Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man
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Two study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg-1.min-1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.
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A 72 pmol/l increase in plasma insulin for 72-96 h in healthy NGT insulin-sensitive individuals reduces insulin-stimulated glucose disposal by 30-40%, accounted for entirely by impaired nonoxidative glucose disposal, without altering insulin-mediated suppression of hepatic glucose production.
“Del Prato et al. ( 50 ) demonstrated that a 72 pmol/l (11 μU/ml) increase in the plasma insulin concentration in healthy NGT insulin-sensitive individuals for as little as 72–96 h reduced insulin-stimulated glucose disposal (insulin clamp technique) by 30–40%. The defect in insulin action was accounted for entirely by impaired nonoxidative glucose disposal (Fig. A9). On the other hand, chronic eug”
From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [50]
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References 50 · Cited by 322
- Authors
- Del Prato, S., Leonetti, F., Simonson, D. C., Sheehan, P., Matsuda, M., & DeFronzo, R. A.
- Affiliations
- Audie L. Murphy Memorial VA Hospital (US)
- Brigham and Women's Hospital (US)
- University of Padua (IT)
- Venue
- Diabetologia
- Published
- 1994-10
- Volume
- 37
- Issue
- 10
- Pages
- 1025-1035
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2161160210
- Cited by
- 322
- References
- 50
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 10 · 2023: 8 · 2022: 12 · 2021: 7 · 2020: 20 · 2019: 18 · 2018: 12 · 2017: 9 · 2016: 12 · 2015: 10 · 2014: 10 · 2013: 13 · 2012: 11
- FWCI
- 6.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- National Institutes of Health (AM 24 092, 5r01am024092-06)
- Geriatric Research Education and Clinical Center
- National Institute on Aging (AG00233)
- National Center for Research Resources (M01RR01346, M01RR001346)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- hyperglycemia, insulin resistance, insulin secretion, insulin sensitivity, hepatic glucose production, glucose oxidation, glycogen synthesis
- MeSH terms
- Insulin Secretion, Adult, Blood Glucose, Cholesterol, Female, Glucose, Glycogen, Humans, Hyperglycemia, Hyperinsulinism, Insulin, Insulin Resistance, Liver, Male, Triglycerides, Glucose Clamp Technique
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