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Berry SA, Liarakos AL, Koutroukas V, Choudhary P, Wilmot EG, Iqbal A. The challenge of assessing impaired awareness of hypoglycaemia in diabetes in the era of continuous glucose monitoring: A narrative review of evidence and translation into clinical practice. Diabetes Obes Metab 2025; 27:2363-2376. [PMID: 39996361 PMCID: PMC11965031 DOI: 10.1111/dom.16284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/27/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025]
Abstract
Iatrogenic hypoglycaemia remains a major barrier in diabetes care. Over time, and with repeated hypoglycaemic episodes, the physiological responses to hypoglycaemia can become blunted, resulting in impaired awareness of hypoglycaemia (IAH). In IAH, the onset of cognitive dysfunction precedes the onset of autonomic symptoms, often preventing appropriate self-treatment, thus increasing the frequency of severe hypoglycaemia (SH). Historically, IAH has been assessed with questionnaires, such as the Gold and Clarke scores, which were developed in the 1990s. A stepwise change in diabetes management in the last few decades has been the deployment of continuous glucose monitoring (CGM). CGM allows people with diabetes to set alarms that can warn them of hypoglycaemia or even impending hypoglycaemia, thus providing a degree of 'technological' awareness. This creates a challenge in assessing awareness status, as people may be alerted to low-sensor glucose events before they experience any symptoms. CGM also allows the introduction of new measures of hypoglycaemia exposure such as time below range, which might complement traditional methods of risk assessment. These changes in the field prompt a need for reassessment of the measures of IAH. This narrative review evaluates the current epidemiology of SH and IAH, explores different measures of IAH, and evaluates the relationship between CGM metrics, IAH and SH. We conclude that a clinical approach involving traditional questionnaires, or newer updated alternatives such as the Hypo A-Q awareness scale, combined with CGM metrics and clinical assessment of human factors is recommended in the absence of a clearly superior measure.
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Affiliation(s)
- Simon A. Berry
- Division of Clinical Medicine, School of Medicine and Population HealthUniversity of SheffieldSheffieldUK
| | - Alexandros L. Liarakos
- Department of Diabetes and EndocrinologyUniversity Hospitals of Derby and Burton NHS Foundation Trust, Royal Derby HospitalDerbyUK
- School of Medicine, Faculty of Medicine and Health SciencesUniversity of NottinghamNottinghamUK
| | | | | | - Emma G. Wilmot
- Department of Diabetes and EndocrinologyUniversity Hospitals of Derby and Burton NHS Foundation Trust, Royal Derby HospitalDerbyUK
- School of Medicine, Faculty of Medicine and Health SciencesUniversity of NottinghamNottinghamUK
| | - Ahmed Iqbal
- Division of Clinical Medicine, School of Medicine and Population HealthUniversity of SheffieldSheffieldUK
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Fabricius TW, Verhulst C, Svensson CH, Wienberg M, Duijnhouwer AL, Tack CJ, Kristensen PL, de Galan BE, Pedersen‐Bjergaard U, the Hypo‐RESOLVE consortium. Effects of insulin-induced hypoglycaemia on cardiac function in people with type 1 and type 2 diabetes and people without diabetes. Diabetes Obes Metab 2025; 27:2768-2776. [PMID: 40045554 PMCID: PMC11964998 DOI: 10.1111/dom.16283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 04/04/2025]
Abstract
AIMS Cardiovascular disease is the most common complication and cause of death in people with diabetes. Hypoglycaemia is independently associated with the development of cardiovascular complications, including death. The aim of this study was to assess changes in cardiac function and workload during acute hypoglycaemia in people with and without diabetes and to explore the role of diabetes type, magnitude of the adrenaline response, and other phenotypic traits. MATERIALS AND METHOD We enrolled people with type 1 diabetes (n = 24), people with insulin-treated type 2 diabetes (n = 15) and controls without diabetes (n = 24). All participants underwent a hyperinsulinaemic-normoglycaemic-(5.3 ± 0.3 mmol/L)-hypoglycaemic (2.8 ± 0.1 mmol/L)-glucose clamp. Cardiac function was assessed by echocardiography, with left ventricular ejection fraction (LVEF) as the primary endpoint. RESULTS During hypoglycaemia, LVEF increased significantly in all groups compared to baseline (6.2 ± 5.2%, p < 0.05), but the increase was significantly lower in type 1 diabetes compared to controls without diabetes (5.8 ± 3.4% vs. 9.4 ± 5.0%, p = 0.03, 95% CI difference: -5.0, -0.3). In people with type 1 diabetes, ΔLVEF was inversely associated with diabetes duration (β: -0.16, 95% CI: -0.24, -0.53, p = 0.001) and recent exposure to hypoglycaemia (β: -0.30, 95% CI: -0.53, -0.07, p = 0.015). Hypoglycaemia also increased global longitudinal strain (GLS) in controls without diabetes (p < 0.05), but this did not occur in the two diabetes subgroups (p > 0.10). CONCLUSIONS Hypoglycaemia increased LVEF in all groups, but the increase diminished with longer disease duration and prior exposure to hypoglycaemia in type 1 diabetes, suggesting adaptation to recurrent hypoglycaemia. The increment in GLS observed in controls was blunted in people with diabetes. More research is needed to determine the clinical relevance of these findings.
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Affiliation(s)
- Therese Wilbek Fabricius
- Department of Endocrinology and NephrologyNordsjællands HospitalHillerødDenmark
- Novo NordiskSøborgDenmark
| | - Clementine Verhulst
- Department of Internal MedicineRadboud University Medical CentreNijmegenThe Netherlands
| | | | - Malene Wienberg
- Department of CardiologyNordsjællands HospitalHillerødDenmark
| | | | - Cees J. Tack
- Department of Internal MedicineRadboud University Medical CentreNijmegenThe Netherlands
| | - Peter L. Kristensen
- Department of Endocrinology and NephrologyNordsjællands HospitalHillerødDenmark
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Bastiaan E. de Galan
- Department of Internal MedicineRadboud University Medical CentreNijmegenThe Netherlands
- CARIM School for Cardiovascular DiseasesMaastricht UniversityMaastrichtThe Netherlands
- Department of Internal MedicineMaastricht University Medical CentreMaastrichtNetherlands
| | - Ulrik Pedersen‐Bjergaard
- Department of Endocrinology and NephrologyNordsjællands HospitalHillerødDenmark
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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Aleksic S, Lontchi-Yimagou E, Mitchell W, Boyle C, Matias P, Manavalan A, Goyal A, Carey M, Gabriely I, Hawkins M. Effects of Intranasal Naloxone on Hypoglycemia-associated Autonomic Failure in Susceptible Individuals. J Clin Endocrinol Metab 2025; 110:462-470. [PMID: 39026458 PMCID: PMC11747680 DOI: 10.1210/clinem/dgae479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/09/2024] [Accepted: 07/09/2024] [Indexed: 07/20/2024]
Abstract
CONTEXT Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counterregulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally yet is not feasible therapeutically. OBJECTIVE To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally induced HAAF. DESIGN Randomized, double-blinded, placebo-controlled crossover study. SETTING Academic research center. PARTICIPANTS Healthy nondiabetic volunteers. INTERVENTIONS Paired 2-day studies, 5 to 10 weeks apart, each consisting of 3 consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): 2 on day 1 with administration of intranasal naloxone vs placebo, followed by the third episode on day 2. MAIN OUTCOME MEASURES Differences in counterregulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs placebo studies. RESULTS Out of 17 participants, 9 developed HAAF, confirming variable interindividual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and GH responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. CONCLUSION This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable interindividual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.
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Affiliation(s)
- Sandra Aleksic
- Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | | | | | - Caroline Boyle
- Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | | | | | - Akankasha Goyal
- New York University Langone Medical Center, New York, NY 10017, USA
| | - Michelle Carey
- Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20903, USA
| | - Ilan Gabriely
- Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Hermanns N, Ehrmann D, Kulzer B, Klinker L, Haak T, Schmitt A. Somatic and mental symptoms associated with dysglycaemia, diabetes-related complications and mental conditions in people with diabetes: Assessments in daily life using continuous glucose monitoring and ecological momentary assessment. Diabetes Obes Metab 2025; 27:61-70. [PMID: 39375863 PMCID: PMC11618240 DOI: 10.1111/dom.15983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/16/2024] [Accepted: 09/16/2024] [Indexed: 10/09/2024]
Abstract
AIM To analyse the potential drivers (glucose level, complications, diabetes type, gender, age and mental health) of diabetes symptoms using continuous glucose monitoring (CGM) and ecological momentary assessment. MATERIALS AND METHODS Participants used a smartphone application to rate 25 diabetes symptoms in their daily lives over 8 days. These symptoms were grouped into four blocks so that each symptom was rated six times on 2 days (noon, afternoon and evening). The symptom ratings were associated with the glucose levels for the previous 2 hours, measured with CGM. Linear mixed-effects models were used, allowing for nested random effects and the conduct of N = 1 analysis of individual associations. RESULTS In total, 192 individuals with type 1 diabetes and 179 with type 2 diabetes completed 6380 app check-ins. Four symptoms showed a significant negative association with glucose values, indicating higher ratings at lower glucose (speech difficulties, P = .003; coordination problems, P = .00005; confusion, P = .049; and food cravings, P = .0003). Four symptoms showed a significant positive association with glucose values, indicating higher scores at higher glucose (thirst, P = .0001; urination, P = .0003; taste disturbances, P = .021; and itching, P = .0120). There were also significant positive associations between microangiopathy and eight symptoms. Elevated depression and diabetes distress were associated with higher symptom scores. N = 1 analysis showed highly idiosyncratic associations between symptom reports and glucose levels. CONCLUSIONS The N = 1 analysis facilitated the creation of personalized symptom profiles related to glucose levels with consideration of factors such as complications, gender, body mass index, depression and diabetes distress. This approach can enhance precision monitoring for diabetes symptoms in precision medicine.
