Recurrent Severe Hypoglycemia Research Articles

A case of systemic lupus erythematosus in a patient with Noonan syndrome with recurrent severe hypoglycemia.

Noonan syndrome (NS) is a dominantly inherited genetic disorder with mutations in genes encoding components or regulators of the RAS/mitogen-activated protein kinase pathway. Its diagnosis is based on characteristic features, including typical facial features, a short stature, congenital heart disease, mild developmental delay, and cryptorchidism. Patients with NS sometimes develop autoimmune diseases, such as Hashimoto's thyroiditis and, rarely, systemic lupus erythematosus (SLE). We herein present a 29-year-old Japanese female with NS complicated by SLE and repeated severe hypoglycemia. The patient was diagnosed with SLE based on thrombocytopenia, nephritis, a positive antinuclear antibody titer (1:640), and a positive anti-dsDNA antibody. The patient was treated with a glucocorticoid, mycophenolate mofetil, and tacrolimus, which attenuated both SLE and hypoglycemia. Since insulin receptor antibody levels were higher to the upper normal range and decreased after treatment, hypoglycemia probably appeared to be attributed to type B insulin resistance syndrome (TBIRS). We herein present the first case of SLE in NS complicated by TBIRS. Although NS is a rare disease, we need to consider the complication of autoimmune diseases, including SLE.

Insulin independence following islet transplantation improves long-term metabolic outcomes.

Pancreatic islet allotransplantation is an effective therapy for type 1 diabetes mellitus, restoring glycaemic control and hypoglycaemic awareness in patients with recurrent severe hypoglycaemia. Insulin independence following transplant is being increasingly reported; however, this is not a primary endpoint in the UK. Having surpassed 10 years of islet transplantation in Scotland, we aimed to evaluate the impact of insulin independence following transplant on metabolic outcomes and graft survival. We conducted a retrospective analysis on data collected prospectively between 2011 and 2022. Patients who underwent islet transplantation in Scotland up to the 31st January 2020 were included. Primary endpoint was graft survival (stimulated C-peptide >50 pmol/L). Secondary endpoints included GOLD score, HbA1c, C-peptide and insulin requirement. Outcomes were compared between patients who achieved insulin independence at any point following transplant versus those who did not. 60 patients were included. 74.5% experienced >50 severe hypoglycaemic episodes in the year preceding transplant. There was a 55.0% decrease in insulin requirement following transplant and 30.0% achieved insulin independence. Mean graft survival time was 9.0 years (95% CI 7.2-10.9) in patients who achieved insulin independence versus 4.4 years (95% CI 3.4-5.3) in patients who did not. Insulin independence was associated with significantly improved graft function, glycaemic control and hypoglycaemic awareness at 1 year. This is the largest UK single-centre study on islet transplant to date. Our findings demonstrate significantly improved outcomes in patients who achieved insulin independence following islet transplantation.

Recurrent Non-islet Cell Tumor Hypoglycemia Secondary to Hepatocellular Carcinoma: Case Report and Literature Review.

Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome caused by tumors other than insulinoma that is primarily due to excessive production of insulin-like growth factor-II (IGF-II). The prevalence of NICTH is likely underestimated because of a lack of clinical recognition. A 41-year-old male with massive malignant liver tumors presented with recurrent severe hypoglycemia, weight loss, and liver cirrhosis. NICTH related to IGF-II produced by hepatocellular carcinoma was diagnosed based on clinical symptoms, biochemical tests, and elevated IGF-II/IGF-I ratio. Initial treatment with intravenous glucose and parenteral nutrition showed limited efficacy. Glucocorticoids and recombinant human growth hormone led to progressive improvement in blood glucose levels. Due to extensive tumor burden and liver failure, surgical resection was not feasible, and the patient ultimately succumbed to refractory hypoglycemia and passed away in two weeks. Early recognition and diagnosis of NICTH are crucial in patients with recurrent hypoglycemia and large tumors. Surgical resection is the preferred treatment option, but supportive care and pharmacological interventions, such as glucocorticoids and growth hormone, can help manage refractory hypoglycemia. Further research is needed to explore novel treatment options, including anti-IGF-I and -IGF-II neutralizing antibodies.

