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Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross-sectional analysis of baseline data from the PR-IAH study

Diabetology & Metabolic Syndrome volume 15, Article number: 79 (2023) Cite this article

Abstract

Background

Hypoglycemia in type 1 diabetes (T1D) is associated with mortality and morbidity, especially when awareness of hypoglycemia is impaired. This study aimed to investigate the protective and risk factors for impaired awareness of hypoglycemia (IAH) in adults with T1D.

Methods

This cross-sectional study enrolled 288 adults with T1D (mean age, 50.4 ± 14.6 years; male, 36.5%; diabetes duration, 17.6 ± 11.2 years; mean HbA1c level, 7.7 ± 0.9%), who were divided into IAH and non-IAH (control) groups. A survey was conducted to assess hypoglycemia awareness using the Clarke questionnaire. Diabetes histories, complications, fear of hypoglycemia, diabetes distress, hypoglycemia problem-solving abilities, and treatment data were collected.

Results

The prevalence of IAH was 19.1%. Diabetic peripheral neuropathy was associated with an increased risk of IAH (odds ratio [OR] 2.63; 95% confidence interval [CI] 1.13–5.91; P = 0.014), while treatment with continuous subcutaneous insulin infusion and hypoglycemia problem-solving perception scores were associated with a decreased risk of IAH (OR, 0.48; 95% CI, 0.22–0.96; P = 0.030; and OR, 0.54; 95% CI, 0.37–0.78; P = 0.001, respectively). There was no difference in continuous glucose monitoring use between the groups.

Conclusion

We identified protective factors in addition to risk factors for IAH in adults with T1D. This information may help manage problematic hypoglycemia.

Trial registration

University hospital Medical Information Network (UMIN) Center: UMIN000039475). Approval date 13 February 2020.

Background

Adults with type 1 diabetes mellitus (T1D) and impaired awareness of hypoglycemia (IAH) have a reduced ability to perceive hypoglycemic symptoms and are at risk of severe hypoglycemic events because of less than immediate appropriate corrective therapy [1]. Autonomic symptoms are typically lost before general malaise and neuroglycopenic symptoms. Therefore, individuals with IAH may plan to loosen tight glucose management and intentionally omit insulin injection to prevent severe hypoglycemia (SH). In individuals with T1D, IAH is highly prevalent with or without continuous glucose monitoring (CGM) [2]. Although recurrent hypoglycemia [3], diabetic neuropathy [4], longer diabetes duration [5], genetic factors [6], and personality traits of alexithymia and perfectionism [7] are candidate risk factors for IAH, their pathogenesis is still unclear. In individuals with IAH, counter-regulatory responses are blunted to subsequent hypoglycemic episodes due to recurrent mild to moderate hypoglycemia. This is called hypoglycemia-associated autonomic failure, which is a cellular adaptation [8]. It is also unclear which lifestyle factors are associated with the risk of IAH, although antecedent exercise, excessive drinking, psychological stress, and sleep disturbance may induce recurrent hypoglycemia [9, 10]. In contrast, diabetes treatment technologies (e.g. CGM and continuous subcutaneous insulin infusion (CSII)), and hypoglycemia-solving abilities might affect IAH status. Therefore, this study aimed to investigate the protective and risk factors of IAH in adults with T1D.

Materials and methods

This is an exploratory and cross-sectional study, using the STROBE instrument included in reports of cross-sectional studies. The study was approved by the National Hospital Organization (NHO) Central Research Ethics Committee (R2-0117002). Participants and Settings Between February 2020 and March 2022, we enrolled adults with IAH at seven NHO collaborator center in Japan. The inclusion criteria were type 1 diabetes, diabetes duration ≥ 1 year, age ≥ 20 years, and attending a collaborating center. The exclusion criteria were non-insulin therapy, anti-dementia drug use, and inappropriate cases (i.e. difficulties to answer the survey) judged by the research director or coordinators.

Diabetic complications

Treatment of diabetic retinopathy, nephropathy, and peripheral neuropathy was performed by certified diabetologists according to the treatment guidelines for diabetes 2018–2019.