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Affiliation(s)
- Norbert Hermanns
- Research Institute of the Diabetes‐Academy Mergentheim (FIDAM)Bad MergentheimGermany
- Department of Clinical Psychology and PsychotherapyUniversity of BambergBambergGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
- Diabetes Center Mergentheim (DZM)Diabetes ClinicBad MergentheimGermany
| | - Dominic Ehrmann
- Research Institute of the Diabetes‐Academy Mergentheim (FIDAM)Bad MergentheimGermany
- Department of Clinical Psychology and PsychotherapyUniversity of BambergBambergGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
| | - Bernhard Kulzer
- Research Institute of the Diabetes‐Academy Mergentheim (FIDAM)Bad MergentheimGermany
- Department of Clinical Psychology and PsychotherapyUniversity of BambergBambergGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
- Diabetes Center Mergentheim (DZM)Diabetes ClinicBad MergentheimGermany
| | - Laura Klinker
- Research Institute of the Diabetes‐Academy Mergentheim (FIDAM)Bad MergentheimGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
- Diabetes Center Mergentheim (DZM)Diabetes ClinicBad MergentheimGermany
| | - Thomas Haak
- Diabetes Center Mergentheim (DZM)Diabetes ClinicBad MergentheimGermany
| | - Andreas Schmitt
- Research Institute of the Diabetes‐Academy Mergentheim (FIDAM)Bad MergentheimGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
- Diabetes Center Mergentheim (DZM)Diabetes ClinicBad MergentheimGermany
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Dodamani MH, Hatwal J, Batta A. Role of intestinal glucagon-like peptide-1 in impaired counter-regulatory responses to hypoglycemia. World J Diabetes 2024; 15:2394-2398. [PMID: 39676808 PMCID: PMC11580583 DOI: 10.4239/wjd.v15.i12.2394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/08/2024] [Accepted: 10/23/2024] [Indexed: 11/18/2024] Open
Abstract
Patients with type 1 diabetes mellitus (T1DM) experience multiple episodes of hypoglycemia, resulting in dysfunctional counter-regulatory responses with time. The recent experimental study by Jin et al explored the role of intestinal glucagon-like peptide-1 (GLP-1) in impaired counter-regulatory responses to hypoglycemia. They identified intestinal GLP-1 along with GLP-1 receptor (GLP-1R) as the new key players linked with impaired counter-regulatory responses to hypoglycemia in type 1 diabetic mice. They also demonstrated that excessive expression of GLP-1 and GLP-1R was associated with attenuated sympathoadrenal responses and decreased glucagon secretion. The study has enormous clinical relevance as defective counter regulation and hypoglycemia unawareness negatively impacts the intensive glycemic management approach in this group of patients. However, the physiological processes must be validated in dedicated human studies to comprehensively understand the pathophysiology of this complex relationship, and to clarify the true extent of impaired hypoglycemia counter regulation by intestinal GLP-1. For now, following the results of the index study and other similar studies, GLP-1 analogues usage in T1DM must be carefully monitored, as there is an inherent risk of worsening the already impaired counter-regulatory responses in these patients. Further studies in the future could identify other key players involved in this clinically relevant interaction.
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Affiliation(s)
| | - Juniali Hatwal
- Department of Internal Medicine, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India
| | - Akash Batta
- Department of Cardiology, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
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Arshad MF, Walkinshaw E, Solomon AL, Bernjak A, Rombach I, Little SA, Shaw JA, Heller SR, Iqbal A. Diabetic autonomic neuropathy does not impede improvement in hypoglycaemia awareness in adults: Sub-study results from the HypoCOMPaSS trial. Diabet Med 2024; 41:e15340. [PMID: 38741266 PMCID: PMC7617341 DOI: 10.1111/dme.15340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 03/22/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024]
Abstract
AIMS Impaired awareness of hypoglycaemia (IAH) increases the risk of severe hypoglycaemia in people with type 1 diabetes mellitus (T1DM). IAH can be reversed through meticulous avoidance of hypoglycaemia. Diabetic autonomic neuropathy (DAN) has been proposed as an underlying mechanism contributing to IAH; however, data are inconsistent. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on IAH reversibility inT1DM. METHODS Participants with T1DM and IAH (Gold score ≥4) recruited to the HypoCOMPaSS (24-week 2 × 2 factorial randomised controlled) trial were included. All underwent screening for cardiac autonomic function testing at baseline and received comparable education and support aimed at avoiding hypoglycaemia and improving hypoglycaemia awareness. Definite CAN was defined as the presence of ≥2 abnormal cardiac reflex tests. Participants were grouped according to their CAN status, and changes in Gold score were compared. RESULTS Eighty-three participants (52 women [62.7%]) were included with mean age (SD) of 48 (12) years and mean HbA1c of 66 (13) mmol/mol (8.2 [3.3] %). The mean duration of T1DM was 29 (13) years. The prevalence of CAN was low with 5/83 (6%) participants having definite autonomic neuropathy with 11 (13%) classified with possible/early neuropathy. All participants, regardless of the autonomic function status, showed a mean improvement in Gold score of ≥1 (mean improvement -1.2 [95% CI -0.8, -1.6]; p < 0.001). CONCLUSIONS IAH can be improved in people with T1DM, and a long duration of disease, with and without cardiac autonomic dysfunction. These data suggest that CAN is not a prime driver for modulating IAH reversibility.
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Affiliation(s)
- Muhammad Fahad Arshad
- University of Sheffield, Sheffield, UK
- Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Emma Walkinshaw
- University of Sheffield, Sheffield, UK
- Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | | | | | | | - Stuart A. Little
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - James A.M. Shaw
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Simon R Heller
- University of Sheffield, Sheffield, UK
- Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Ahmed Iqbal
- University of Sheffield, Sheffield, UK
- Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
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Baxter F, Baillie N, Dover A, Stimson RH, Gibb F, Forbes S. 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. PLoS One 2024; 19:e0297601. [PMID: 38875308 PMCID: PMC11178233 DOI: 10.1371/journal.pone.0297601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 05/14/2024] [Indexed: 06/16/2024] Open
Abstract
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.
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Affiliation(s)
- Faye Baxter
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Nicola Baillie
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Anna Dover
- Department of Diabetes and Endocrinology, Outpatient Department 2, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Roland H Stimson
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Department of Diabetes and Endocrinology, Outpatient Department 2, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Fraser Gibb
- Department of Diabetes and Endocrinology, Outpatient Department 2, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
| | - Shareen Forbes
- BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Department of Diabetes and Endocrinology, Outpatient Department 2, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
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Lee MH, Gooley J, Obeyesekere V, Lu J, Paldus B, Hendrieckx C, MacIsaac RJ, McAuley SA, Speight J, Vogrin S, Jenkins AJ, Holmes-Walker DJ, O’Neal DN, Ward GM. Hybrid Closed Loop in Adults With Type 1 Diabetes and Severely Impaired Hypoglycemia Awareness. J Diabetes Sci Technol 2024:19322968241245627. [PMID: 38613225 PMCID: PMC11572158 DOI: 10.1177/19322968241245627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/14/2024]
Abstract
BACKGROUND Benefits of hybrid closed-loop (HCL) systems in a high-risk group with type 1 diabetes and impaired awareness of hypoglycemia (IAH) have not been well-explored. METHODS Adults with Edmonton HYPO scores ≥1047 were randomized to 26-weeks HCL (MiniMed™ 670G) vs standard therapy (multiple daily injections or insulin pump) without continuous glucose monitoring (CGM) (control). Primary outcome was percentage CGM time-in-range (TIR; 70-180 mg/dL) at 23 to 26 weeks post-randomization. Major secondary endpoints included magnitude of change in counter-regulatory hormones and autonomic symptom responses to hypoglycemia at 26-weeks post-randomization. A post hoc analysis evaluated glycemia risk index (GRI) comparing HCL with control groups at 26 weeks post-randomization. RESULTS Nine participants (median [interquartile range (IQR)] age 51 [41, 59] years; 44% male; enrolment HYPO score 1183 [1058, 1308]; Clarke score 6 [6, 6]; n = 5 [HCL]; n = 4 [control]) completed the study. Time-in-range was higher using HCL vs control (70% [68, 74%] vs 48% [44, 50%], P = .014). Time <70 mg/dL did not differ (HCL 3.8% [2.7, 3.9] vs control 6.5% [4.3, 8.6], P = .14) although hypoglycemia episode duration was shorter (30 vs 50 minutes, P < .001) with HCL. Glycemia risk index was lower with HCL vs control (38.1 [30.0, 39.2] vs 70.8 [58.5, 72.4], P = .014). Following 6 months of HCL use, greater dopamine (24.0 [12.3, 27.6] vs -18.5 [-36.5, -4.8], P = .014), and growth hormone (6.3 [4.6, 16.8] vs 0.5 [-0.8, 3.0], P = .050) responses to hypoglycemia were observed. CONCLUSIONS Six months of HCL use in high-risk adults with severe IAH increased glucose TIR and improved GRI without increased hypoglycemia, and partially restored counter-regulatory responses. CLINICAL TRIAL REGISTRATION ACTRN12617000520336.
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Affiliation(s)
- Melissa H. Lee
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
| | - Judith Gooley
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
| | - Varuni Obeyesekere
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
| | - Jean Lu
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
| | - Barbora Paldus
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
| | - Christel Hendrieckx
- School of Psychology, Deakin University, Geelong, VIC, Australia
- The Australian Centre for Behavioural Research in Diabetes, Diabetes Victoria, Melbourne, VIC, Australia
| | - Richard J. MacIsaac
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
| | - Sybil A. McAuley
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
- Department of Endocrinology & Diabetes, The Alfred, Melbourne, VIC, Australia
| | - Jane Speight
- School of Psychology, Deakin University, Geelong, VIC, Australia
- The Australian Centre for Behavioural Research in Diabetes, Diabetes Victoria, Melbourne, VIC, Australia
| | - Sara Vogrin
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
| | - Alicia J. Jenkins
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
- National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - D. Jane Holmes-Walker
- Department of Endocrinology, Westmead Hospital, The University of Sydney, Sydney, NSW, Australia
| | - David N. O’Neal
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
| | - Glenn M. Ward
- Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
- Department of Endocrinology and Diabetes, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
- Department of Clinical Biochemistry, St Vincent’s Hospital Melbourne, Melbourne, VIC, Australia
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapy for Type 1 Diabetes. Exp Clin Endocrinol Diabetes 2024; 132:125-135. [PMID: 38365208 DOI: 10.1055/a-2166-6695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
Affiliation(s)
- Thomas Haak
- Diabetes Centre Bad Mergentheim, Bad Mergentheim, Germany
| | | | - Andreas Fritsche
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany
| | | | | | | | - Harald H Klein
- Department of Internal Medicine I - General Internal Medicine, Endocrinology and Diabetology, Gastroenterology and Hepatology, Bergmannsheil University Hospitals, Bochum, Germany
| | - Til Uebel
- prima-diab Practice Drs. Uebel/Nittka/Mayer/Merkle, Ittlingen, Germany
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Hölzen L, Schultes B, Meyhöfer SM, Meyhöfer S. Hypoglycemia Unawareness-A Review on Pathophysiology and Clinical Implications. Biomedicines 2024; 12:391. [PMID: 38397994 PMCID: PMC10887081 DOI: 10.3390/biomedicines12020391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 01/31/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Hypoglycemia is a particular problem in people with diabetes while it can also occur in other clinical circumstances. Hypoglycemia unawareness describes a condition in which autonomic and neuroglycopenic symptoms of hypoglycemia decrease and hence are hardly perceivable. A failure to recognize hypoglycemia in time can lead to unconsciousness, seizure, and even death. The risk factors include intensive glycemic control, prior episodes of severe hypoglycemia, long duration of diabetes, alcohol consumption, exercise, renal failure, and sepsis. The pathophysiological mechanisms are manifold, but mainly concern altered brain glucose sensing, cerebral adaptations, and an impaired hormonal counterregulation with an attenuated release of glucagon, epinephrine, growth hormone, and other hormones, as well as impaired autonomous and neuroglycopenic symptoms. Physiologically, this counterregulatory response causes blood glucose levels to rise. The impaired hormonal counterregulatory response to recurrent hypoglycemia can lead to a vicious cycle of frequent and poorly recognized hypoglycemic episodes. There is a shift in glycemic threshold to trigger hormonal counterregulation, resulting in hypoglycemia-associated autonomic failure and leading to the clinical syndrome of hypoglycemia unawareness. This clinical syndrome represents a particularly great challenge in diabetes treatment and, thus, prevention of hypoglycemia is crucial in diabetes management. This mini-review provides an overview of hypoglycemia and the associated severe complication of impaired hypoglycemia awareness and its symptoms, pathophysiology, risk factors, consequences, as well as therapeutic strategies.