The Effect of Insulin Degludec Versus Insulin Glargine U100 on Glucose Metrics Recorded During Continuous Glucose Monitoring in People With Type 1 Diabetes and Recurrent Nocturnal Severe Hypoglycemia.

Comparing continuous glucose monitoring (CGM)-recorded metrics during treatment with insulin degludec (IDeg) versus insulin glargine U100 (IGlar-100) in people with type 1 diabetes (T1D) and recurrent nocturnal severe hypoglycemia. This is a multicenter, two-year, randomized, crossover trial, including 149 adults with T1D and minimum one episode of nocturnal severe hypoglycemia within the last two years. Participants were randomized 1:1 to treatment with IDeg or IGlar-100 and given the option of six days of blinded CGM twice during each treatment. CGM traces were reviewed for the percentage of time-within-target glucose range (TIR), time-below-range (TBR), time-above-range (TAR), and coefficient of variation (CV). Seventy-four participants were included in the analysis. Differences between treatments were greatest during the night (23:00-06:59). Treatment with IGlar-100 resulted in 54.0% vs 49.0% with IDeg TIR (70-180 mg/dL) (estimated treatment difference [ETD]: -4.6%, 95% confidence interval [CI]: -9.1, -0.0, P = .049). TBR was lower with IDeg at level 1 (54-69 mg/dL) (ETD: -1.7% [95% CI: -2.9, -0.5], P < .05) and level 2 (<54 mg/dL) (ETD: -1.3% [95% CI: -2.1, -0.5], P = .001). TAR was higher with IDeg compared with IGlar-100 at level 1 (181-250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.3], P < .05) and level 2 (> 250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.2], P < .05). The mean CV was lower with IDeg than that with IGlar-100 (ETD: -3.4% [95% CI: -5.6, -1.2], P < .05). For people with T1D suffering from recurrent nocturnal severe hypoglycemia, treatment with IDeg, compared with IGlar-100, results in a lower TBR and CV during the night at the expense of more TAR.

396-P: The Humanistic Burden of Type 1 Diabetes in U.S. Adults With or Without Recurrent Severe Hypoglycemic Events—A Qualitative Interview Study

Introduction: Despite advances in technology, many people with type 1 diabetes (T1D) still experience severe hypoglycemic events (SHEs). This study explored the perceived humanistic burden of T1D in adults using continuous glucose monitor (CGM) in the US with or without recurrent SHEs. Methods: In 60-minute semi-structured interviews, adult CGM users with self-reported T1D diagnosis (≥5 yrs.) described the burden of TID on quality of life (QoL). Participants ranked the ‘top 3’ negative impacts of T1D on QoL. Subgroup analyses were conducted in participants with recurrent SHE (rSHE; ≥2 SHEs last yr.) and without recurrent SHE (nSHE; ≤1 SHEs last yr.). Results: Participants (N=31; 42% rSHEs, 58% nSHEs) were 74% female and 81% were married. Mean age of T1D diagnosis was 28 yrs. Median SHEs in the past year in the rSHE group were 3 and in the nSHE group were 0. Both groups had mean HbA1c of 7.1%. rSHE and nSHE participants used hybrid closed loop systems (hCLS) (53.8% vs. 44.4%), multiple daily injections (23.1% vs. 33.3%) and continuous subcutaneous insulin infusion pump without hCLS (23.1% vs. 22.2%), respectively. All participants reported negative impacts on physical health, mental health, sleep, relationships, leisure activities, work/studies, and sex life. The ‘top 3’ ranked impacts for the rSHE cohort were physical health and sleep (tied at first) followed by leisure activities. Impacts to physical health, mental health, and relationships were ‘top 3’ for the nSHE cohort. Conclusions: Recurrent severe hypoglycemia is observed to persist despite use of advanced diabetes technology. Negative impacts on physical health ranked as the primary concern in both rSHE and nSHE cohorts. However, moderate variability in ranked negative impact order was observed between the cohorts. Disclosure A.Boateng-kuffour: None. P.Callahan: Consultant; Rhythm Pharmaceuticals, Inc., Abbott Diabetes, HealthCore Inc., BMS, Employee; Vertex Pharmaceuticals Incorporated, Genesis Research. K.Chandarana: Employee; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.L.Gaglia: Advisory Panel; Dompé, Consultant; Vertex Pharmaceuticals Incorporated, Abata Therapeutics, Avotres Inc., Current Health, Research Support; Avotres Inc., Dompé, Imcyse, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. M.Phinney: None. E.Guzman ortega: Research Support; Vertex Pharmaceuticals Incorporated. R.N.Krupnick: Consultant; Vertex Pharmaceuticals Incorporated. M.Reaney: None. W.H.Polonsky: Consultant; Abbott Diabetes, Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Insulet Corporation, Intuity Medical, Inc., MannKind Corporation, Provention Bio, Inc., Sanofi-Aventis U.S., Vertex Pharmaceuticals Incorporated.