Diabetic retinopathy was assessed by an ophthalmologist using retinal photography. Retinopathy was classified as absent, simple, preproliferative, and proliferative. Diabetic nephropathy was classified as stage 1 to 5 based on the estimated glomerular filtration rate and albuminuria or hemodialysis stage [11]. Diabetic peripheral neuropathy (DPN) was considered present following the criteria after patients were diagnosed with diabetes and excluded polyneuropathy, except diabetic polyneuropathy. DPN was determined to be positive in the presence of ≥ two of the three criteria: (1) subjective neurological symptoms (pain, dysesthesia, or numbness in the bilateral lower extremities); (2) decreased or absent bilateral Achilles tendon reflexes; and (3) diminished bilateral vibratory sensation (hypesthesia) at the malleolus medialis (< 10 s at 128 Hz using a tuning fork) [12]. Coefficient of variation of R-R intervals (CV-RR) was calculated automatically by a computed analyzer that collected 100 R-R intervals and divided the standard deviation by the mean value. CV-RR < 3% was indicative of diabetic cardiac autonomic neuropathy (DCAN) [13]. The mean QTc interval was calculated using Bazett’s formula, and a QTc > 440 ms was considered prolonged [14].Hemoglobin A1c (HbA1c) level, glycated hemoglobin (GA) level, levels of liver enzymes, and lipid profiles were collected from the medical records. Furthermore, the GA/HbA1c ratio, which reflects glucose variability, was calculated by dividing the GA level by the HbA1c level [15].

Impaired awareness of hypoglycemia and hypoglycemic symptoms

The IAH was determined using the Clarke method [16] and a score ≥ 4 implies IAH. Hypoglycemic symptoms were evaluated using the Edinburgh hypoglycemia scale [17, 18]. Self-reported number of SH episodes, defined as “hypoglycemia that you were unable to treat yourself,” in the preceding year was also collected.

Diabetes-related distress and hypoglycemia problem-solving abilities

Distress related diabetes management was assessed using the PAID questionnaire and high score of ≥ 40 points indicates severe distress [19, 20]. The Hypoglycemia Fear Survey (HFS) were used to have a fear of hypoglycemia [21, 22]. The general utility index was calculated using the EuroQoL 5-dimension (EQ-5D) [23, 24]. The hypoglycemia problem-solving scale (HPSS), which has 24 items and seven subscales, was used for hypoglycemia problem-solving ability [25].

Lifestyle factors

Self-administered questionnaires regarding lifestyle factors (exercise, dietary habits, drinking, smoking, and sleep habits) were collected [26], and sleep debt [27] and healthy lifestyle score [28] were calculated.

Sample size

The prevalence of IAH is approximately 20% [29]. Therefore, a minimum sample size of 200 completers (40 participants with IAH and 160 participants without IAH) was needed to achieve an appropriate significance level of 5% and power of 0.8, if the prevalence of IAH of 20% and effect size of 0.5 (medium) were estimated.

Data analyses

Qualitative variables were compared using Fisher’s exact test. Quantitative variables were compared using the t-test or the Mann–Whitney U test. Logistic regression was performed to estimate the odds ratio (OR) with 95% confidence interval (CI). Cronbach’s alpha was calculated to assess the internal consistency. Correlation coefficients (Spearman’s rho, ρ) between the HPSS and psychological distress scales was examined using Spearman’s rank correlation. All P-values < 0.05 indicated significant dependencies. The analysis was conducted using R program version 4.1.2.

Results

Participants

The study was conducted on 288 adults with T1D and IAH (mean age, 50.4 ± 14.6 years; male, 36.5%; diabetes duration, 17.6 ± 11.2 years; mean HbA1c level, 7.7 ± 0.9%), who were divided into control and IAH groups.

Diabetic complications, treatment, lifestyle factors, and laboratory data

DPN was more prevalent in the IAH group than in the control group. Moreover, the prescription rate of mecobalamin was higher in the IAH group than that in the control group. There was no difference in HbA1c levels and other complications, except DPN, between the groups. Treatment with CSII was less prevalent in the IAH group than in the control group, but there was no difference in CGM usage between the groups (Table 1). There was no difference in healthy lifestyle score, sleep debt, and excessive drinking rate between the groups (Table 2). There was no difference in laboratory data, including HbA1c level and GA/HbA1c ratio, between the groups (Table 3).

Table 1 Baseline characteristics of the study participants
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Table 2 Lifestyle factors in adults with T1D with or without IAH
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Table 3 Laboratory data of the study participants
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DPN was associated with an increased risk of IAH (OR, 2.63; 95% CI, 1.13-5.91; P = 0.014), while treatment with CSII was associated with a decreased risk of IAH (OR, 0.48; 95% CI, 0.22-0.96; P = 0.030) (Table 4). There was no difference in CGM usage, CV-RR, and QTc intervals between the groups.