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Affiliation(s)
- Laura Hölzen
- Institute for Endocrinology & Diabetes, University of Lübeck, 23562 Lübeck, Germany; (L.H.); (B.S.)
- Department of Internal Medicine 1, Endocrinology & Diabetes, University of Lübeck, 23562 Lübeck, Germany
| | - Bernd Schultes
- Institute for Endocrinology & Diabetes, University of Lübeck, 23562 Lübeck, Germany; (L.H.); (B.S.)
- Metabolic Center St. Gallen, friendlyDocs Ltd., 9016 St. Gallen, Switzerland
| | - Sebastian M. Meyhöfer
- Institute for Endocrinology & Diabetes, University of Lübeck, 23562 Lübeck, Germany; (L.H.); (B.S.)
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Svenja Meyhöfer
- Institute for Endocrinology & Diabetes, University of Lübeck, 23562 Lübeck, Germany; (L.H.); (B.S.)
- Department of Internal Medicine 1, Endocrinology & Diabetes, University of Lübeck, 23562 Lübeck, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
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11
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Lega IC, Yale JF, Chadha A, Paty B, Roscoe R, Snider M, Steier J, Bajaj HS, Barnes T, Gilbert J, Honshorst K, Kim J, Lewis J, MacDonald B, MacKay D, Mansell K, Senior P, Rabi D, Sherifali D. Hypoglycemia in Adults. Can J Diabetes 2023; 47:548-559. [PMID: 37821214 DOI: 10.1016/j.jcjd.2023.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
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12
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes – Kurzfassung der S3-Leitlinie (AWMF-Registernummer: 057-013; 4. Auflage 2018). DIABETOL STOFFWECHS 2023; 18:S136-S147. [DOI: 10.1055/a-2075-9984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Thomas Haak
- Diabetes-Klinik Bad Mergentheim, Bad Mergentheim, Deutschland
| | - Stefan Gölz
- Diabetesschwerpunktpraxis Esslingen, Esslingen, Deutschland
| | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Deutschland
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen, Deutschland
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13
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De Fano M, Porcellati F, Fanelli CG, Corio S, Mazzieri A, Lucidi P, Bolli GB, Bassotti G. The role of gastric emptying in glucose homeostasis and defense against hypoglycemia: Innocent bystander or partner in crime? Diabetes Res Clin Pract 2023; 203:110828. [PMID: 37481116 DOI: 10.1016/j.diabres.2023.110828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 06/30/2023] [Accepted: 07/11/2023] [Indexed: 07/24/2023]
Abstract
Maintenance of plasma glucose (PG) homeostasis is due to a complex network system. Even a minor fall in PG activates multiple neuroendocrine actions promoting hormonal, metabolic and behavioral responses, which prevent and ultimately recover hypoglycemia, primarily neuroglycopenia. Among these responses, gastric emptying (GE) plays an important role by coordinated mechanisms which regulate transit and absorption of nutrients through the small intestine. A bidirectional relationship between GE and glycemia has been established: GE may explain the up to 30-40 % variance in glycemic response following a carbohydrate-rich meal. In addition, acute and chronic hyperglycemia induce deceleration of GE after meals. Hypoglycemia accelerates GE, but its role in counterregulation has been poorly investigated. The role of GE as a counterregulatory mechanism has been confirmed in pathophysiological conditions, such as gastroparesis or following recurrent hypoglycemia. Therefore, it could represent an "ancestral" mechanism, highly conservative and effective in all individuals, conditions and clinical contexts. Recent guidelines recommend GLP-1 receptor agonists (GLP-1RAs) either as the first injectable therapy for type 2 diabetes mellitus or in combination with insulin. Considering the potential impact on GE, it would be important to study subjects on GLP-1 RAs during hypoglycemia, to establish whether a possible deceleration of GE impairs glucose counterregulation.
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Affiliation(s)
- Michelantonio De Fano
- Endocrine and Metabolic Sciences Section, Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Francesca Porcellati
- Endocrine and Metabolic Sciences Section, Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
| | - Carmine G Fanelli
- Endocrine and Metabolic Sciences Section, Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Sofia Corio
- Endocrine and Metabolic Sciences Section, Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessio Mazzieri
- Endocrine and Metabolic Sciences Section, Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Paola Lucidi
- Endocrine and Metabolic Sciences Section, Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Geremia B Bolli
- Endocrine and Metabolic Sciences Section, Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Gabrio Bassotti
- Gastroenterology, Hepatology and Digestive Endoscopy Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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14
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIE DIABETOLOGIE 2023; 19:647-657. [DOI: 10.1007/s11428-023-01046-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/15/2023] [Indexed: 01/06/2025]
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15
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Germine LT, Han SD, Chaytor NS. New Methods Permit a Science of Everyday Functioning in Type 1 Diabetes. Diabetes Care 2023; 46:1330-1331. [PMID: 37339350 PMCID: PMC10300512 DOI: 10.2337/dci23-0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 04/17/2023] [Indexed: 06/22/2023]
Affiliation(s)
- Laura T. Germine
- Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA
- Department of Psychiatry, Harvard Medical School, Boston, MA
| | - S. Duke Han
- Department of Family Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Naomi S. Chaytor
- Department of Community and Behavioral Health, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA
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16
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Flatt AJ, Peleckis AJ, Dalton-Bakes C, Nguyen HL, Ilany S, Matus A, Malone SK, Goel N, Jang S, Weimer J, Lee I, Rickels MR. Automated Insulin Delivery for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes with Hypoglycemia Unawareness. Diabetes Technol Ther 2023; 25:302-314. [PMID: 36763336 PMCID: PMC10171955 DOI: 10.1089/dia.2022.0506] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Objective: Automated insulin delivery (AID) may benefit individuals with long-standing type 1 diabetes where frequent exposure to hypoglycemia impairs counterregulatory responses. This study assessed the effect of 18 months AID on hypoglycemia avoidance and glucose counterregulatory responses to insulin-induced hypoglycemia in long-standing type 1 diabetes complicated by impaired awareness of hypoglycemia. Methods: Ten participants mean ± standard deviation age 49 ± 16 and diabetes duration 34 ± 16 years were initiated on AID. Continuous glucose monitoring was paired with actigraphy to assess awake- and sleep-associated hypoglycemia exposure every 3 months. Hyperinsulinemic hypoglycemic clamp experiments were performed at baseline, 6, and 18 months postintervention. Hypoglycemia exposure was reduced by 3 months, especially during sleep, with effects sustained through 18 months (P ≤ 0.001) together with reduced glucose variability (P < 0.01). Results: Hypoglycemia awareness and severity scores improved (P < 0.01) with severe hypoglycemia events reduced from median (interquartile range) 3 (3-10) at baseline to 0 (0-1) events/person·year postintervention (P = 0.005). During the hypoglycemic clamp experiments, no change was seen in the endogenous glucose production (EGP) response, however, peripheral glucose utilization during hypoglycemia was reduced following intervention [pre: 4.6 ± 0.4, 6 months: 3.8 ± 0.5, 18 months: 3.4 ± 0.3 mg/(kg·min), P < 0.05]. There were increases over time in pancreatic polypeptide (Pre:62 ± 29, 6 months:127 ± 44, 18 months:176 ± 58 pmol/L, P < 0.01), epinephrine (Pre: 199 ± 53, 6 months: 332 ± 91, 18 months: 386 ± 95 pg/mL, P = 0.001), and autonomic symptom (Pre: 6 ± 2, 6 months: 6 ± 2, 18 months: 10 ± 2, P < 0.05) responses. Conclusions: AID led to a sustained reduction of hypoglycemia exposure. EGP in response to insulin-induced hypoglycemia remained defective, however, partial recovery of glucose counterregulation was evidenced by a reduction in peripheral glucose utilization likely mediated by increased epinephrine secretion and, together with improved autonomic symptoms, may contribute to the observed clinical reduction in hypoglycemia.
