiting factor for achieving good glycemic control in people with type 1 diabetes (T1D). Insulin degludec (IDeg) is proven to lower the risk of self-reported NH. As most episodes of NH are asymptomatic, we assessed differences in occurrence of NH by hourly plasma glucose (PG) measurements at treatments with IDeg or insulin glargine U100 (IGlar) in people with T1D suffering from recurrent nocturnal severe hypoglycemia. Materials and Methods: Pre-defined optional substudy of the HypoDeg trial, a 2-year investigator-initiated, randomized, cross-over trial where 149 participants with T1D were randomized to treatment with IDeg or IGlar. Fifty-one participants (mean (SD) age 58 (13) years, diabetes duration 28 (14) years and HbA1c 7.8 (1) %) were admitted for two nights for hourly blinded plasma glucose measurements for a minimum of one night (23:00h to 07:00h) during each 1-year treatment period. The primary endpoints were NH at level 1 (PG ≤ 3.9 mmol/L) and level 2 (PG &amp;lt; 3.0 mmol/L). Results: We collected data from 196 nights. A total of 57 nights (regardless of level) in 33 participants were hypoglycemic, including 20 nights with symptomatic hypoglycemia. The incidence of NH at level 1 was lower when treated with IDeg [17 events in 97 nights (18%)] as compared to IGlar [36 events in 99 nights (36%)], corresponding to a hazard ratio (HR) of 0.39 (95% CI: 0.22-0.71; p=0.002) during treatment with IDeg. At level 2, the incidence of NH was also lower during treatment with IDeg [8 events in 97 nights (8%)] as compared to IGlar [20 events in 99 nights (20%)], corresponding to an HR of 0.36 [95% CI: 0.16-0.80; p=0.013] during treatment with IDeg. Conclusion: In people with T1D and recurrent nocturnal severe hypoglycemia, treatment with IDeg as compared to IGlar results in a clinically significant lower rate of NH at both levels of hypoglycemia. Disclosure J. M. Brøsen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. H. D. Parving: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S. R. Agesen: Employee; Self; Novo Nordisk. P. L. Kristensen: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. A. Alibegovic: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. H. U. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: None. C. Hedetoft: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C. B. Juhl: None. Funding Novo Nordisk

"Hyperglycemia aversiveness": Investigating an overlooked problem among adults with type 1 diabetes.

To investigate the problem of adults with type 1 diabetes (T1D) who purposefully keep their glucose levels low, and to explore contributors to, and possible impact of, this potentially dangerous phenomenon. We developed three self-report items as a means to identify individuals who endorse a consistent preference for hypoglycemia over hyperglycemia ("Hyperglycemia Aversives"). In a large T1D survey (n = 219), validated measures of well-being, emotional distress and hypoglycemic awareness, and glycemic metrics derived from the past 14-day period, were used to examine whether Hyperglycemia Aversives could be characterized as a distinct group. Hyperglycemia Aversives comprised 16.4% of the sample. This unique group demonstrated significantly higher mean %TIR (71.6% vs. 63.6%) and %TBR (5.1% vs. 2.2%), lower mean %TAR > 250 mg/dL (6.0% vs. 10.1%), and higher rates of impaired hypoglycemic awareness and recurrent severe hypoglycemia episodes than the remaining study sample ("Non-Aversives") (all ps < 0.01). The two groups did not demonstrate significant differences on psychosocial outcomes. We identified a group of T1D adults reporting a consistent preference for hypoglycemia over hyperglycemia. These individuals achieve significantly greater %TIR and less %TAR, but at the cost of greater %TBR and more frequent severe hypoglycemia episodes.

Citrin deficiency mimicking mitochondrial depletion syndrome

BackgroundNeonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane.Case presentationWe report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70–1)_(212 + 1_231–1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months.ConclusionsAs CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.