Table 4 Odds ratio of interest variables for IAH in adults with T1D
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Hypoglycemic symptoms, diabetes distress, and hypoglycemia problem-solving abilities

The mean autonomic symptom scores, except for palpitations and hunger in the IAH group compared to the control group, were significantly reduced, while the mean neuroglycopenic symptom scores were relatively lower in the control group than in the IAH group. The scores are shown in (Table 5). The average PAID and HFS-worry scores in the IAH group were significantly higher than those in the control group, and there was no difference in the PHQ-9 and HFS-behavior scores between the groups. The HPSS, composed of 24 items, demonstrated high internal consistency, as reflected by a Cronbach’s alpha coefficient of 0.883. A weak positive correlation of the HPSS score with HFS-B (ρ = 0.331, P<0.001) and HFS-W (ρ = 0.162, P = 0.006) were observed, although no significant correlation of the HPSS with age, HbA1c, PAID and PHQ-9 scores were observed. Hypoglycemia problemsolving perception score of HPSS was associated with a decreased risk of IAH (OR, 0.54; 95% CI, 0.37–0.78; P = 0.001), although there was no difference in the other six subscales between groups.

Table 5 Hypoglycemic symptoms in adults with T1D with or without IAH
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Discussion

This is the first study to identify protective factors (treatment with CSII and higher problem-solving perception) and risk factors (DPN) of IAH in Japanese adults with T1D.

DPN and IAH

Cross-sectional and observational studies have indicated that DPN, cardiac autonomic neuropathy, and gastroparesis are associated with SH [30, 32,33,34, 31]. However, Olsen et al. reported that IAH was not associated with autonomic dysfunction or DPN in adults with T1D[35]. Conversely, Flatt et al. reported that peripheral neuropathy was more prevalent in patients with SH than in patients without SH in the 24-month follow-up of the HypoCOMPASS study (39% vs. 4.7%, respectively) [36]. This discrepancy between the results is unknown. The diagnostic criteria, ethnicity, and differences in the population with diabetes may explain this. Furthermore, the mechanism by which DPN causes IAH remains unclear. CV-RR and abnormality of the QTc interval were not associated with severe hypoglycemic attacks in this study although SH attacks were independently associated with a prolonged QTc interval in 3,248 patients with T1D from the EURODIAB IDDM Complications Study [34]. DPN is associated with cognitive impairments in adults with T1D [37]. In this study, we observed deficits in autonomic symptoms in adults with T1D and IAH. Cognitive impairment may affect the perception of hypoglycemia. In addition, repeated hypoglycemia can cause DPN as reported in animal experiments. Further large and long-standing examinations are required to confirm these issues in the future.

Diabetes-related technologies

In this study, treatment with CSII was less prevalent in adults with T1D and IAH although CGM devices were not associated with an increased risk of IAH. New technologies, including CGM, aim to improve the awareness status of hypoglycemia. However, several studies have suggested that IAH persists even with CGM usage. Reddy et al. reported that rtCGM (Dexcom G5) more effectively reduces time spent in hypoglycemia at 8 weeks compared to isCGM (Abbott Freestyle Libre) in 40 adults with T1D and IAH using a multiple daily injections (MDI) regimen [38]. Moreover, rtCGM systems reduce unawareness of hypoglycemia in children, adolescents, and adults with T1D [39]. Further examinations including rtCGM and large samples are required to confirm these issues because the rtCGM usage rate was low in this study. Conversely, treatment with CSII may be useful in reducing unawareness of hypoglycemia in adults with T1D. The clinical statement for the management of problematic hypoglycemia (2015) recommended structured education, MDI with real-time CGM or CSII, a sensor-augmented pump with or without a low glucose suspension feature, and pancreatic islet transplantation [40]. Observational studies based on these guidelines are needed to confirm these issues in the future.