Glycogen Storage Disease Type Ia, Different Clinical Manifestations and Outcome: A Case Series

Background: Conversion of glucose-6-phosphate to glucose is the final step in both glycogenolysis and gluconeogenesis. In glycogen storage disease type Ia (GSD type Ia), decreased activity of the enzyme glucose6-phosphatase leads to an increased concentration of glucose-6- phosphate within the hepatocytes and shunting into alternative pathway with the following consequences: hyperlactatemia, hyperuricemia and hypertriglyceridemia. Patients develop hypoglycemia within 3 to 4 hours after a meal.&#x0D; Case Report: We reported four patients with GSD type Ia with different clinical manifestations such as hypoglycemia, hepatomegaly, lactic acidosis, hyperchylomicronemia, and hyperuricemia and also described their prognosis.&#x0D; Conclusion: Previously, many children with GSD Ia died in infancy or early childhood. Recurrent severe hypoglycemia can cause brain damage, but the prognosis has improved dramatically with early diagnosis and long term maintenance of optimal metabolic control.

Severe Recurrent Nocturnal Hypoglycemia During Chemotherapy With 6-mercaptopurine in 2 Children With Acute Lymphoblastic Leukemia.

Mercaptopurine (6MP) and methotrexate are the cornerstones of maintenance therapy in pediatric patients with acute lymphoblastic leukemia. However, although bone marrow suppression and liver dysfunction are common side effects of these antimetabolites, 6MP-induced hypoglycemia during the maintenance phase is rare. Guidelines and international protocols are well established for the management of bone marrow suppression and liver dysfunction, but promptly identifying 6MP-induced hypoglycemia is the key to its control. Here we report 2 cases of leukemia that developed hypoglycemia during the maintenance phase. Both patients were boys younger than 6 years of age and both suffered symptomatic morning hypoglycemia induced by 6MP (which was diagnosed after excluding all other possible causes). Successful management included changing the time of 6MP administration from evening to morning. Other management options are also discussed.

Autonomic dysfunction and risk of severe hypoglycemia among individuals with type 2 diabetes.

There are limited data on the link between cardiac autonomic neuropathy (CAN) and severe hypoglycemia in type 2 diabetes. Here, we evaluated the associations of CAN with severe hypoglycemia among 7,421 adults with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes study. CAN was defined using ECG-derived measures. Cox's and Andersen-Gill regression models were used to generate HRs (HRs) for the first and recurrent severe hypoglycemic episodes, respectively. Over 4.7 years, there were 558 first and 811 recurrent hypoglycemic events. Participants with CAN had increased risks of a first episode or recurrent episodes of severe hypoglycemia. The intensity of glycemic management modified the CAN association with hypoglycemia. In the standard glycemic management group, compared with those of participants without CAN, HRs for a first severe hypoglycemia event and recurrent hypoglycemia were 1.58 and 1.96, respectively. In the intensive glycemic management group, HRs for a first severe hypoglycemia event and recurrent hypoglycemia were 1.10 and 1.24, respectively. In summary, CAN was independently associated with higher risks of a first hypoglycemia event and recurrent hypoglycemia among adults with type 2 diabetes, with the highest risk observed among those on standard glycemic management.