Difficulties in Correction of Recurrent Hypoglycemia in a Patient With a Progressive Course of Malignant Metastatic Insulinoma

This article describes a clinical observation of a patient with a progressive course of malignant metastatic insulinoma, despite repeated embolization and chemoembolization (CE) of the right and left hepatic arteries with doxorubicin and gemcitabine, with metastatic liver lesion and subsequent increase in the size of secondary foci. The key clinical problem was severe recurrent hypoglycemia, which persisted against the background of massive intravenous (IV) glucose infusions, short-acting somatostatin therapy, and subcutaneous (SC) glucagon injections, which not only was an impediment to the pathogenic cytostatic therapy but also has led to the fatal outcome of the patient. J Endocrinol Metab. 2020;10(5):140-143 doi: https://doi.org/10.14740/jem666

Transplant strategies for type 1 diabetes: whole pancreas, islet and porcine beta cell therapies.

Whole-organ pancreas and islet transplantations are performed in a highly selected group of patients with diabetes mellitus, primarily those with type 1 diabetes mellitus, complicated by recurrent severe hypoglycaemia or renal failure requiring kidney transplantation. Clinical accessibility to pancreases or islets, and patient characteristics and therapeutic goals, may dictate choice of procedure. Pancreas transplantation is most often performed simultaneous with a kidney transplant, but patients with particularly labile type 1 diabetes may be considered for a pancreas transplant alone. While highly successful at restoring insulin independence, pancreas transplants carry the significant risks of major surgery and immunosuppression. Islet transplantation is a relatively minor procedure, usually performed for labile type 1 diabetes with severe hypoglycaemia. It is highly successful at resolving hypoglycaemia, but more than one pancreas donor may be required for insulin independence. Both pancreas and islet transplantation are limited in applicability by a paucity of deceased donors. Pigs provide one promising replenishable source of islets. Porcine islets can successfully reverse diabetes mellitus in non-human primates under the appropriate immunosuppressive conditions, with promise for eventually translating this success to a larger population of patients with diabetes mellitus in the future. Graphical abstract.

Reduction of Recurrent Severe Hypoglycemia and Hypoglycemia Unawareness in Type 2 Diabetes by Treatment Modification and Diabetes Education

Reduction of Recurrent Severe Hypoglycemia and Hypoglycemia Unawareness in Type 2 Diabetes by Treatment Modification and Diabetes Education

Cardiac Autonomic Neuropathy Is Not Reversed by Euglycemia Following Islet Transplantation.

Cardiac autonomic neuropathy (CAN) is a significant cause of morbidity and mortality for people with type 1 (T1D) and type 2 (T2D) diabetes. Heart rate variability (HRV) has been shown to be a marker of CAN with 24-hour Holter monitoring being a robust modality to assess HRV. To investigate the impact of hypoglycemia on CAN and its potential reversibility with islet transplantation, we compared HRV assessment by 24-hour Holter monitor on a total of 109 subjects from 5 cohorts: (1) T1D with recurrent severe hypoglycemia and on waiting list for islet transplant, (2) T1D following islet cell transplantation (ICT), (3) T2D without hypoglycemia, (4) individuals with prediabetes, and (5) controls without diabetes. SD of the normal-normal interval, square root of the mean squared differences of successive normal-normal intervals (rMSSD) and total spectral power were analyzed. There was no significant difference in HRV parameters between T1D subjects and T1D post ICT suggesting CAN is not reversible at a median of 4 years postislet transplant. There was a significant difference in controls and T1D in rMSSD and between controls and T2D in total power. The differential effect on rMSSD in T1D and T2D suggests potential greater impact of hypoglycemia on rMSSD. Achieving euglycemia after ICT may not reverse CAN once established with no significant difference in HRV parameters at a median of 4 years postislet transplant. Differential effects of T1D as compared with T2D on CAN were identified.