Limitation of the study

The strength of the study includes a validated self-administered questionnaire. However, our study had some limitations. This study used a cross-sectional study design to make a causal inference. DPN was estimated as presence or absence; therefore, the severity of peripheral neuropathy was not evaluated. Even with more prescription of mecobalamin, that could be a confusing factor because some studies showed a positive contribution on the DPN symptoms [41]. Evaluating the severity of DPN would provide the information on the relation of IAH and mecobalamin treatment with DPN. DCAN was evaluated using the CV-RR in this study. DCAN is an underdiagnosed cardiovascular complication in individuals with diabetes. In an animal model, DCAN was evaluated using histology patterns and cardiac nerve densities. QTc intervals are affected by other factors, such as obesity, arteriosclerotic macroangiopathy, and autonomic [42]. Nerve conduction studies and sympathetic skin responses are reliable methods in detecting DCAN. Furthermore, definite DCAN was defined as ≥ 2 positive cardiac autonomic tests [43]. Further examination, including the definite DCAN method, is required to compare DCAN and IAH status.

Implication for practice

We adopted the Clarke method; however, the prevalence of IAH using the Clarke method is likely to be underestimated according to the CGM data. IAH is prevalent in adults with T1D. Moreover, the diagnosis of DPN is challenging [44, 45]. Careful attention should be paid to diabetes distress and fear of hypoglycemia. We identified protective factors for IAH as treatment with CSII and problem-solving perception of HPSS. CSII improved hypoglycemia awareness in the research setting [40], while CSII use in IAH group was less prevalent in this study. The reason of low prevalence of CSII use in IAH is not clear. Personality or diabetes distress might lower the opportunity to use CSII in this group. We should consider CSII or structured education in adults with T1D and IAH [46]. Problem-solving, which is defined as a self-directed cognitive-behavioral process by which people attempt to cope with a difficult situation, is a behavioral strategy in diabetes management. They refer to a mental process that involves discovering, analyzing, and solving problems. The problem-solving perception factor explained most of the variance between the seven factors. The problem-solving perception subscale consists of four reverse items: discouraged for failure to prevent hypoglycemia, feeling depressed or angry because of difficulties in preventing hypoglycemia, worrying about how to prevent hypoglycemia but have not taken any action, and reduced self-esteem. The intervention based on the HPSP effectively improved HbA1c levels and hypoglycemia problem-solving ability in individuals with hypoglycemia [47]. We should take into account an education program with an increased problem-solving ability of adults with T1D and IAH. This study showed that HPSS scale was easy to use and help adults with T1D and IAH in their life. However, we need to build a multidisciplinary team to educate adults with T1D and IAH using HPSS.

In conclusion, we identified protective factors in addition to risk factors for IAH in Japanese adults with T1D. This information may help manage problematic hypoglycemia. IAH has a complex pathophysiology and might lead to serious and potentially lethal consequences in patients with T1D [48]. A stepwise approach using diabetes-related technologies [49] was needed to educate and treat patients with T1D and IAH in the future.

Abbreviations

CGM:

continuous glucose monitoring

CI:

confidence interval

CSII:

continuous subcutaneous insulin infusion

DCAN:

diabetic cardiac autonomic neuropathy

DPN:

diabetic peripheral neuropathy

HbA1c:

hemoglobin A1c

IAH:

impaired awareness of hypoglycemia

isCGM:

intermittently scanned continuous glucose monitoring

MDI:

multiple daily injection

rtCGM:

real-time continuous glucose monitoring

T1D:

type 1 diabetes

References

  1. Ahmed L, Heller S. Managing hypoglycaemia. Best pract res clin endocrinol metab. 2016; 30(3):413–30.

  2. Lin Y, Hung M, Sharma A, et al. Impaired awareness of hypoglycemia continues to be a risk factor for severe hypoglycemia despite the use of continuous glucose monitoring system in type 1 diabetes. Endocr Pract. 2019;25(6):517–25.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Martín-Timón I, Del Cañizo-Gómez FJ. Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World J Diabetes. 2015;6(7):912–26.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fanelli C, Pampanelli S, Lalli C, et al. Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation. Diabetes. 1997;46(7):1172–81.

    Article  CAS  PubMed  Google Scholar 

  5. Olsen SE, Asvold BO, Frier BM, et al. Hypoglycaemia symptoms and impaired awareness of hypoglycaemia in adults with type 1 diabetes: the association with diabetes duration. Diabet Med. 2014;31(10):1210–7.

    Article  CAS  PubMed  Google Scholar 

  6. Schouwenberg BJ, Coenen MJ, Paterson AD, et al. Genetic determinants of impaired awareness of hypoglycemia in type 1 diabetes. Pharmacogenet Genomics. 2017;27(9):323–8.