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Affiliation(s)
- Anneliese J. Flatt
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Amy J. Peleckis
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Cornelia Dalton-Bakes
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Huong-Lan Nguyen
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sarah Ilany
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Austin Matus
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Susan K. Malone
- Rory Meyers College of Nursing, New York University, New York, New York, USA
| | - Namni Goel
- Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA
| | - Sooyong Jang
- PRECISE Center, Department of Computer and Information Science, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James Weimer
- PRECISE Center, Department of Computer and Information Science, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Insup Lee
- PRECISE Center, Department of Computer and Information Science, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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17
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Ali N, El Hamdaoui S, Schouwenberg BJ, Tack CJ, de Galan BE. Fall in prevalence of impaired awareness of hypoglycaemia in individuals with type 1 diabetes. Diabet Med 2023; 40:e15042. [PMID: 36645139 DOI: 10.1111/dme.15042] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/17/2023]
Abstract
AIMS Impaired awareness of hypoglycaemia (IAH) has been reported to affect up to a third of people with type 1 diabetes. Whether the increased use of sensor technology has changed its prevalence remains unknown. The aim of this study was to investigate the current prevalence of IAH and its change over time in a cohort of individuals with type 1 diabetes. METHODS IAH was assessed using the modified Clarke questionnaire in adults with type 1 diabetes. Participants were recruited from the diabetes outpatient clinic from February 2020 through April 2021. The scores were compared to similar data collected during previous assessments in 2006, 2010 and 2016 respectively. RESULTS A total of 488 individuals (51.2% male) with a mean (±SD) age of 51.3 ± 15.9 years, median [Q1-Q3] diabetes duration of 30 [16-40] years and mean HbA1c of 60 ± 12 mmol/mol (7.7 ± 1.1%) were included. Sensors were used by 85% of the study population. IAH was present among 78 (16.0%) participants, whereas 86 (17.6%) participants had a history of severe hypoglycaemia. By comparison, the prevalence of IAH equalled 32.5% in 2006, 32.3% in 2010 and 30.1% in 2016 (p for trend <0.001), while the proportion of individuals reporting severe hypoglycaemia equalled 21.2%, 46.7% and 49.8% respectively (p for trend 0.010). Comparing sequential assessments over time, the proportion of individuals with persistent IAH decreased from 74.0% and 63.6% between 2006 and 2016 to 32.5% in 2020. CONCLUSIONS Among individuals with type 1 diabetes and high use of sensor technology, the current prevalence of IAH was 16%, about 50% lower as compared to previous years.
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Affiliation(s)
- Namam Ali
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Soumia El Hamdaoui
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bas J Schouwenberg
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Cees J Tack
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bastiaan E de Galan
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands
- CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, the Netherlands
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIABETES AKTUELL 2023; 21:30-42. [DOI: 10.1055/a-2012-3827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Thomas Haak
- Diabetes-Klinik Bad Mergentheim, Bad Mergentheim, Deutschland
| | - Stefan Gölz
- Diabetesschwerpunktpraxis Esslingen, Esslingen, Deutschland
| | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Deutschland
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen, Deutschland
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19
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Robertson RP. Endocrine Function and Metabolic Outcomes After Pancreas and Islet Transplantation. TRANSPLANTATION OF THE PANCREAS 2023:801-815. [DOI: 10.1007/978-3-031-20999-4_57] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Sanchez-Rangel E, Deajon-Jackson J, Hwang JJ. Pathophysiology and management of hypoglycemia in diabetes. Ann N Y Acad Sci 2022; 1518:25-46. [PMID: 36202764 DOI: 10.1111/nyas.14904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
In the century since the discovery of insulin, diabetes has changed from an early death sentence to a manageable chronic disease. This change in longevity and duration of diabetes coupled with significant advances in therapeutic options for patients has fundamentally changed the landscape of diabetes management, particularly in patients with type 1 diabetes mellitus. However, hypoglycemia remains a major barrier to achieving optimal glycemic control. Current understanding of the mechanisms of hypoglycemia has expanded to include not only counter-regulatory hormonal responses but also direct changes in brain glucose, fuel sensing, and utilization, as well as changes in neural networks that modulate behavior, mood, and cognition. Different strategies to prevent and treat hypoglycemia have been developed, including educational strategies, new insulin formulations, delivery devices, novel technologies, and pharmacologic targets. This review article will discuss current literature contributing to our understanding of the myriad of factors that lead to the development of clinically meaningful hypoglycemia and review established and novel therapies for the prevention and treatment of hypoglycemia.
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Affiliation(s)
- Elizabeth Sanchez-Rangel
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jelani Deajon-Jackson
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Janice Jin Hwang
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA.,Division of Endocrinology, Department of Internal Medicine, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, USA
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Verhulst CEM, Fabricius TW, Teerenstra S, Kristensen PL, Tack CJ, McCrimmon RJ, Heller S, Evans ML, Amiel SA, Pedersen-Bjergaard U, de Galan BE. Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review. Diabetologia 2022; 65:1601-1612. [PMID: 35867127 PMCID: PMC9477942 DOI: 10.1007/s00125-022-05749-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 05/06/2022] [Indexed: 02/05/2023]
Abstract
AIM/HYPOTHESIS The physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. METHODS A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR. RESULTS A total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2-4.2] vs 3.4 [2.8-3.9 mmol/l]), noradrenaline (3.2 [3.2-3.7] vs 3.0 [2.8-3.1] mmol/l), cortisol (3.5 [3.2-4.2]) vs 2.8 [2.8-3.4] mmol/l) and growth hormone (3.8 [3.3-3.8] vs. 3.2 [3.0-3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. CONCLUSIONS/INTERPRETATION People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses. FUNDING This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. REGISTRATION This systematic review is registered in PROSPERO (CRD42019120083).
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Affiliation(s)
- Clementine E M Verhulst
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands.
| | - Therese W Fabricius
- Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark.
| | - Steven Teerenstra
- Section Biostatistics, Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Peter L Kristensen
- Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cees J Tack
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands
| | | | - Simon Heller
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Mark L Evans
- Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Stephanie A Amiel
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Ulrik Pedersen-Bjergaard
- Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bastiaan E de Galan
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands
- Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Centre, Maastricht, the Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands
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22
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIABETOL STOFFWECHS 2022; 17:S133-S144. [DOI: 10.1055/a-1916-2101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Thomas Haak
- Diabetes-Klinik Bad Mergentheim, Bad Mergentheim, Deutschland
| | - Stefan Gölz
- Diabetesschwerpunktpraxis Esslingen, Esslingen, Deutschland
| | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Deutschland
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen, Deutschland
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Flatt AJ, Chen E, Peleckis AJ, Dalton-Bakes C, Nguyen HL, Collins HW, Millar JS, Gallop RJ, Rickels MR. Evaluation of Clinical Metrics for Identifying Defective Physiologic Responses to Hypoglycemia in Long-Standing Type 1 Diabetes. Diabetes Technol Ther 2022; 24:737-748. [PMID: 35758724 PMCID: PMC9529296 DOI: 10.1089/dia.2022.0103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Repeated hypoglycemia exposure leads to impaired awareness of hypoglycemia (IAH) and the development of defective counterregulatory responses. To date, only pancreas or islet transplantation has demonstrated normalization of hypoglycemia awareness and the endogenous glucose production (EGP) response to defend against insulin-induced hypoglycemia in long-standing type 1 diabetes (T1D). This study aims to validate clinical metrics of IAH (Clarke score), hypoglycemia severity (HYPO score), glycemic lability (lability index), and continuous glucose monitoring (CGM) as predictors of absent autonomic symptom (AS) recognition and defective glucose counterregulation during insulin-induced hypoglycemia, thus enabling early identification of individuals with compromised physiologic defense against clinically significant hypoglycemia. Forty-three subjects with mean ± standard deviation age 43 ± 13 years and T1D duration 28 ± 13 years, including 32 with IAH and 11 with hypoglycemia awareness (Aware), and 12 nondiabetic control subjects, underwent single-blinded randomized-paired hyperinsulinemic-euglycemic and hypoglycemic clamp experiments. Receiver operating characteristic (ROC) curves and sensitivity analyses were performed to assess metric prediction of absent AS recognition and defective EGP responses to hypoglycemia. Clarke score and CGM measures of hypoglycemia exposure demonstrated good ability to predict absent AS recognition (area under the curve ≥0.80). A composite threshold of IAH-Clarke ≥4 with ROC curve-derived thresholds for CGM measures of hypoglycemia exposure showed high specificity and predictive value in identifying an absent AS response during the hypoglycemic clamp. Metrics demonstrated poor ability to predict defective glucose counterregulation by the EGP response, which was impaired even in the Aware group. Screening for IAH alongside assessment of CGM data can increase the specificity for identifying individuals with absent hypoglycemia symptom recognition who may benefit from further intervention.
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Affiliation(s)
- Anneliese J. Flatt
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Elizabeth Chen
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Amy J. Peleckis
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Cornelia Dalton-Bakes
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Huong-Lan Nguyen
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Heather W. Collins
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - John S. Millar
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Robert J. Gallop
- Department of Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, Pennsylvania, USA
| | - Michael R. Rickels
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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24
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Koeneman M, Olde Bekkink M, van Meijel L, Bredie S, de Galan B. Effect of Hypoglycemia on Heart Rate Variability in People with Type 1 Diabetes and Impaired Awareness of Hypoglycemia. J Diabetes Sci Technol 2022; 16:1144-1149. [PMID: 33855894 PMCID: PMC9445333 DOI: 10.1177/19322968211007485] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND People with impaired awareness of hypoglycemia (IAH) are at elevated risk of severe, potentially hazardous, hypoglycemia and would benefit from a device alerting to hypoglycemia. Heart rate variability (HRV) changes with hypoglycemia due to sympathetic activity. Since IAH is associated with suppressed sympathetic activity, we investigated whether hypoglycemia elicits a measurable change in HRV in patients with T1D and IAH. METHOD Eligible participants underwent a modified hyperinsulinemic euglycemic hypoglycemic clamp (glucose nadir, 43.1 ± 0.90 mg/dl), while HRV was measured by a VitalConnect HealthPatch. Measurements of HRV included Root Mean Square of the Successive Differences (RMSSD) and low to high frequency (LF:HF) ratio. Wilcoxon rank-sum test was used for testing within-subject HRV changes. RESULTS We included 12 participants (8 female, mean age 57 ± 12 years, mean HbA1c 57 ± 5 mmol/mol (7.4 ± 0.4%)). Symptoms increased from 4.0 (1.5-7.0) at euglycemia to 7.5 (5.0-11.0) during hypoglycemia (P = .003). In response to hypoglycemia, the LF:HF ratio and RMSSD increased when normalized for data obtained during euglycemia (both P < .01). The LF:HF ratio increased in 6 participants (50%) and declined in one other participant (8%). The RMSSD decreased in 3 (25%) and increased in 4 (33%) participants. In 2 patients, no change in HRV could be detected in response to hypoglycemia. CONCLUSIONS This study reveals that hypoglycemia-induced changes in HRV are retained in the majority of people with T1D and IAH, and that these changes can be detected by a wearable device. Real-time HRV seems usable for detection of hypoglycemia in patients with IAH.
