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Cited by 120Diabetes Management and ResearchPancreatic function and diabetesDiabetes and associated disorders

Early Loss of the Glucagon Response to Hypoglycemia in Adolescents With Type 1 Diabetes

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Siafarikas, Aris, Johnston, Robert J., Bulsara, Max K., O’Leary, Peter, Jones, Timothy W., Davis, Elizabeth A.·2012·Diabetes Care
DOI 10.2337/dc11-2010PMC PMC3402257
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Abstract

OBJECTIVE: To assess the glucagon response to hypoglycemia and identify influencing factors in patients with type 1 diabetes compared with nondiabetic control subjects. RESEARCH DESIGN AND METHODS: Hyperinsulinemic hypoglycemic clamp studies were performed in all participants. The glucagon response to both hypoglycemia and arginine was measured, as well as epinephrine, cortisol, and growth hormone responses to hypoglycemia. Residual β-cell function was assessed using fasting and stimulated C-peptide. RESULTS: Twenty-eight nonobese adolescents with type 1 diabetes (14 female, mean age 14.9 years [range 11.2–19.8]) and 12 healthy control subjects (6 female, 15.3 years [12.8–18.7]) participated in the study. Median duration of type 1 diabetes was 0.66 years (range 0.01–9.9). The glucagon peak to arginine stimulation was similar between groups (P = 0.27). In contrast, the glucagon peak to hypoglycemia was reduced in the group with diabetes (95% CI): 68 (62–74) vs. 96 (87–115) pg/mL (P < 0.001). This response was greater than 3 SDs from baseline for only 7% of subjects with type 1 diabetes in comparison with 83% of control subjects and was lost at a median duration of diabetes of 8 months and as early as 1 month after diagnosis (R = −0.41, P < 0.01). There was no correlation in response with height, weight, BMI, and HbA1c. Epinephrine, cortisol, and growth hormone responses to hypoglycemia were present in both groups. CONCLUSIONS: The glucagon response to hypoglycemia in adolescents with type 1 diabetes is influenced by the duration of diabetes and can be lost early in the course of the disease.

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  • Glucagon response declines with age of diabetes; counterregulatory response wanes with duration of diabetes following a logarithmic relationship.

    “it has been shown that glucagon secretion is dependent on the duration of diabetes; 15-17 that is, counterregulatory response wanes with duration of diabetes 15 following a logarithmic relationship.”

    From The UVA/PADOVA Type 1 Diabetes Simulator: New Features (2014) · cites this paper as [16]

    The Results (Counterregulatory response; Regression analysis, page unavailable) report that the glucagon response to hypoglycemia declined with diabetes duration in adolescents with type 1 diabetes. The paper reports a correlation and uses linear regression; it does not establish the claimed logarithmic relationship. Its finding also concerns the glucagon response specifically, not every counterregulatory hormone response. (LLM, conf=0.88)

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  • Hypoglycemia in the range of ∼2.5-3.5 mmol/L typically fails to trigger a clinically meaningful increase in plasma glucagon levels within months of T1D diagnosis.

    “Hypoglycemia in the range of ∼2.5–3.5 mmol/L typically fails to trigger a clinically meaningful increase in plasma glucagon levels (systemic values fail to rise above ∼60 pg/mL when the expected increase is >100 pg/mL) within months of T1D diagnosis ( Siafarikas et al., 2012 ),”

    From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Siafarikas et al., 2012

  • α-cells fail to meet the demand for glucose counterregulation, becoming increasingly unresponsive to hypoglycemia with longer duration diabetes and progressive insulin deficiency.

    “However, α-cells fail to meet this demand, becoming increasingly “blind” (unresponsive) to hypoglycemia with longer duration diabetes and progressive insulin deficiency ( Madsbad et al., 1982 ; Cryer, 2005 ; Siafarikas et al., 2012 ; Zenz et al., 2018 ).”

    From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Siafarikas et al., 2012

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Authors
Siafarikas, A., Johnston, R. J., Bulsara, M. K., O’Leary, P., Jones, T. W., & Davis, E. A.
Affiliations
  • The University of Western Australia (AU)
  • Princess Margaret Hospital for Children (AU)
  • Department of Biochemistry, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
  • The Kids Research Institute Australia (AU)
Corresponding author
Davis, Elizabeth A.
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2012-07-14
Volume
35
Issue
8
Pages
1757-1762
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc11-2010
PMC
PMC3402257
OpenAlex
W2154643153
Cited by
120
References
37
Citations by year
2026: 8 · 2025: 10 · 2024: 10 · 2023: 7 · 2022: 6 · 2021: 17 · 2020: 10 · 2019: 5 · 2018: 12 · 2017: 8 · 2016: 5 · 2015: 9 · 2014: 7 · 2013: 5 · 2012: 1
FWCI
5.65
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes Care (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
  • ResearchOnline@ND (The University of Notre Dame) (submittedVersion)
  • eSpace (Curtin University) (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
type 1 diabetes, glucagon response, hypoglycemia, adolescents, arginine stimulation, diabetes duration, residual beta-cell function, C-peptide, epinephrine, cortisol, growth hormone, hyperinsulinemic hypoglycemic clamp
MeSH terms
Adolescent, Arginine, Child, Diabetes Mellitus, Type 1, Epinephrine, Female, Glucagon, Humans, Hydrocortisone, Hypoglycemia, Male, Growth Hormone

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