    Article  CAS  PubMed  Google Scholar 

  7. Naito A, Nwokolo M, Smith EL, et al. Personality traits of alexithymia and perfectionism in impaired awareness of hypoglycemia in adults with type 1 diabetes - an exploratory study. J Psychosom Res. 2021;150:110634.

    Article  PubMed  Google Scholar 

  8. Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005;54(12):3592–601.

    Article  CAS  PubMed  Google Scholar 

  9. Milman S, Leu J, Shamoon H, et al. Magnitude of exercise-induced β-endorphin response is associated with subsequent development of altered hypoglycemia counterregulation. J Clin Endocrinol Metab. 2012;97:623–31.

    Article  CAS  PubMed  Google Scholar 

  10. Jones TW, Porter P, Sherwin RS, et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med. 1998;338(23):1657–62.

    Article  CAS  PubMed  Google Scholar 

  11. Furuichi K, Shimizu M, Hara A, et al. Diabetic Nephropathy: a comparison of the clinical and pathological features between the CKD Risk classification and the classification of Diabetic Nephropathy 2014 in Japan. Intern Med. 2018;57(23):3345–50.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Himeno T, Kamiya H, Nakamura J. Lumos for the long trail: strategies for clinical diagnosis and severity staging for diabetic polyneuropathy and future directions. J Diabetes Investig. 2020;11(1):5–16.

    Article  PubMed  Google Scholar 

  13. Enomoto M, Ishizu T, Seo Y, et al. Myocardial dysfunction identified by three-dimensional speckle tracking echocardiography in type 2 diabetes patients relates to complications of microangiopathy. J Cardiol. 2016;68(4):282–7.

    Article  PubMed  Google Scholar 

  14. Pecori Giraldi F, Toja PM, Michailidis G, et al. High prevalence of prolonged QT interval duration in male patients with Cushing’s disease. Exp Clin Endocrinol Diabetes. 2011;119(4):221–4.

    Article  CAS  PubMed  Google Scholar 

  15. Ogawa A, Hayashi A, Kishihara E, et al. New indices for predicting glycaemic variability. PLoS ONE. 2012;7(9):e46517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Clarke WL, Cox DJ, Gonder-Frederick LA, et al. Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care. 1995;18(4):517–22.

    Article  CAS  PubMed  Google Scholar 

  17. Deary IJ, Hepburn DA, Macleod KM, et al. Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis. Diabetologia. 1993;36(8):771–7.

    Article  CAS  PubMed  Google Scholar 

  18. Stefenon P, Silveira ALMD, Giaretta LS, et al. Hypoglycemia symptoms and awareness of hypoglycemia in type 1 diabetes mellitus: cross-cultural adaptation and validation of the portuguese version of three questionnaires and evaluation of its risk factors. Diabetol Metab Syndr. 2020;12:15.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Welch GW, Jacobson AM, Polonsky WH. The Problem Areas in Diabetes Scale. An evaluation of its clinical utility. Diabetes Care. 1997;20(5):760–6.

    Article  CAS  PubMed  Google Scholar 

  20. Oluchi SE, Manaf RA, Ismail S, et al. Health Related Quality of Life measurements for diabetes: a systematic review. Int J Environ Res Public Health. 2021;18(17):9245.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cox DJ, Irvine A, Gonder-Frederick L, et al. Fear of hypoglycemia: quantification, validation, and utilization. Diabetes Care. 1987;10(5):617–21.

    Article  CAS  PubMed  Google Scholar 

  22. Murata T, Kuroda A, Matsuhisa M, et al. Predictive factors of the adherence to real-time continuous glucose monitoring sensors: a prospective observational study (PARCS STUDY). J Diabetes Sci Technol. 2021;15(5):1084–92.

    Article  CAS  PubMed  Google Scholar 

  23. Tsuchiya A, Ikeda S, Ikegami N, et al. Estimating an EQ-5D population value set: the case of Japan. Health Econ. 2002;11(4):341–53.