269-OR: Effect of Insulin Degludec on Frequency of Severe Hypoglycemia in Patients with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycemia: The HypoDeg Trial

Background and Aims: The long-acting insulin analog degludec reduces the risk of nocturnal hypoglycemia in patients with type 1 diabetes (T1D). The HypoDeg trial compared the effect of insulin degludec to insulin glargine U100 on frequency of nocturnal hypoglycemia in T1D patients with recurrent nocturnal severe hypoglycemia and reported a significant 37% relative risk reduction (RRR) of symptomatic nocturnal hypoglycemia ≤ 3.0 mmol/L with insulin degludec. Here we report the data on severe hypoglycemia (SH). Materials and Methods: In this investigator-initiated, prospective, randomized, open-label, blinded-endpoint crossover trial conducted at 10 centers in Denmark, we recruited 149 T1D patients (&amp;gt;18 years) with ≥2 episodes of nocturnal SH in the preceding two year. Patients were randomly assigned (1:1) to basal-bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. Episodes of SH were reported by telephone and adjudicated blinded to treatment. Results: A total of 136 SH episodes were reported during the maintenance periods: 56 (41%) episodes during treatment with insulin degludec and 80 (59%) episodes during treatment with insulin glargine U100, resulting in a RRR of 35% (95% confidence interval [CI]: 0-60%; p=0.04). This corresponds to an absolute rate reduction of 0.3 episodes (95% CI: 0.0-0.5) per patient-year with insulin degludec. The difference was primarily due to a lower risk of nocturnal episodes (RRR 52%, 95% CI: -10-80%; p=0.08), whereas there was no difference during daytime (RRR 10%, 95% CI: -80-50%; p=0.75). Conclusion: Treatment with insulin degludec in T1D patients with recurrent nocturnal SH resulted in a clinically significant reduced rate of SH compared with insulin glargine U100. Disclosure R.M. Agesen: Employee; Self; Novo Nordisk A/S. A. Alibegovic: Employee; Self; Novo Nordisk A/S. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: Advisory Panel; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi-Aventis. T.K. Hansen: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C.B. Juhl: None. A.K. Jensen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk Inc. H.D. Parving: None. A.L. Sørensen: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. Funding Novo Nordisk A/S

Efficacy of Intermittently Scanned Continuous Glucose Monitoring in the Prevention of Recurrent Severe Hypoglycemia.

Background: People with diabetes experiencing hypoglycemia are at increased risk of recurrence because of attenuated autonomic warning. We assessed the efficacy of intermittently scanned continuous glucose monitoring (isCGM; FreeStyle Libre™, Abbott) compared with usual-care self-monitoring of blood glucose (SMBG) in reducing this risk in type 1 and insulin-treated type 2 diabetes. Methods: Insulin-treated adults with diabetes and an episode of clinically significant biochemical hypoglycemia (blood glucose [BG] <3.0 mM) or symptomatic hypoglycemia and BG <4.0 mM were randomized to 6 months of isCGM (intensive group) or SMBG (control group) against a background of usual care. The primary outcome was hypoglycemia requiring second-party assistance for recovery. Prespecified secondary outcomes included other hypoglycemic episodes (self-reported, and BG <3.0, 3.0-3.9, <4.0 mM) and change in HbA1c at 24 weeks. Results: Of 59 participants (mean age 53.6 years, 44.1% males, median HbA1c 61.8 mmol/mol or 7.8%), 30 were allocated to isCGM and 29 to SMBG. The incidence of severe hypoglycemia was not significantly different between the two groups (incident rate ratio [95% confidence interval]: 1.49 [0.46-5.56], P = 0.47). The incidence of other recorded hypoglycemic episodes in the intervention group was double that in the control group (P < 0.001). There was no difference in the change in HbA1c between the two groups (P = 0.74). There were seven serious adverse events and none was considered related to the intervention. Conclusions: Although isCGM is safe, it does not appear to have a role in preventing recurrent severe hypoglycemia in at-risk individuals with diabetes.