Management and Outcomes of Severe Hypoglycemia Treated by Emergency Medical Services in the U.S. Upper Midwest.

To examine factors associated with emergency department (ED) transport after hypoglycemia treated by emergency medical services (EMS) and assess the impact of ED transport on severe hypoglycemia recurrence. We retrospectively analyzed electronic health records of a multistate advanced life support EMS provider and an integrated healthcare delivery system serving an overlapping geographic area in the upper Midwest. For adults with diabetes treated by EMS for hypoglycemia between 2013 and 2019, we examined rates of ED transport, factors associated with it, and its impact on rates of recurrent hypoglycemia requiring EMS, ED, or hospital care within 3, 7, and 30 days. We identified 1,977 hypoglycemia-related EMS encounters among 1,028 adults with diabetes (mean age 63.5 years [SD 17.7], 55.2% male, 87.4% non-Hispanic White, 42.4% rural residents, and 25.6% with type 1 diabetes), of which 46.4% resulted in ED transport (31.1% of calls by patients with type 1 diabetes and 58.0% of calls by patients with type 2 diabetes). Odds of ED transport were lower in patients with type 1 diabetes (odds ratio [OR] 0.44 [95% CI 0.31-0.62] vs. type 2 diabetes) and higher in patients with prior ED visits (OR 1.38 [95% CI 1.03-1.85]). Within 3, 7, and 30 days, transported patients experienced recurrent severe hypoglycemia 2.8, 5.2, and 10.6% of the time, respectively, compared with 7.4, 11.2, and 22.8% of the time among nontransported patients (all P < 0.001). This corresponds to OR 0.58 (95% CI 0.42-0.80) for recurrent severe hypoglycemia within 30 days for transported versus nontransported patients. When subset by diabetes type, odds of recurrent severe hypoglycemia among transported patients were 0.64 (95% CI 0.43-0.96) and 0.42 (95% CI 0.24-0.75) in type 1 and type 2 diabetes, respectively. Transported patients experienced recurrent hypoglycemia requiring medical attention approximately half as often as nontransported patients, reinforcing the importance of engaging patients in follow-up to prevent recurrent events.

218-OR: The Effect of Insulin Degludec vs. Insulin Glargine U100 on Continuous Glucose Monitoring (CGM) Recorded Glycemic Metrics in People with Type 1 Diabetes and Recurrent Nocturnal Severe Hypoglycemia