    Article  PubMed  Google Scholar 

  24. Shimamoto K, Hirano M, Wada-Hiraike O, et al. Examining the association between menstrual symptoms and health-related quality of life among working women in Japan using the EQ-5D. BMC Women’s Health. 2021;21(1):325.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wu FL, Juang JH, Lin CH. Development and validation of the hypoglycaemia problem-solving scale for people with diabetes mellitus. J Int Med Res. 2016;44(3):592–604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fukasawa T, Tanemura N, Kimura S, et al. Utility of a specific Health Checkup Database Containing Lifestyle Behaviors and Lifestyle Diseases for Employee Health Insurance in Japan. J Epidemiol. 2020;30(2):57–66.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cabeza de Baca T, Chayama KL, Redline S, et al. Sleep debt: the impact of weekday sleep deprivation on cardiovascular health in older women. Sleep. 2019;42(10):zsz149.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Eguchi E, Iso H, Tanabe N, Japan Collaborative Cohort Study Group, et al. Healthy lifestyle behaviours and cardiovascular mortality among japanese men and women: the Japan collaborative cohort study. Eur Heart J. 2012;33(4):467–77.

    Article  PubMed  Google Scholar 

  29. Mcneilly AD, mccrimmon RJ. Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab. Diabetologia. 2018;61(4):743–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mizokami-Stout KR, Li Z, Foster NC, et al. For T1D Exchange Clinic Network; T1D Exchange Clinic Networ k. The contemporary prevalence of Diabetic Neuropathy in Type 1 diabetes: findings from the T1D Exchange. Diabetes Care. 2020;43(4):806–12. Pop-Busui R.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Davis SN, Duckworth W, Emanuele N, et al. Investigators of the Veterans Affairs Diabetes Trial. Effects of severe hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial. Diabetes Care. 2019;42(1):157–63.

    Article  CAS  PubMed  Google Scholar 

  32. Giorda CB, Ozzello A, Gentile S, et al. HYPOS-1 Study Group of AMD. Incidence and risk factors for severe and symptomatic hypoglycemia in type 1 diabetes. Results of the HYPOS-1 study. Acta Diabetol. 2015;52(5):845–53.

    Article  CAS  PubMed  Google Scholar 

  33. Pedersen-Bjergaard U, Pramming S, Heller SR, et al. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev. 2004;20(6):479–86.

    Article  PubMed  Google Scholar 

  34. Stephenson JM, Kempler P, Perin PC, et al. Is autonomic neuropathy a risk factor for severe hypoglycaemia? The EURODIAB IDDM Complications Study. Diabetologia. 1996;39(11):1372–6.

    Article  CAS  PubMed  Google Scholar 

  35. Olsen SE, Bjørgaas MR, Åsvold BO, et al. Impaired awareness of hypoglycemia in adults with type 1 diabetes is not Associated with Autonomic Dysfunction or Peripheral Neuropathy. Diabetes Care. 2016;39(3):426–33.

    Article  CAS  PubMed  Google Scholar 

  36. Flatt AJS, Little SA, Speight J, et al. Predictors of recurrent severe hypoglycemia in adults with type 1 diabetes and impaired awareness of Hypoglycemia during the hypocompass study. Diabetes Care. 2020;43(1):44–52.

    Article  PubMed  Google Scholar 

  37. Ding X, Fang C, Li X, et al. Type 1 diabetes-associated cognitive impairment and diabetic peripheral neuropathy in chinese adults: results from a prospective cross-sectional study. BMC Endocr Disord. 2019;19(1):34.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Reddy M, Jugnee N, El Laboudi A, et al. A randomized controlled pilot study of continuous glucose monitoring and flash glucose monitoring in people with type 1 diabetes and impaired awareness of hypoglycaemia. Diabet Med. 2018;35(4):483–90.

    Article  CAS  PubMed  Google Scholar 

  39. Demir G, Özen S, Çetin H et al. Effect of Education on Impaired Hypoglycemia Awareness and Glycemic Variability in Children and Adolescents with Type 1 Diabetes Mellitus.J Clin Res Pediatr Endocrinol. 2019 May28; 11(2):189–195.

  40. Choudhary P, Rickels MR, Senior PA, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care. 2015;38(6):1016–29.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zheng C, Ou W, Shen H et al. Combined therapy of diabetic peripheral neuropathy with breviscapine and mecobalamin: a systematic review and a meta-analysis of Chinese studies. Biomed Res Int. 2015; 2015: 680756.

  42. Gruden G, Giunti S, Barutta F, Chaturvedi N, et al. Qtc interval prolongation is independently associated with severe hypoglycemic attacks in type 1 diabetes from the EURODIAB IDDM complications study. Diabetes Care. 2012;35(1):125–7.

