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Cited by 595Pancreatic function and diabetesDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Treatment and Management

Glucose Intolerance and Aging: Evidence for Tissue Insensitivity to Insulin

DeFronzo, Ralph A·1979·Diabetes
DOI 10.2337/diab.28.12.1095
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Abstract

The relative contributions of impaired insulin secretion and of impaired tissue sensitivity to insulin to the glucose intolerance of aging were examined in 84 healthy volunteers, ranging in age from 21 to 84 yr, employing the hyperglycemie and euglycemic insulin clamp techniques, respectively. HYPERGLYCEMIC CLAMP. The blood glucose concentration was acutely raised and was maintained at 125 mg/dl above basal levels for 2 h. Since the glucose concentration was held constant, the glucose infusion rate was an index of glucose metabolism (M). In young subjects, M averaged 9.48 ± 0.40 mg/kg · min compared with 6.48 ± 0.28 in old subjects (P < 0.001). When all subjects were considered together, a progressive age-related decline in M was observed (r = –0.665, P < 0.001). The plasma insulin response (I) was biphasic, with an early burst within the first 6 min, followed by a phase of gradually increasing insulin concentration. No difference in either the early or late phases of insulin secretion was observed between young and old subjects. Consequently, the M/l (×100) ratio, an index of tissue sensitivity to endogenous insulin, decreased from 14.90 ± 1.01 to 10.98 ± 0.81 mg/kg min per μU/ml (P < 0.005). EUGLYCEMIC INSULIN CLAMP. The plasma insulin concentration was acutely raised and was maintained at about 100 μU/ml above basal levels by a primed continuous infusion of insulin. The blood glucose concentration was held constant at the basal level by a variable glucose infusion. M/I (×100), again, was a measure of tissue sensitivity to insulin (exogenous) and was decreased in old (4.95 ± 0.31 mg/kg · min per μU/ml) versus young (6.95 ± 0.45) subjects (P < 0.001). Hepatic glucose production was measured with tritiated glucose during the euglycemic clamp study; it declined similarly in young (to 0.13 ± 0.05 mg/kg · min) and old (to 0.09 ± 0.03 mg · min) subjects. In conclusion, under the present experimental conditions, employing intravenous glucose and/or insulin, impaired tissue sensitivity to insulin is the primary factor responsible for the decrease in glucose tolerance observed with advancing age. Since hepatic glucose production is normally suppressed by insulin in old subjects, the site of insulin resistance must reside in peripheral tissues. Beta cell response to glucose, as determined by the hyperglycemie clamp technique, cannot account for the age-related decline in M.

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  • Insulin sensitivity is influenced by genetics, age, acute exercise, physical fitness, dietary nutrients, medications, obesity and body fat distribution.

    “insulin sensitivity is influenced by a number of different factors such as genetics [20], age [21, 22], acute exercise [23], physical fitness [24], dietary nutrients [25], medications [26, 27, 28], obesity [9, 10, 29, 30, 31, 32] and body fat distribution [31, 33, 34, 35, 36, 37, 38].”

    From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [21]

  • Skeletal muscle insulin resistance has been reported in association with normal ageing, dyslipidaemia, polycystic ovary syndrome, chronic kidney failure, heart failure, myotonic dystrophy, and lipodystrophy.

    “Insulin resistance in skeletal muscle also has been reported in association with the normal ageing process [37], dyslipidemia (increased plasma triglyceride/decreased HDL cholesterol) [4, 26], and in association with many disease states including polycystic ovary syndrome (PCOs) [38], chronic kidney failure [39], heart failure [40], myotonic dystrophy [41], and lipodystrophy [42].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [37]

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Authors
DeFronzo, R. A.
Affiliations
Yale University (US)
Corresponding author
DeFronzo, Ralph A
ORCID
DeFronzo, Ralph A
Venue
Diabetes
Publisher
American Diabetes Association
Published
1979-12-01
Volume
28
Issue
12
Pages
1095-1101
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diab.28.12.1095
OpenAlex
W2158394935
Cited by
595
References
0
Citations by year
2026: 2 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 9 · 2021: 7 · 2020: 7 · 2019: 12 · 2018: 7 · 2017: 10 · 2016: 11 · 2015: 6 · 2014: 11 · 2013: 14 · 2012: 11
FWCI
19.70
Type
journal article
Language
en
Open access
closed
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
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 Treatment and Management
Keywords
impaired glucose tolerance, aging, insulin resistance, insulin secretion, hyperglycemic clamp, euglycemic clamp, hepatic glucose production, glucose metabolism, hepatic insulin sensitivity, skeletal muscle insulin sensitivity, adipose tissue insulin sensitivity, beta-cell function, hepatic insulin resistance
MeSH terms
Adult, Age Factors, Aged, Blood Glucose, Female, Glucose, Humans, Hyperglycemia, Insulin, Male, Middle Aged

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