Background and Aims: Insulin Degludec (IDeg) , in comparison with Insulin Glargine U100 (IGla) , reduces the risk of hypoglycemic events in people with type 1 diabetes (T1D) . The impact on CGM assessed glycemic metrics: the coefficient of variation (CV) , time in range (TIR) , time below range (TBR) , and time-above range (TAR) is less known. We present CGM results from the HypoDeg trial comparing treatment with IDeg and IGla in people with T1D and recurrent nocturnal severe hypoglycemia. Materials and Methods: This is a pre-defined optional substudy of the HypoDeg trial: a 2-year investigator-initiated, randomized, cross-over trial comparing treatment with IDeg or IGla in 149 participants with T1D and at least one nocturnal severe hypoglycemic event within the last two years. Participants underwent 2 x 6 days of blinded CGM (Medtronic iPro) in each treatment arm after 6 and 12 months of treatment. Seventy-four participants completed at least one CGM period in each treatment arm. The endpoints were CV, TIR (3.9 - 10.0 mmol/L) , TBR at level 2 (&amp;lt; 3.0 mmol/L) and TAR (&amp;gt;10.0mmol/L, &amp;gt;13.9mmol/L) . Time spent in, below, or above range provided as percentage of readings. Results: We collected 261 CGM traces with a mean (SD) observation period of 5.9 (0.7) days. The all-day CV was lower with IDeg than IGla, with a mean (SE) CV of 40.5% (0.9) and 42.5% (0.9) , respectively (p=0.009) . A difference in CV during the night (23:00h to 07:00h) drove this, with a mean CV of 35.7% (1.1) for IDeg versus 39.6% (1.1) for IGla (p=0.001) . The all-day level 2 TBR was lower with IDeg than IGla, with a mean TBR of 1.8% (0.4) and 3.1% (0.4) , respectively (p=0.001) . The percentages of TIR and TAR were not different between treatments. Conclusion: In people with T1D prone to nocturnal severe hypoglycemia, treatment with IDeg results in a lower mean CV, reaching the definition of stable glucose levels during the night and a lower all-day TBR than IGla. Disclosure J.M.Brøsen: None. S.Lerche: None. K.Nørgaard: Advisory Panel; Medtronic, Novo Nordisk A/S, Consultant; Novo Nordisk A/S, Research Support; Dexcom, Inc., Medtronic, Novo Nordisk A/S, Zealand Pharma A/S, Speaker's Bureau; Medtronic, Stock/Shareholder; Novo Nordisk A/S. L.Tarnow: None. B.Thorsteinsson: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. R.Agesen: Employee; Novo Nordisk A/S. A.Alibegovic: Employee; Novo Nordisk A/S, Novo Nordisk A/S. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. P.Gustenhoff: Advisory Panel; Abbott Diagnostics. T.K.Hansen: None. C.Hedetoft: None. C.R.Stolberg: None. C.B.Juhl: None. Funding Novo Nordisk

Hypoglycemia Subtypes in Type 1 Diabetes: An Exploration of the Hypoglycemia Fear Survey-II.

OBJECTIVEThe Hypoglycemia Fear Survey-II (HFS-II) is a well-validated measure of fear of hypoglycemia in people with type 1 diabetes. The aim of this study was to explore the relationships between hypoglycemia worries, behaviors, and cognitive barriers to hypoglycemia avoidance and hypoglycemia awareness status, severe hypoglycemia, and HbA1c.RESEARCH DESIGN AND METHODSParticipants with type 1 diabetes (n = 178), with the study population enriched for people at risk for severe hypoglycemia (49%), completed questionnaires for assessing hypoglycemia fear (HFS-II), hyperglycemia avoidance (Hyperglycemia Avoidance Scale [HAS]), diabetes distress (Problem Areas In Diabetes [PAID]), and cognitive barriers to hypoglycemia avoidance (Attitudes to Awareness of Hypoglycemia [A2A]). Exploratory factor analysis was applied to the HFS-II. We sought to establish clusters based on HFS-II, A2A, Gold, HAS, and PAID using k-means clustering.RESULTSFour HFS-II factors were identified: Sought Safety, Restricted Activity, Ran High, and Worry. While Sought Safety, Restricted Activity, and Worry increased with progressively impaired awareness and recurrent severe hypoglycemia, Ran High did not. With cluster analysis we outlined four clusters: two clusters with preserved hypoglycemia awareness were differentiated by low fear/low cognitive barriers to hypoglycemia avoidance (cluster 1) versus high fear and distress and increased Ran High behaviors (cluster 2). Two clusters with impaired hypoglycemia awareness were differentiated by low fear/high cognitive barriers (cluster 3) as well as high fear/low cognitive barriers (cluster 4).CONCLUSIONSThis is the first study to define clusters of hypoglycemia experience by worry, behaviors, and cognitive barriers to hypoglycemia avoidance. The resulting subtypes may be important in understanding and treating problematic hypoglycemia.

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