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Affiliation(s)
- Mats Koeneman
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- REshape Innovation Center, Radboud University Medical Center, Nijmegen, The Netherlands
- Mats Koeneman, Radboud University Medical Center, Geert Grooteplein Zuid 10, P.O. Box 9101, Nijmegen, 6500 HB, The Netherlands.
| | - Marleen Olde Bekkink
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lian van Meijel
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sebastian Bredie
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- REshape Innovation Center, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bastiaan de Galan
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
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25
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Kröger J. Hypoglykämische Notfälle. DIE DIABETOLOGIE 2022; 18:716-725. [DOI: 10.1007/s11428-022-00941-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/12/2022] [Indexed: 01/06/2025]
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26
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Hermanns N, Ehrmann D, Heinemann L, Freckmann G, Waldenmaier D, Calhoun P. Real-Time Continuous Glucose Monitoring Can Predict Severe Hypoglycemia in People with Type 1 Diabetes: Combined Analysis of the HypoDE and DIAMOND Trials. Diabetes Technol Ther 2022; 24:603-610. [PMID: 35604794 DOI: 10.1089/dia.2022.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Objective: We combined data from two landmark trials (DIAMOND and HypoDE) to examine the diagnostic performance of low glucose measurements derived from open and masked continuous glucose monitoring (CGM) to predict the occurrence of future severe hypoglycemia (SH). Methods: We analyzed hypoglycemia parameters (low blood glucose index [LBGI], % <70 mg/dL, 54-69 mg/dL [level 1 hypoglycemia] and <54 mg/dL [level 2 hypoglycemia]) from masked CGM over 14 days during baseline and from open CGM over 14 days after randomization. We used receiver operating characteristics (ROC) curves to evaluate the screening performance of these measures to predict future SH. Positive likelihood ratios were calculated to indicate the overall diagnostic performance of these parameters. Results: Data from 288 individuals with type 1 diabetes (mean age 45.6 ± 12.8 years, diabetes duration 20.7 ± 13.7 years, HbA1c 8.2% ± 1.0%, Hypoglycemia Unawareness Score 3.4 ± 2.1) were analyzed. Area under ROC-curve (AUC) for LBGI and % <70 mg/dL ranged between 0.68 and 0.75, indicating that LBGI and % <70 mg/dL could significantly predict future SH. Significance of AUC regarding % <54 mg/dL were mixed (0.63-0.72). Positive and negative likelihood ratios ranged between 1.82 to 3.40 and 0.56 to 0.32, respectively. Suggested optimal cutoff values were remarkedly lower in open CGM than in masked CGM. Conclusion: These results indicate that CGM-derived hypoglycemic parameters have a good screening performance to significantly predict future clinical hypoglycemia. In addition, this analysis suggests that cutoff values to indicate elevated hypoglycemia risk in the future are substantially lower in open CGM than in masked CGM. ClinicalTrials.gov registration numbers: HypoDE: NCT02671968. DIAMOND: NCT02282397.
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Affiliation(s)
- Norbert Hermanns
- Research Institute Diabetes Academy Mergentheim (FIDAM), Bad Mergentheim, Germany
- Department of Clinical Psychology and Psychotherapy, University of Bamberg, Bamberg, Germany
| | - Dominic Ehrmann
- Research Institute Diabetes Academy Mergentheim (FIDAM), Bad Mergentheim, Germany
- Department of Clinical Psychology and Psychotherapy, University of Bamberg, Bamberg, Germany
| | | | - Guido Freckmann
- Institut für Diabetes-Technologie, Forschungs-und Entwicklungsgesellschaft mbH an der Universität Ulm, Ulm, Germany
| | - Delia Waldenmaier
- Institut für Diabetes-Technologie, Forschungs-und Entwicklungsgesellschaft mbH an der Universität Ulm, Ulm, Germany
| | - Peter Calhoun
- Jaeb Center for Health Research, Tampa, Florida, USA
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Bolli GB, Cheng AYY, Owens DR. Insulin: evolution of insulin formulations and their application in clinical practice over 100 years. Acta Diabetol 2022; 59:1129-1144. [PMID: 35854185 PMCID: PMC9296014 DOI: 10.1007/s00592-022-01938-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 07/01/2022] [Indexed: 11/22/2022]
Abstract
The first preparation of insulin extracted from a pancreas and made suitable for use in humans after purification was achieved 100 years ago in Toronto, an epoch-making achievement, which has ultimately provided a life-giving treatment for millions of people worldwide. The earliest animal-derived formulations were short-acting and contained many impurities that caused adverse reactions, thereby limiting their therapeutic potential. However, since then, insulin production and purification improved with enhanced technologies, along with a full understanding of the insulin molecule structure. The availability of radio-immunoassays contributed to the unravelling of the physiology of glucose homeostasis, ultimately leading to the adoption of rational models of insulin replacement. The introduction of recombinant DNA technologies has since resulted in the era of both rapid- and long-acting human insulin analogues administered via the subcutaneous route which better mimic the physiology of insulin secretion, leading to the modern basal-bolus regimen. These advances, in combination with improved education and technologies for glucose monitoring, enable people with diabetes to better meet individual glycaemic goals with a lower risk of hypoglycaemia. While the prevalence of diabetes continues to rise globally, it is important to recognise the scientific endeavour that has led to insulin remaining the cornerstone of diabetes management, on the centenary of its first successful use in humans.
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Bisgaard Bengtsen M, Møller N. Review: experimentally induced hypoglycemia-associated autonomic failure in humans: determinants, designs and drawbacks. J Endocr Soc 2022; 6:bvac123. [PMID: 36042977 PMCID: PMC9419494 DOI: 10.1210/jendso/bvac123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Indexed: 11/19/2022] Open
Abstract
Context Iatrogenic hypoglycemia remains one of the leading hindrances of optimal glycemic management in insulin-treated diabetes. Recurring hypoglycemia leads to a condition of hypoglycemia-associated autonomic failure (HAAF). HAAF refers to a combination of (i) impaired hormonal counterregulatory responses and (ii) hypoglycemia unawareness to subsequent hypoglycemia, substantially increasing the risk of severe hypoglycemia. Several studies since the 1990s have experimentally induced HAAF, yielding variable results. Objective The aim of this review was to assess the varying designs, clinical outcomes, potential assets, and drawbacks related to these studies. Method A systemic literature search was conducted on PubMed and Embase in winter 2021 to include all human studies attempting to experimentally induce HAAF. In different combinations, the search terms used were “hypoglycemia-associated autonomic failure,” “HAAF,” “hypoglycemia,” “recurring,” “recurrent,” “repeated,” “consecutive,” and “unawareness,” yielding 1565 publications. Inclusion criteria were studies that had aimed at experimentally inducing HAAF and measuring outcomes of hormonal counterregulation and awareness of hypoglycemia. Results The literature search yielded 27 eligible publications, of which 20 were successful in inducing HAAF while statistical significantly impairing both hormonal counterregulation and impairing awareness of hypoglycemia to subsequent hypoglycemia. Several factors were of significance as regards inducing HAAF: Foremost, the duration of antecedent hypoglycemia should be at least 90 minutes and blood glucose should be maintained below 3.4 mmol/L. Other important factors to consider are the type of participants, insulin dosage, and the risk of unintended hypoglycemia prior to the study. Conclusion Here we have outlined the most important factors to take into consideration when designing a study aimed at inducing HAAF, including to take into consideration other disease states susceptible to hypoglycemia, thus hopefully clarifying the field and allowing qualified studies in the future.
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Affiliation(s)
| | - Niels Møller
- Department of Endocrinology and Internal Medicine , Aarhus University Hospital, Denmark
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29
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Sharifi Y, Ebrahimpur M, Tamehrizadeh SS. Hypoglycemic unawareness: challenges, triggers, and recommendations in patients with hypoglycemic unawareness: a case report. J Med Case Rep 2022; 16:283. [PMID: 35858952 PMCID: PMC9301883 DOI: 10.1186/s13256-022-03498-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 06/14/2022] [Indexed: 11/24/2022] Open
Abstract
Background Hypoglycemia is a fairly common complication in diabetic patients, particularly in those on insulin therapy. Hypoglycemia symptoms are classified into two types: autonomic and neuroglycopenic symptoms. If a person develops neuroglycopenic symptoms before the appearance of autonomic symptoms or is asymptomatic until blood sugar levels are very low, the patient will develop hypoglycemic unawareness (HU). Case presentation A 25-year-old Iranian woman with HU presented with a severe hypoglycemic episode. This episode was characterized by loss of consciousness and focal neural deficits, which were unusual symptoms in the patient, who was a medical intern with type 1 diabetes and currently being treated with regular and NPH insulin. Conclusions Hypoglycemia is a common complication in diabetic patients receiving oral or insulin therapy. A patient who is unaware of their condition may experience severe and potentially fatal episodes. These incidents can negatively affect their daily lives as well as their careers and jobs. Hypoglycemia-associated autonomic failure is a possible cause for patients with multiple episodes of severe hypoglycemia. IThe use of a continuous glucose monitoring device with an alarm, if available, can be an excellent option for these patients.
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Affiliation(s)
- Yasaman Sharifi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, First Floor, No 10, Jalal-Al-Ahmad Street, North Kargar Avenue, Tehran, 14117-13137, Iran. .,Radiology Department, Iran University of Medical Sciences, Tehran, Iran.