Difficulties in Correction of Recurrent Hypoglycemia in a Patient With a Progressive Course of Malignant Metastatic Insulinoma

This article describes a clinical observation of a patient with a progressive course of malignant metastatic insulinoma, despite repeated embolization and chemoembolization (CE) of the right and left hepatic arteries with doxorubicin and gemcitabine, with metastatic liver lesion and subsequent increase in the size of secondary foci. The key clinical problem was severe recurrent hypoglycemia, which persisted against the background of massive intravenous (IV) glucose infusions, short-acting somatostatin therapy, and subcutaneous (SC) glucagon injections, which not only was an impediment to the pathogenic cytostatic therapy but also has led to the fatal outcome of the patient. J Endocrinol Metab. 2020;10(5):140-143 doi: https://doi.org/10.14740/jem666

How has psycho-behavioural research advanced our understanding of hypoglycaemia in type 1 diabetes?

Almost 100 years since the discovery of insulin, hypoglycaemia remains a barrier for people with type 1 diabetes to achieve and maintain blood glucose at levels which prevent long-term diabetes-related complications. Although hypoglycaemia is primarily attributable to the limitations of current treatment and defective hormonal counter-regulation in type 1 diabetes, the central role of psycho-behavioural factors in preventing, recognizing and treating hypoglycaemia has been acknowledged since the early 1980s. Over the past 25 years, as documented in the present review, there has been a substantial increase in psycho-behavioural research focused on understanding the experience and impact of hypoglycaemia. The significant contributions have been in understanding the impact of hypoglycaemia on a person's emotional well-being and aspects of life (e.g. sleep, driving, work/social life), identifying modifiable psychological and behavioural risk factors, as well as in developing psycho-behavioural interventions to prevent and better manage (severe) hypoglycaemia. The impact of hypoglycaemia on family members has also been confirmed. Structured diabetes education programmes and psycho-behavioural interventions with a focus on hypoglycaemia have both been shown to be effective in addressing problematic hypoglycaemia. However, the findings have also revealed the complexity of the problem and the need for a personalized approach, taking into account the individual's knowledge of, and emotional/behavioural reactions to hypoglycaemia. Evidence is emerging that people with persistent and recurrent severe hypoglycaemia, characterized by deeply entrenched cognitions and lack of concern around hypoglycaemia, can benefit from tailored cognitive behavioural therapy.

Predictors of Recurrent Severe Hypoglycemia in Adults With Type 1 Diabetes and Impaired Awareness of Hypoglycemia During the HypoCOMPaSS Study.

The HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of biochemical hypoglycemia without compromising overall glycemic control would restore sufficient hypoglycemia awareness to prevent recurrent severe hypoglycemia in the majority of participants with established type 1 diabetes. Before starting the study, we planned to investigate associations between baseline characteristics and recurrent severe hypoglycemia over 2 years' follow-up. A total of 96 adults with type 1 diabetes and impaired awareness of hypoglycemia participated in a 24-week 2 × 2 factorial randomized controlled trial comparing insulin delivery and glucose monitoring modalities, with the goal of rigorous biochemical hypoglycemia avoidance. The analysis included 71 participants who had experienced severe hypoglycemia in the 12-month prestudy with confirmed absence (complete responder) or presence (incomplete responder) of severe hypoglycemia over 24 months' follow-up. There were 43 (61%) complete responders and 28 (39%) incomplete responders experiencing mean ± SD 1.5 ± 1.0 severe hypoglycemia events/person-year. At 24 months, incomplete responders spent no more time with glucose ≤3 mmol/L (1.4 ± 2.1% vs. 3.0 ± 4.8% for complete responders; P = 0.26), with lower total daily insulin dose (0.45 vs. 0.58 units/24 h; P = 0.01) and greater impairment of hypoglycemia awareness (Clarke score: 3.8 ± 2.2 vs. 2.0 ± 1.9; P = 0.01). Baseline severe hypoglycemia rate (16.9 ± 16.3 vs. 6.4 ± 10.8 events/person-year; P = 0.002) and fear of hypoglycemia were higher in incomplete responders. Peripheral neuropathy was more prevalent in incomplete responders (11 [39%] vs. 2 [4.7%]; P < 0.001) with a trend toward increased autonomic neuropathy. Recurrent severe hypoglycemia was associated with higher preintervention severe hypoglycemia rate, fear of hypoglycemia, and concomitant neuropathy.