    Article  PubMed  Google Scholar 

  43. Spallone V, Ziegler D, Freeman R, et al. Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011;27(7):639–53.

    Article  PubMed  Google Scholar 

  44. Carmichael J, Fadavi H, Ishibashi F, et al. Advances in screening, early diagnosis and Accurate Staging of Diabetic Neuropathy. Front Endocrinol (Lausanne). 2021;12:671257.

    Article  PubMed  Google Scholar 

  45. Cheshire WP, Freeman R, Gibbons CH, et al. Electrodiagnostic assessment of the autonomic nervous system: a consensus statement endorsed by the american Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology. Clin Neurophysiol. 2021;132(2):666–82.

    Article  PubMed  Google Scholar 

  46. Ahmed L, Heller S. The role of structured education in the management of hypoglycaemia. Diabetologia. 2018;61(4):751–60.

    Article  Google Scholar 

  47. Wu FL, Lin CH, Lin CL, et al. Effectiveness of a problem-solving program in improving problem-solving ability and Glycemic Control for Diabetics with Hypoglycemia. Int J Environ Res Public Health. 2021;18(18):9559.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lin YK, Fisher SJ, Pop-Busui R. Hypoglycemia unawareness and autonomic dysfunction in diabetes: Lessons learned and roles of diabetes technologies. J Diabetes Investig. 2020;11(6):1388–402.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Jin SM. Stepwise Approach to Problematic Hypoglycemia in Korea: Educational, Technological, and transplant interventions. Endocrinol Metab (Seoul). 2017;32(2):190–19.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to the NHO Diabetology group.

Funding

The PR-IAH study with funding from the National Hospital Organization Clinical research (NHO) (Grant number: H31-NHO (Endocrinology and Nephrology)-01).

Author information

Authors and Affiliations

  1. Division of Preventive Medicine, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, 612-8555, Kyoto, Japan

    Naoki Sakane, Masayuki Domichi, Akiko Suganuma & Seiko Sakane

  2. Diabetes center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, 540-0006, Osaka, Japan

    Ken Kato, Sonyun Hata & Erika Nishimura

  3. Department of Diabetes and Endocrinology, National Hospital Organization Mie National Hospital, 357 Ozatokubota-cho, 514-0125, Tsu, Mie, Japan

    Rika Araki

  4. Department of Diabetes and Metabolism, National Hospital Organization Hyogo-Chuo National Hospital, 1314Ohara, 669-1515, Sanda, Hyogo, Japan

    Kunichi kouyama

  5. Department of Diabetes and Endocrinology, National Hospital Organization Himeji Medical Center, 68 Honmachi, 670-0012, Himeji, Hyogo, Japan

    Masako Hatao

  6. Department of Diabetes, Endocrinology and Metabolism, National Hospital Organization Kokura Medical Center, 10-1 Harugaoka, Kitakyushu Kokuraminami-ku, 802-0803, Fukuoka, Japan

    Yuka Matoba

  7. Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center, 1711-1 Tamasu, Okayama Kita-ku, 701-1192, Okayama, Japan

    Yuichi Matsushita

  8. Department of Clinical Nutrition, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, 612-8555, Kyoto, Japan

    Takashi Murata

  9. Diabetes Center, National Hospital Organization Kyoto Medical Center, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, 612-8555, Kyoto, Japan

    Takashi Murata

  10. Department of Nursing, Chang Gung University of Science and Technology, No. 261, Wenhua 1st Rd, Guishan District, 333, Taoyuan City, Taiwan

    Fei Ling Wu

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Contributions

Authors’ contributions statement: NS conceived the ideas. MD analyzed the data. NS acquired the funding. SH, EN, RA,KK,MH,YM, YM, and KK collected the data. NS and AS written the original draft. TM, SS, FW reviewed and written the article.

Corresponding author

Correspondence to Naoki Sakane.

Ethics declarations

Ethics approval and consent to participate

Approval of the research protocol:This study was approved by t the National Hospital Organization Central Review Board (NHOCRB/ R2-0117002、R3-0614027).

Informed consent: or substitute for it was obtained from all patients for being included in the study.

Animal studies

N/A.

Conflict of interest disclosures

None to be declared.

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Sakane, N., Kato, K., Hata, S. et al. Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross-sectional analysis of baseline data from the PR-IAH study. Diabetol Metab Syndr 15, 79 (2023). https://doi.org/10.1186/s13098-023-01024-x

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  • DOI: https://doi.org/10.1186/s13098-023-01024-x

Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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