| | - Mahbube Ebrahimpur
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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30
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DIE DIABETOLOGIE 2022; 18:612-622. [DOI: 10.1007/s11428-022-00920-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/17/2022] [Indexed: 01/06/2025]
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31
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Tak S, Jain A. Severe hypoglycemia and cardiovascular disease. CURRENT OPINION IN ENDOCRINE AND METABOLIC RESEARCH 2022; 24:100357. [DOI: 10.1016/j.coemr.2022.100357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapy of Type 1 Diabetes. Exp Clin Endocrinol Diabetes 2022; 130:S39-S48. [PMID: 35373309 DOI: 10.1055/a-1624-3340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
| | | | - Andreas Fritsche
- Department of Internal Medicine IV, University Hospital, Tübingen, Germany
| | | | - Thorsten Siegmund
- Diabetes, Hormones and Metabolism Centre, Private Practice at the Isar Hospital, Munich, Germany
| | | | - Harald H Klein
- Department of Endocrinology and Diabetes, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany
| | - Til Uebel
- prima-diab Practice Dres. Uebel, Ittlingen, Germany
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Chacko E. Minimizing Hypoglycemia Using a Five-Step Diabetes Management Program. Clin Diabetes 2022; 40:233-239. [PMID: 35669304 PMCID: PMC9160533 DOI: 10.2337/cd21-0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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34
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Chow EYK, Heller S. Hypoglycaemia in Diabetes. ENDOCRINOLOGY AND DIABETES 2022:375-386. [DOI: 10.1007/978-3-030-90684-9_35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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35
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Hoffman EG, Jahangiriesmaili M, Mandel ER, Greenberg C, Aiken J, D’Souza NC, Pasieka A, Teich T, Chan O, Liggins R, Riddell MC. Somatostatin Receptor Antagonism Reverses Glucagon Counterregulatory Failure in Recurrently Hypoglycemic Male Rats. Endocrinology 2021; 162:6363563. [PMID: 34477204 PMCID: PMC8482965 DOI: 10.1210/endocr/bqab189] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Indexed: 12/12/2022]
Abstract
Recent antecedent hypoglycemia is a known source of defective glucose counter-regulation in diabetes; the mechanisms perpetuating the cycle of progressive α-cell failure and recurrent hypoglycemia remain unknown. Somatostatin has been shown to suppress the glucagon response to acute hypoglycemia in rodent models of type 1 diabetes. We hypothesized that somatostatin receptor 2 antagonism (SSTR2a) would restore glucagon counterregulation and delay the onset of insulin-induced hypoglycemia in recurrently hypoglycemic, nondiabetic male rats. Healthy, male, Sprague-Dawley rats (n = 39) received bolus injections of insulin (10 U/kg, 8 U/kg, 5 U/kg) on 3 consecutive days to induce hypoglycemia. On day 4, animals were then treated with SSTR2a (10 mg/kg; n = 17) or vehicle (n = 12) 1 hour prior to the induction of hypoglycemia using insulin (5 U/kg). Plasma glucagon level during hypoglycemia was ~30% lower on day 3 (150 ± 75 pg/mL; P < .01), and 68% lower on day 4 in the vehicle group (70 ± 52 pg/mL; P < .001) compared with day 1 (219 ± 99 pg/mL). On day 4, SSTR2a prolonged euglycemia by 25 ± 5 minutes (P < .05) and restored the plasma glucagon response to hypoglycemia. Hepatic glycogen content of SSTR2a-treated rats was 35% lower than vehicle controls after hypoglycemia induction on day 4 (vehicle: 20 ± 7.0 vs SSTR2a: 13 ± 4.4 µmol/g; P < .01). SSTR2a treatment reverses the cumulative glucagon deficit resulting from 3 days of antecedent hypoglycemia in healthy rats. This reversal is associated with decreased hepatic glycogen content and delayed time to hypoglycemic onset. We conclude that recurrent hypoglycemia produces glucagon counterregulatory deficiency in healthy male rats, which can be improved by SSTR2a.
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Affiliation(s)
- Emily G Hoffman
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Mahsa Jahangiriesmaili
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Erin R Mandel
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Caylee Greenberg
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Julian Aiken
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Ninoschka C D’Souza
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Aoibhe Pasieka
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Trevor Teich
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
| | - Owen Chan
- Department of Internal Medicine—Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, UT 84112, USA
| | | | - Michael C Riddell
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada
- Correspondence: Michael C. Riddell, PhD, School of Kinesiology and Health Science, Muscle Health Research Centre, York University, 4700 Keele Street, Toronto, ON, Canada, M3J 1P3.
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van Meijel LA, Tack CJ, de Galan BE. Effect of short-term use of dapagliflozin on impaired awareness of hypoglycaemia in people with type 1 diabetes. Diabetes Obes Metab 2021; 23:2582-2589. [PMID: 34338413 PMCID: PMC9292159 DOI: 10.1111/dom.14505] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/11/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
AIM Impaired awareness of hypoglycaemia (IAH) affects about 25% of patients with type 1 diabetes (T1DM). IAH can be reversed by strict avoidance of hypoglycaemia for at least 3 weeks. Adjunctive treatment with sodium glucose cotransporter 2 inhibitors may reduce the risk of hypoglycaemia through reduction of glucose variability. We tested the hypothesis that short-term use of dapagliflozin may improve awareness of hypoglycaemia in people with T1DM and IAH. MATERIALS AND METHODS Fifteen patients with T1DM and IAH were included in this randomized double-blind, placebo-controlled cross-over trial (age 49.7 ± 14.6 years, 40% men, disease duration 24.1 ± 14.2 years, glycated haemoglobin 7.5 ± 0.8% (58.6 ± 8.4 mmol/mol). They were treated with dapagliflozin 10 mg once daily or matching placebo, with a washout period of 2 weeks. At the end of each treatment period, participants underwent a modified hyperinsulinaemic normoglycaemic-hypoglycaemic glucose clamp (glucose nadir 2.5 mmol/L). Blinded continuous glucose monitors were used in the final treatment weeks. RESULTS Treatment with dapagliflozin significantly improved glycated haemoglobin [-0.32 ± 0.10 vs. 0.22 ± 0.13% (-4.1 ± 0.9 vs. 2.3 ± 1.4 mmol/mol), dapagliflozin vs. placebo, p = .007] and glucose variability (standard deviation, 2.6 ± 0.2 vs. 3.1 ± 0.3 mmol/L, p = .029), but did not affect the frequency of hypoglycaemia. During the hypoglycaemic clamp, dapagliflozin did not affect symptom responses (8.0 ± 3.4 vs. 5.2 ± 1.6, p = .31), but significantly reduced the need for exogenous glucose to maintain hypoglycaemia (3.2 ± 0.3 vs. 4.1 ± 0.4 mg/kg/min, p = .022). CONCLUSIONS Eight weeks of treatment with dapagliflozin did not restore hypoglycaemic awareness in people with T1DM and impaired awareness of hypoglycaemia, but ameliorated some clinical aspects.
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Affiliation(s)
- Lian A. van Meijel
- Department of Internal MedicineRadboud University Medical CenterNijmegenThe Netherlands
- Department of Internal MedicineMaxima Medical CenterVeldhovenThe Netherlands
| | - Cees J. Tack
- Department of Internal MedicineRadboud University Medical CenterNijmegenThe Netherlands
| | - Bastiaan E. de Galan
- Department of Internal MedicineRadboud University Medical CenterNijmegenThe Netherlands
- Department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
- CARIM School for Cardiovascular DiseasesMaastricht UniversityMaastrichtThe Netherlands
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes – Kurzfassung der S3-Leitlinie (AWMF-Registernummer: 057-013; 2. Auflage). DIABETOL STOFFWECHS 2021. [DOI: 10.1055/a-1515-8682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
| | | | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen
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Porcellati F, Di Mauro S, Mazzieri A, Scamporrino A, Filippello A, De Fano M, Fanelli CG, Purrello F, Malaguarnera R, Piro S. Glucagon as a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin? Biomolecules 2021; 11:biom11091281. [PMID: 34572493 PMCID: PMC8464883 DOI: 10.3390/biom11091281] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently with respect to past years. Novel scientific evidence leads to advances concerning physiopathological mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the important aspects of this field.
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Affiliation(s)
- Francesca Porcellati
- Department of Medicine and Surgery, Perugia University School of Medicine, Via Gambuli 1, 06126 Perugia, Italy; (F.P.); (A.M.); (M.D.F.); (C.G.F.)
| | - Stefania Di Mauro
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; (S.D.M.); (A.S.); (A.F.); (F.P.); (S.P.)
| | - Alessio Mazzieri
- Department of Medicine and Surgery, Perugia University School of Medicine, Via Gambuli 1, 06126 Perugia, Italy; (F.P.); (A.M.); (M.D.F.); (C.G.F.)
| | - Alessandra Scamporrino
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; (S.D.M.); (A.S.); (A.F.); (F.P.); (S.P.)
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; (S.D.M.); (A.S.); (A.F.); (F.P.); (S.P.)
| | - Michelantonio De Fano
- Department of Medicine and Surgery, Perugia University School of Medicine, Via Gambuli 1, 06126 Perugia, Italy; (F.P.); (A.M.); (M.D.F.); (C.G.F.)
| | - Carmine Giuseppe Fanelli
- Department of Medicine and Surgery, Perugia University School of Medicine, Via Gambuli 1, 06126 Perugia, Italy; (F.P.); (A.M.); (M.D.F.); (C.G.F.)
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; (S.D.M.); (A.S.); (A.F.); (F.P.); (S.P.)
| | - Roberta Malaguarnera
- Faculty of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy
- Correspondence: ; Tel.: +39-0935-536577
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; (S.D.M.); (A.S.); (A.F.); (F.P.); (S.P.)
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Muradoğlu S, Yeşiltepe Mutlu G, Gökçe T, Can E, Hatun Ş. An Evaluation of Glucagon Injection Anxiety and Its Association with the Fear of Hypoglycemia among the Parents of Children with Type 1 Diabetes. J Clin Res Pediatr Endocrinol 2021; 13:285-292. [PMID: 33491925 DOI: 10.1007/978-3-030-67455-7_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
Abstract
OBJECTIVE Hypoglycemia is a common acute complication of type 1 diabetes (T1D), which may cause seizure, loss of consciousness, and temporary motor or sensory impairment. Glucagon administration is an effective way of treating severe hypoglycemia, especially in a free-living setting. Nonetheless, families have difficulties in managing severe hypoglycemia due to their anxiety and challenges with current glucagon administration techniques. The aim of the current study was to explore the associations between parental fear of hypoglycemia (FoH) and their general anxiety level, and in particular, their attitudes towards and thoughts on glucagon administration. METHODS Parents of children with T1D completed questionnaires assessing background and clinical information, FoH, generalized anxiety disorder (GAD) and parental anxiety for glucagon administration (PAGA). RESULTS Sixty-eight parents participated. Positive correlations were found between parental GAD-7 score and both FoH and the number of night-time blood glucose measurements and there was a negative correlation with the child’s age. Parents mean self-evaluation score of their competence in glucagon administration was 6 (standard deviation±2.9) on a scale of 0 to 10. Unsurprisingly, this score was negatively correlated with the PAGA scores. There was no significant difference between children using continuous glucose monitoring system and self-monitoring of blood glucose in terms of parental FoH, anxiety and misconceptions about glucagon administration. CONCLUSION The results showed that parents of children with T1D had anxiety and fear connected with hypoglycemia and glucagon administration. Structured and practical training should be implemented to increase parents’ self-confidence including annual refresher training for home glucagon administration.
