Opioid receptor activation impairs hypoglycemic Counterregulation in humans
Open accessAbstract
Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 μg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ∼30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF’s development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.
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Antecedent opioid receptor activation with morphine in healthy subjects resulted in defective counter-regulation in response to subsequent hypoglycemia, including a reduction in epinephrine and EGP.
“a prior study by our group demonstrated that antecedent opioid receptor activation with morphine in healthy subjects resulted in defective counter-regulation in response to subsequent hypoglycemia, including a reduction in epinephrine and EGP (6).”
From Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure (2020) · cites this paper as [6]
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Self-citationPotential approaches to prevent hypoglycemia-associated autonomic failure
Lontchi-Yimagou, E., You, J. Y., Carey, M., Gabriely, I., Shamoon, H., & Hawkins, M. (2018) · Journal of Investigative Medicine · doi:10.1136/jim-2017-000582 · Cited by 12 · see citing works
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- Authors
- Carey, M., Gospin, R., Goyal, A., Tomuta, N., Sandu, O., Mbanya, A., Lontchi-Yimagou, E., Hulkower, R., Shamoon, H., Gabriely, I., & Hawkins, M.
- Affiliations
- Albert Einstein College of Medicine (US)
- Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY
- Corresponding author
- Hawkins, Meredith
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2017-08-31
- Volume
- 66
- Issue
- 11
- Pages
- 2764-2773
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC5652610
- OpenAlex
- W2752310372
- Semantic Scholar
- 9325e8c9b1e0431fd5e0aacbda0ddd18eb2054dd
- Cited by
- 23
- References
- 55
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 1 · 2017: 1
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK069861, DK48321)
- National Center for Advancing Translational Science (UL1TR001073)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- opioid receptor activation, morphine, hypoglycemia-associated autonomic failure, hypoglycemic counterregulation, epinephrine response, endogenous glucose production, hypoglycemic symptoms, type 1 diabetes, tight glycemic control, iatrogenic hypoglycemia
- MeSH terms
- Adult, Blood Glucose, C-Peptide, Epinephrine, Female, Glucose, Humans, Hydrocortisone, Hypoglycemia, Insulin, Male, Morphine, Norepinephrine, Receptors, Opioid, Glucose Clamp Technique, Cross-Over Studies
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