Cognitions Associated With Hypoglycemia Awareness Status and Severe Hypoglycemia Experience in Adults With Type 1 Diabetes.

Impaired awareness of hypoglycemia (IAH) and recurrent severe hypoglycemia (RSH) remain problematic for people with type 1 diabetes (T1D), despite major therapeutic advances. We explored beliefs around hypo- and hyperglycemia in adults with T1D with, and without, IAH and RSH. A cross-sectional U.S. multicenter survey included Attitudes to Awareness of Hypoglycemia (A2A; a 19-item questionnaire concerning beliefs about hypoglycemia), the Gold score (single item: awareness of hypoglycemia), and a question about severe hypoglycemia over the preceding year. The survey was emailed to 6,200 adult participants of the annual T1D Exchange clinic registry data collection. A2A data were subjected to principal component analysis with varimax rotation. Among 1,978 respondents (response rate 32%), 61.7% were women, mean ± SD age was 39.6 ± 16.3 years, and T1D duration was 23.1 ± 13.8 years. Thirty-seven percent reported IAH, 16% RSH, and 9% both. A2A items segregated into three factors, differently distributed by hypoglycemia experience. Respondents with IAH or RSH expressed appropriate concern about hypoglycemia, but those with IAH were more likely to prioritize hyperglycemia concerns than those with intact awareness (P = 0.002). Those with RSH showed greater normalization of asymptomatic hypoglycemia than those without (P = 0.019) and trended toward prioritizing hyperglycemia concerns (P = 0.097), driven by those with both IAH and RSH. Adults with T1D with IAH and RSH report specific cognitions about hypoglycemia and hyperglycemia, which may act as barriers to hypoglycemia avoidance and recovery of awareness. These may be modifiable and present a target for enhancing engagement of vulnerable people with strategies to avoid future hypoglycemia.

The effect of insulin degludec on risk of symptomatic nocturnal hypoglycaemia in adults with type 1 diabetes and high risk of nocturnal severe hypoglycaemia (the HypoDeg trial): study rationale and design

BackgroundHypoglycaemia, especially nocturnal, remains the main limiting factor of achieving good glycaemic control in type 1 diabetes.The effect of first generation long-acting insulin analogues in reducing nocturnal hypoglycaemia is well documented in patient with type 1 diabetes. The effect of the newer long-acting insulin degludec on risk of nocturnal hypoglycaemia remains undocumented in patients with type 1 diabetes and recurrent severe nocturnal hypoglycaemia.The HypoDeg trial is designed to investigate whether insulin degludec in comparison with insulin glargine U100 is superior in limiting the occurrence of nocturnal hypoglycaemia in patients with recurrent nocturnal severe hypoglycaemia. This paper reports the study design of the HypoDeg trial.Methods/designA Danish investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, two-year cross-over study investigating the effect of insulin degludec versus insulin glargine U100 on frequency of nocturnal hypoglycaemia in patients with type 1 diabetes and one or more episodes of nocturnal severe hypoglycaemia during the preceding two years as the major inclusion criteria. Patients are randomised (1:1) to basal therapy with insulin degludec or insulin glargine. Insulin aspart is used as bolus therapy in both treatment arms.DiscussionIn contrast to most other insulin studies the HypoDeg trial includes only patients at high risk of hypoglycaemia. The HypoDeg trial will compare treatment with insulin degludec to insulin glargine U100 in terms of risk of nocturnal hypoglycaemic episodes in patients with type 1 diabetes with the greatest potential to benefit from near-physiological insulin replacement therapy. www.clinicaltrials.gov: NCT02192450.