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Affiliation(s)
- Serra Muradoğlu
- Koç University Faculty of Medicine, Department of Pediatric Endocrinology and Diabetes, İstanbul, Turkey
| | - Gül Yeşiltepe Mutlu
- Koç University Faculty of Medicine, Department of Pediatric Endocrinology and Diabetes, İstanbul, Turkey
| | - Tuğba Gökçe
- Koç University Faculty of Medicine, Department of Pediatric Endocrinology and Diabetes, İstanbul, Turkey
| | - Ecem Can
- Koç University Faculty of Medicine, Department of Pediatric Endocrinology and Diabetes, İstanbul, Turkey
| | - Şükrü Hatun
- Koç University Faculty of Medicine, Department of Pediatric Endocrinology and Diabetes, İstanbul, Turkey
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Matus A, Trout KK, Sawyer AM, Riegel B. Sleep and hypoglycaemia symptom perception in adults with type-1 diabetes mellitus: A mixed-methods review. J Adv Nurs 2021; 78:14-25. [PMID: 34212428 DOI: 10.1111/jan.14947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/19/2021] [Accepted: 06/15/2021] [Indexed: 11/30/2022]
Abstract
AIMS The study aims to review, synthesize and integrate primary research on the relationship between sleep and hypoglycaemia symptom perception in adults with type-1 diabetes. DESIGN This mixed-methods review follows a convergent segregated approach to synthesis and integration of qualitative and quantitative evidence. DATA SOURCES With assistance of a biomedical librarian, a search of four databases was conducted (PubMed, CINAHL, Embase and PsycINFO) in June 2020. The review included primary research measuring sleep and hypoglycaemia symptom perception in adults (age ≥ 18 years) with type-1 diabetes in English. Studies that exclusively addressed children, type-2 diabetes or outcomes unrelated to sleep and hypoglycaemia symptom perception were excluded. REVIEW METHODS Screening focused on title and abstract review (n = 624). Studies not excluded after screening (n = 35) underwent full-text review. References of each study selected for inclusion (n = 6) were hand searched with one study added. All studies included in the review (n = 7) were critically appraised with JBI Critical Appraisal tools, and then data were extracted with systematic evaluation. RESULTS Quantitative synthesis found sleep reduces the magnitude of detectable symptoms and one's capacity to detect them. Qualitative synthesis found that individuals with type-1 diabetes perceive unpredictable severity, frequency and awareness of symptoms while asleep as an oppressive, lingering threat. Integration of findings highlights the troublesome duality of sleep's relationship with hypoglycaemia symptom perception. CONCLUSIONS Sleep presents a challenging time for individuals with type-1 diabetes. Further research examining the relationship between sleep and hypoglycaemia symptom perception is recommended as the number of studies limits this review. IMPACT Symptom perception is the main physiologic defense against severe hypoglycaemia in type-1 diabetes. This review found that sleep's relationship with hypoglycaemia symptoms has unique physiological and psychological components to address when providing comprehensive care. This review may inform future lines of inquiry that develop into interventions, improvements in practice and risk reduction for hypoglycaemia-related complications.
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Affiliation(s)
- Austin Matus
- School of Nursing, University of Pennsylvania, Philadelphia, PA, USA
| | - Kimberly K Trout
- School of Nursing, University of Pennsylvania, Philadelphia, PA, USA
| | - Amy M Sawyer
- School of Nursing, University of Pennsylvania, Philadelphia, PA, USA
| | - Barbara Riegel
- School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.,Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia.,International Center for Self-Care Research, Australian Catholic University, Melbourne, Victoria, Australia
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41
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Burckhardt MA, Abraham MB, Dart J, Smith GJ, Paramalingam N, O'Dea J, de Bock M, Davis EA, Jones TW. Impact of Hybrid Closed Loop Therapy on Hypoglycemia Awareness in Individuals with Type 1 Diabetes and Impaired Hypoglycemia Awareness. Diabetes Technol Ther 2021; 23:482-490. [PMID: 33555982 DOI: 10.1089/dia.2020.0593] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Objective: This study evaluated the efficacy of using a hybrid closed loop (HCL) system in restoring hypoglycemia awareness in individuals with impaired awareness of hypoglycemia (IAH). Research Design and Methods: Participants with IAH (Gold score ≥4) were recruited into a randomized crossover pilot study. They participated in two 8-week periods using a HCL system (Medtronic 670G™) (intervention) and standard insulin pump therapy (control). Hyperinsulinemic hypoglycemic clamp studies were undertaken at baseline and at the end of each study period for the evaluation of the counter-regulatory hormonal and symptomatic responses to hypoglycemia. Results: Seventeen participants (mean age [standard deviation] 35.8 years [11.2 years]) were included in the study. Peak epinephrine levels (median, interquartile range [IQR]) in response to hypoglycemia were similar postintervention and control periods; 234.7 pmol/L (109.2; 938.9) versus 188.3 pmol/L (133.7; 402.9), P = 0.233. However, both peak adrenergic and neuroglycopenic symptom scores were higher after intervention; 5.0 (4.5; 9.0) versus 4.0 (4.0; 5.5), P = 0.009, and 8.5 (6.0; 15.0) versus 6.5 (6.0; 7.0) P = 0.014, respectively. Self-reported hypoglycemia awareness improved: median (IQR) Gold score was 4.0 (3.0; 5.5) versus 5.5 (4.5; 6.0); intervention versus control, P = 0.033. Time spent <3.9 and <3.0 mmol/L was lower in the intervention group than in control, P = 0.002. Other patient-reported outcomes (hypoglycemia fear and diabetes treatment satisfaction) did not change. Conclusions: A short-term use of a HCL system failed to demonstrate an improvement in counter-regulatory hormonal responses. However, higher hypoglycemia symptom scores during controlled hypoglycemia, better self-reported hypoglycemia awareness, and less time spent in hypoglycemia suggest the potential benefits of a HCL system in people with IAH. Trial Registration: anzctr.org.au Identifier: ACTRN12616000909426.
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Affiliation(s)
- Marie-Anne Burckhardt
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Mary B Abraham
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Julie Dart
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
| | - Grant J Smith
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Nirubasini Paramalingam
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Joanne O'Dea
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Martin de Bock
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Elizabeth A Davis
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Timothy W Jones
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
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Grunberger G, Sherr J, Allende M, Blevins T, Bode B, Handelsman Y, Hellman R, Lajara R, Roberts VL, Rodbard D, Stec C, Unger J. American Association of Clinical Endocrinology Clinical Practice Guideline: The Use of Advanced Technology in the Management of Persons With Diabetes Mellitus. Endocr Pract 2021; 27:505-537. [PMID: 34116789 DOI: 10.1016/j.eprac.2021.04.008] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To provide evidence-based recommendations regarding the use of advanced technology in the management of persons with diabetes mellitus to clinicians, diabetes-care teams, health care professionals, and other stakeholders. METHODS The American Association of Clinical Endocrinology (AACE) conducted literature searches for relevant articles published from 2012 to 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established AACE protocol for guideline development. MAIN OUTCOME MEASURES Primary outcomes of interest included hemoglobin A1C, rates and severity of hypoglycemia, time in range, time above range, and time below range. RESULTS This guideline includes 37 evidence-based clinical practice recommendations for advanced diabetes technology and contains 357 citations that inform the evidence base. RECOMMENDATIONS Evidence-based recommendations were developed regarding the efficacy and safety of devices for the management of persons with diabetes mellitus, metrics used to aide with the assessment of advanced diabetes technology, and standards for the implementation of this technology. CONCLUSIONS Advanced diabetes technology can assist persons with diabetes to safely and effectively achieve glycemic targets, improve quality of life, add greater convenience, potentially reduce burden of care, and offer a personalized approach to self-management. Furthermore, diabetes technology can improve the efficiency and effectiveness of clinical decision-making. Successful integration of these technologies into care requires knowledge about the functionality of devices in this rapidly changing field. This information will allow health care professionals to provide necessary education and training to persons accessing these treatments and have the required expertise to interpret data and make appropriate treatment adjustments.
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Affiliation(s)
| | - Jennifer Sherr
- Yale University School of Medicine, New Haven, Connecticut
| | - Myriam Allende
- University of Puerto Rico School of Medicine, San Juan, Puerto Rico
| | | | - Bruce Bode
- Atlanta Diabetes Associates, Atlanta, Georgia
| | | | - Richard Hellman
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | | | | | - David Rodbard
- Biomedical Informatics Consultants, LLC, Potomac, Maryland
| | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | - Jeff Unger
- Unger Primary Care Concierge Medical Group, Rancho Cucamonga, California
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43
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes. DER DIABETOLOGE 2021; 17:411-421. [DOI: 10.1007/s11428-021-00764-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/14/2021] [Indexed: 01/06/2025]
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45
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Eik Filho W, Wanczinski Ferrari BJ, Masetto Antunes M, Batista Travassos P, Medri de Souza H, Menezes de Souza E, Barbosa Bazotte R. Glycerol Potentiates the Effects of Glucose in Promoting Glucose Recovery During Hypoglycemia: From Basic to Clinical Investigations and Their Therapeutic Application. J Med Food 2020; 24:908-915. [PMID: 33297841 DOI: 10.1089/jmf.2020.0126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We compared the effect of oral glucose versus oral glucose combined with glycerol (glucose + glycerol) in promoting glucose recovery during hypoglycemia. These studies were carried out in two series of experiments. In the first series of experiments, 16 overnight fasted rats received an intraperitoneal injection of lispro insulin (1 IU/kg), and 25 min later, they received oral water (control), glucose (0.25 g/kg), glycerol (2.5 g/kg), or glucose (0.25 g/kg) + glycerol (2.5 g/kg). In the second series of experiments on 164 eligible type 1 diabetic (T1D) patients, 30 individuals with a history of hypoglycemia were recruited. Five volunteers did not meet the inclusion criteria and two subjects were excluded after starting the clinical investigation; 23 patients concluded the study. All patients with symptoms of hypoglycemia ingested oral glucose (15 g) or glucose (15 g) + glycerol (9.45 g). To treat hypoglycemia in T1D patients, preparations containing glucose alone or glucose + glycerol were used alternately (2 weeks/2 weeks) in a double-blind crossover scheme. Throughout the clinical research (4 weeks), glucose concentrations were assessed with a continuous glucose monitoring device and the results after the use of glucose alone or glucose + glycerol preparations were compared. Oral glucose combined with glycerol was more effective in promoting glucose recovery in comparison with glucose alone, not only in rats but also in T1D patients. Taken together, our experimental and clinical investigations reported the best performance of oral administration of glucose + glycerol in comparison with isolated glucose.
