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Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus.

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Shamoon, H, Friedman, S, Canton, C, Zacharowicz, L, Hu, M, Rossetti, L·1994·Journal of Clinical Investigation
DOI 10.1172/jci117267PMC PMC294484
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Abstract

We evaluated skeletal muscle counterregulation during hypoglycemia in nine subjects with non-insulin-dependent diabetes mellitus (NIDDM) (HbA1c 9.4 +/- 0.5%, nl < 6.2%) compared with six normal controls, matched for age (51 +/- 3 and 49 +/- 5 yr, respectively) and body mass index (27.3 +/- 1.2 and 27.0 +/- 2.1 kg/m2). After 60 min of euglycemia (plasma insulin approximately 140 microU/ml), plasma glucose was lowered to 62 +/- 2 mg/dl by 120 min. Hypoglycemia induced a 2.2-fold greater increase in plasma epinephrine in NIDDM (P < 0.001), while the plasma glucagon response was blunted (P < 0.01). Hepatic glucose output ([3H-3]glucose) suppressed similarly during euglycemia, but during hypoglycemia was greater in NIDDM (P < 0.005). Conversely, glucose uptake during euglycemia was 150% greater in controls (P < 0.01) and remained persistently higher than in NIDDM during hypoglycemia. In NIDDM, plasma FFA concentrations were approximately fivefold greater (P < 0.001), and plasma lactate levels were approximately 40% higher than in controls during hypoglycemia (P < 0.01); the rates of glycolysis from plasma glucose were similar in the two groups despite a 49% lower rate of glucose uptake in NIDDM (3.4 +/- 0.9 vs. 6.9 +/- 1.3 mg/kg per minute, P < 0.001). Muscle glycogen synthase activity fell by 42% with hypoglycemia (P < 0.01) in NIDDM but not in controls. In addition, glycogen phosphorylase was activated by 56% during hypoglycemia in NIDDM only (P < 0.01). Muscle glucose-6-phosphate concentrations rose during hypoglycemia by a twofold greater increment in NIDDM (P < 0.01). Thus, skeletal muscle participates in hypoglycemia counterregulation in NIDDM, directly by decreased removal of plasma glucose and, indirectly, by providing lactate for hepatic gluconeogenesis. Consequently, in addition to inherent insulin resistance in NIDDM, the enhanced plasma epinephrine response during hypoglycemia may partially offset impaired glucagon secretion and counteract the effects of hyperinsulinemia on liver, fat, and skeletal muscle.

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  • In type 2 diabetes, the glucagon response to hypoglycemia has been diversely reported as being either modestly diminished or preserved.

    “In type 2 diabetes, the glucagon response to hypoglycemia has been diversely reported as being either modestly diminished (16, 30,50) or preserved (33,34,37,38).”

    From Hypoglycemia in Type 2 Diabetes (2005) · cites this paper as [50]

  • Plasma free fatty acids increase in response to hypoglycemia in type 2 diabetes but do not in type 1 diabetes.

    “Plasma free fatty acids increase in response to hypoglycemia in type 2 diabetes (30,33,50) but do not in type 1 diabetes (54).”

    From Hypoglycemia in Type 2 Diabetes (2005) · cites this paper as [50]

  • In many people with type 2 diabetes who have insulin resistance, the lipolytic effects of epinephrine outweigh the effects of insulin on adipose tissue.

    “In many people with type 2 diabetes who have insulin resistance, the lipolytic effects of epinephrine outweigh the effects of insulin on adipose tissue (50).”

    From Hypoglycemia in Type 2 Diabetes (2005) · cites this paper as [50]

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Research works printed but not linked: 2

  1. [1]1. Cryer, P. E. 1993. Iatrogenic hypoglycemia in IDDM. Consequences, risk factors and prevention. In Diabetes Annual, Vol. 7. S. M. Marshall, P. D. Home, K. G. M. M. Alberti, L. Krall, editors. Elsevier Science Publishers, Amsterdam, 317-331.
  2. [7]7. Gerich, J., M. Haymond, R. Rizza, C. Verdonk, and J. Miles. 1981. Hormonal and substrate determinants of hepatic glucose production in man. In The Regulation of Carbohydrate Formation and Utilization in Mammals. C. Veneziale, editor. University Park Press, Baltimore, 419–457.

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Related

Authors
Shamoon, H., Friedman, S., Canton, C., Zacharowicz, L., Hu, M., & Rossetti, L.
Affiliations
Albert Einstein College of Medicine (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1994-06-01
Volume
93
Issue
6
Pages
2562-2571
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci117267
PMC
PMC294484
OpenAlex
W2092734860
Cited by
57
References
58
Citations by year
2024: 2 · 2023: 1 · 2020: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 2 · 2012: 3
FWCI
1.17
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Diabetes Association
  • National Institutes of Health (5r01dk047477-02)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R029-DK 42177, R01-DK47477, DK20541)
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, Cardiovascular Risks, and Lipoproteins
Keywords
hypoglycemia counterregulation, skeletal muscle, epinephrine, glucagon, hepatic glucose production, muscle glucose uptake, free fatty acids, lactate, glycogen phosphorylase, glucose-6-phosphate, glycolysis, insulin resistance, HbA1c, euglycemic clamp
MeSH terms
Adult, Blood Glucose, C-Peptide, Diabetes Mellitus, Type 2, Epinephrine, Fatty Acids, Nonesterified, Female, Glucose, Phosphorylases, Glycogen Synthase, Humans, Insulin, Liver, Male, Middle Aged, Muscles

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