Outcomes of people with severe hypoglycaemia requiring prehospital emergency medical services management: a prospective study.

The aim of this work was to investigate clinical outcomes following severe hypoglycaemia requiring prehospital emergency medical services (EMS) management. We carried out a prospective, observational study of adults with diabetes attended by prehospital EMS for management of severe hypoglycaemia between April 2016 and July 2017. Information on precipitants, hospitalisation, length of hospital stay and recurrence was collected at 1 and 3months following the episode of severe hypoglycaemia. Median and logistic regression models examined predictive factors. Five hundred and five adults (61% male, median age 67years) participated in the study. Fifty-two per cent had type 1 diabetes, 43% type 2 diabetes and 5% were unsure of their diabetes type. Following EMS management of the index episode of severe hypoglycaemia, 50.3% were transported to hospital. Of those transported, 41.3% were admitted to hospital for ongoing management (20.8% of all participants). The following factors predicted hospital admission: older age (OR 1.28 [95% CI 1.02, 1.60] per 10years), greater number of comorbidities (OR 1.27 [95% CI 1.08, 1.48] per morbidity), moderate-severe injury accompanying the hypoglycaemia (OR 5.24 [95% CI 1.07, 25.8] compared with nil-mild injury) and unknown cause of hypoglycaemia (OR 2.21 [95% CI 1.24, 3.94] compared with known cause). The median (interquartile range) length of hospital stay was 4 (2-7) days. During follow-up, recurrent severe hypoglycaemia attended by prehospital EMS was experienced by 10.7% of participants. Predictive factors of recurrent severe hypoglycaemia in 3months were decreased HbA1c (OR 1.97 [95% CI 1.27, 3.06] per 10mmol/mol decrease) and a greater number of antecedent severe hypoglycaemia episodes (OR 1.12 [95% CI 1.03, 1.23] per episode). Following an episode of severe hypoglycaemia managed by EMS, one-fifth of participants required hospital admission, more likely in those with advancing age, increasing comorbidities and injury and one-tenth required EMS again for severe hypoglycaemia in a 3month period, more likely in those with a greater number of antecedent episodes and lower HbA1c. Knowledge of these factors associated with admission and recurrence provides an opportunity for development of targeted strategies aimed at prevention of severe hypoglycaemia in those most vulnerable.

Early detection of cognitive impairment in patients with insulinoma

Long-standing hypoglycemia can cause cognitive impairment, and whether recurrent severe hypoglycemia impacts cognitive function in patients with insulinoma has not been studied. This study focused on exploring the cognitive function in patients with insulinoma. A prospective study was conducted to assess cognitive function in patients with insulinoma by administering the Montreal Cognitive Assessment (MoCA) questionnaire between January 2016 and July 2017, and patients with cognitive impairment were followed up to undergo the MoCA test 1 year after surgery. The MoCA scores after surgery were compared with the scores before surgery, and the associations between cognitive impairment and relevant factors were further evaluated by multiple linear regression analysis. Eighteen out of thirty-four patients (53%) with insulinoma were screened positive for cognitive impairment as defined by a MoCA score <26. Performance in certain cognitive domains, including visuospatial and executive functions, delayed memory, attention, language, and abstraction, was significantly worse in patients with cognitive impairment. Multivariate analysis indicated that MoCA scores correlated significantly with tumor grade and years of education. Eight patients with cognitive impairment were lost to follow-up. The remaining ten patients with cognitive impairment showed improvements 1 year postoperatively, and seven patients recovered to normal cognitive function. Cognitive impairment was found in patients with insulinoma and was reversible in some patients 1 year after surgery. More studies are needed to explore the underlying mechanisms of the existence and reversibility of cognitive impairment in patients with insulinoma.

Myeloproliferative disorder: a rare cause of insulin auto-immune syndrome leading to recurrent severe hypoglycaemia

Myeloproliferative disorder: a rare cause of insulin auto-immune syndrome leading to recurrent severe hypoglycaemia