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Affiliation(s)
- Wilson Eik Filho
- Department of Medicine, Endocrinology Unit, State University of Maringá, Maringá, Paraná, Brazil
| | | | - Marina Masetto Antunes
- Post-Graduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Paraná, Brazil
| | | | - Helenir Medri de Souza
- Department of Physiological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Eniuce Menezes de Souza
- Post-Graduate Program in Biostatistics, State University of Maringá, Maringá, Paraná, Brazil
| | - Roberto Barbosa Bazotte
- Post-Graduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Paraná, Brazil.,Post-Graduate Program in Biological Sciences, State University of Maringá, Maringá, Paraná, Brazil.,Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná, Brazil
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46
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Gilor C, Duesberg C, Elliott DA, Feldman EC, Mundinger TO, Taborsky GJ, Nelson RW, Havel PJ. Co-impairment of autonomic and glucagon responses to insulin-induced hypoglycemia in dogs with naturally occurring insulin-dependent diabetes mellitus. Am J Physiol Endocrinol Metab 2020; 319:E1074-E1083. [PMID: 33044845 PMCID: PMC7792666 DOI: 10.1152/ajpendo.00379.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
This study aimed to investigate the contributions of two factors potentially impairing glucagon response to insulin-induced hypoglycemia (IIH) in insulin-deficient diabetes: 1) loss of paracrine disinhibition by intra-islet insulin and 2) defects in the activation of the autonomic inputs to the islet. Plasma glucagon responses during hyperinsulinemic-hypoglycemic clamps ([Formula: see text]40 mg/dL) were assessed in dogs with spontaneous diabetes (n = 13) and in healthy nondiabetic dogs (n = 6). Plasma C-peptide responses to intravenous glucagon were measured to assess endogenous insulin secretion. Plasma pancreatic polypeptide, epinephrine, and norepinephrine were measured as indices of parasympathetic and sympathoadrenal autonomic responses to IIH. In 8 of the 13 diabetic dogs, glucagon did not increase during IIH (diabetic nonresponder [DMN]; ∆ = -6 ± 12 pg/mL). In five other diabetic dogs (diabetic responder [DMR]), glucagon responses (∆ = +26 ± 12) were within the range of nondiabetic control dogs (∆ = +27 ± 16 pg/mL). C-peptide responses to intravenous glucagon were absent in diabetic dogs. Activation of all three autonomic responses were impaired in DMN dogs but remained intact in DMR dogs. Each of the three autonomic responses to IIH was positively correlated with glucagon responses across the three groups. The study conclusions are as follows: 1) Impairment of glucagon responses in DMN dogs is not due to generalized impairment of α-cell function. 2) Loss of tonic inhibition of glucagon secretion by insulin is not sufficient to produce loss of the glucagon response; impairment of autonomic activation is also required. 3) In dogs with major β-cell function loss, activation of the autonomic inputs is sufficient to mediate an intact glucagon response to IIH.NEW & NOTEWORTHY In dogs with naturally occurring, insulin-dependent (C-peptide negative) diabetes mellitus, impairment of glucagon responses is not due to generalized impairment of α-cell function. Loss of tonic inhibition of glucagon secretion by insulin is not sufficient, by itself, to produce loss of the glucagon response. Rather, impaired activation of the parasympathetic and sympathoadrenal autonomic inputs to the pancreas is also required. Activation of the autonomic inputs to the pancreas is sufficient to mediate an intact glucagon response to insulin-induced hypoglycemia in dogs with naturally occurring diabetes mellitus. These results have important implications that include leading to a greater understanding and insight into the pathophysiology, prevention, and treatment of hypoglycemia during insulin treatment of diabetes in companion dogs and in human patients.
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Affiliation(s)
- Chen Gilor
- Department of Veterinary Medicine and Epidemiology, University of California, Davis, California
- Department of Small Animal Clinical Sciences, University of Florida, Gainesville, Florida
| | - Cynthia Duesberg
- Department of Veterinary Medicine and Epidemiology, University of California, Davis, California
| | - Denise A Elliott
- Department of Veterinary Medicine and Epidemiology, University of California, Davis, California
| | - Edward C Feldman
- Department of Veterinary Medicine and Epidemiology, University of California, Davis, California
| | | | - Gerald J Taborsky
- Department of Medicine, University of Washington, Seattle, Washington
| | - Richard W Nelson
- Department of Veterinary Medicine and Epidemiology, University of California, Davis, California
| | - Peter J Havel
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California
- Department of Nutrition, School of Veterinary Medicine, University of California, Davis, California
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47
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Haak T, Gölz S, Fritsche A, Füchtenbusch M, Siegmund T, Schnellbächer E, Klein HH, Uebel T, Droßel D. Therapie des Typ-1-Diabetes – Kurzfassung der S3-Leitlinie (AWMF-Registernummer: 057-013; 2. Auflage). DIABETOL STOFFWECHS 2020. [DOI: 10.1055/a-1193-3724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
| | | | - Andreas Fritsche
- Innere Medizin IV, Medizinische Klinik, Universitätsklinikum Tübingen
| | | | | | | | - Harald H. Klein
- Medizinische Universitätsklinik I – Allgemeine Innere Medizin, Endokrinologie und Diabetologie, Gastroenterologie und Hepatologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil
| | - Til Uebel
- prima-diab Praxis Dres. Uebel/Nittka/Mayer/Merkle, Ittlingen
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48
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Lin YK, Groat D, Chan O, Hung M, Sharma A, Varner MW, Gouripeddi R, Facelli JC, Fisher SJ. Associations Between the Time in Hypoglycemia and Hypoglycemia Awareness Status in Type 1 Diabetes Patients Using Continuous Glucose Monitoring Systems. Diabetes Technol Ther 2020; 22:787-793. [PMID: 32267773 PMCID: PMC7699009 DOI: 10.1089/dia.2020.0016] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Background: Continuous glucose monitoring (CGM) systems help reduce hypoglycemia in patients with type 1 diabetes (T1D). It remains unclear whether T1D patients with impaired awareness of hypoglycemia (IAH) continue to develop more hypoglycemia than those with normal hypoglycemia awareness (NA) despite CGM use. Materials and Methods: For this cross-sectional observational study, 99 T1D patients using real-time CGMs for ≥86% of time were recruited. Fifty and 49 patients were found to have NA and IAH (based on the Clarke questionnaire), respectively. Two-week CGM hypoglycemia data were collected. Results: IAH was associated with greater percentages of CGM values <70 and <54 mg/dL (P = 0.012, P = 0.004) compared to NA. Clarke scores correlated positively with the percentage of CGM values <70 and <54 mg/dL (P = 0.013, P = 0.004). IAH was also related to more events with glucose <70 and <54 mg/dL determined either with at ≥1 time point (P = 0.048, P = 0.003) or lasting ≥20 min (P = 0.016, P = 0.004). IAH patients presented with more day-time events with glucose <54 mg/dL (P = 0.015), nocturnal events with glucose levels <70 and <54 mg/dL (P = 0.009, P = 0.007) and longer day-time event duration with glucose levels <70 and <54 mg/dL (P < 0.001, P = 0.006), respectively. Conclusions: T1D patients with IAH continue to experience more hypoglycemia despite dedicated CGM use.
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Affiliation(s)
- Yu Kuei Lin
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Danielle Groat
- Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah, USA
| | - Owen Chan
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Man Hung
- Study Design and Biostatistics Center, Center for Clinical and Translational Sciences, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Anu Sharma
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Michael W. Varner
- Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Ramkiran Gouripeddi
- Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah, USA
| | - Julio C. Facelli
- Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah, USA
| | - Simon J. Fisher
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
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49
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Dagogo-Jack S. Role of the HPA Axis in the Metabolic and Baroreflex Components of Hypoglycemia-Associated Autonomic Failure. J Clin Endocrinol Metab 2020; 105:5863390. [PMID: 32589741 PMCID: PMC7425998 DOI: 10.1210/clinem/dgaa391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 06/22/2020] [Indexed: 11/19/2022]
Affiliation(s)
- Sam Dagogo-Jack
- Division of Endocrinology, Diabetes & Metabolism, University of Tennessee Health Science Center, Memphis, TN, US
- Correspondence and Reprint Requests: Sam Dagogo-Jack, MD, DSc, Division of Endocrinology, Diabetes & Metabolism, University of Tennessee Health Science Center, 920 Madison Avenue, Suite 300A, Memphis, TN 38163. E-mail:
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Sepúlveda E, Poínhos R, Nata G, Carvalho D, Neves JS, Seixas D, Choudhary P, Vicente SG, Amiel SA. Differentiating Hypoglycemia Awareness Status from Hypoglycemia Experience in Tools for Measuring Impaired Awareness of Hypoglycemia. Diabetes Technol Ther 2020; 22:541-545. [PMID: 32175769 PMCID: PMC7336879 DOI: 10.1089/dia.2020.0034] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background: Developing technologies in real-time continuous glucose monitoring (CGM) are successfully reducing severe hypoglycemia (SH) in trials and clinical practice. Their impact on impaired awareness of hypoglycemia, a major risk factor for SH, is uncertain. Methods: The present study examined two scales for assessing hypoglycemia awareness status, the Gold score and the eight-item Minimally Modified Clarke Hypoglycemia Survey (MMCHS), commonly used in trials of CGM, in Portuguese-speaking adults with type 1 diabetes and conducted an exploratory factor analysis on MMCHS. Results: A bifactorial structure in MMCHS was revealed, with a clear distinction between items that measure SH experience and those that measure hypoglycemia awareness status. The latter is associated with the same risk for SH as the Gold score. Conclusions: We conclude that improvement in awareness scores by the MMCHS may reflect only a reduction in SH with no restoration of endogenous awareness, making the current literature consistent in evidence that CGM does not improve endogenous awareness and nonsensor supported protection from SH. This has implications for risk of SH when CGM is not being worn.
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Affiliation(s)
- Eduardo Sepúlveda
- Centre for Psychology at University of Porto, Faculty of Psychology and Educational Sciences, University of Porto, Porto, Portugal
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Rui Poínhos
- Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal
| | - Gil Nata
- Centre for Research and Intervention in Education and Centre for Psychology at University of Porto, University of Porto, Porto, Portugal
| | - Davide Carvalho
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - João Sérgio Neves
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar São João, Porto, Portugal
- Unidade de Investigação Cardiovascular, Departamento de Cirurgia e Fisiologia, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Daniela Seixas
- Institute for Biomedical Imaging and Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Pratik Choudhary
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
- King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Selene G. Vicente
- Centre for Psychology at University of Porto, Faculty of Psychology and Educational Sciences, University of Porto, Porto, Portugal
| | - Stephanie A. Amiel
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
- King's College Hospital NHS Foundation Trust, London, United Kingdom
- Address correspondence to: Stephanie A. Amiel, Diabetes Research Offices, King's College London, Weston Education Centre, 10, Cutcombe Road, London SE5 9RJ, United Kingdom
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