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Evidence for a Circadian Rhythm of Insulin Sensitivity in Patients With NIDDM Caused by Cyclic Changes in Hepatic Glucose Production
Abstract
Diurnal variation in insulin sensitivity in patients with NIDDM has long been suspected but has been difficult to document mainly because of the interdependence of changes in glucose and insulin. Stable serum insulin levels during hyperglycemic clamping in patients with NIDDM in the present study provided the opportunity to examine changes in insulin sensitivity unaffected by changes in blood glucose and insulin concentrations. Six patients with NIDDM (four men and two women, BMI 33.9 ± 2.5) underwent hyperglycemic (11.1 mmol/l, ∼200 mg/dl) clamping for 72 h. Measured were serum insulin, free fatty acid (FFA), cortisol, and growth hormone concentrations and rates of insulin secretion, insulin clearance, and glucose infusion rate (GIR) needed to maintain hyperglycemia. In addition, five patients (three men and two women, BMI 32.6 ± 0.6) underwent hyperglycemic clamping for 24 h with hourly determinations of hepatic glucose production (HGP) and glucose disappearance rates (GRd). GIR, reflecting insulin sensitivity, changed rhythmically with a cycle duration of 22.9 ± 1.4 h and an amplitude of 47.8 ± 11.2%. GIR was lowest at 8:31 a.m. (±52 min) and highest at 7:04 p.m. (±58 min). Circadian changes in GIR were completely accounted for by changes in HGP, while GRd remained unchanged. Plasma levels of FFAs and cortisol also exhibited circadian fluctuations, and their blood levels correlated negatively with GIR (r = −0.72 and −0.64, respectively). We concluded that insulin sensitivity in patients with NIDDM changed with circadian (∼24 h) rhythmicity (decreasing during the night and increasing during the day). These changes were unrelated to blood levels of glucose and insulin, insulin clearance, exercise, food intake, and sleep. They were caused by circadian changes in HGP, which in turn were closely correlated with circadian changes in blood FFA and cortisol levels. We believe that recognition of these circadian changes has implications for the diagnosis and the treatment of patients with NIDDM.
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“the degree of insulin resistance in patients with type 2 diabetes correlates with the elevation in nocturnal NEFA levels [30].”
From Sleep restriction increases free fatty acids in healthy men (2015) · cites this paper as [30]
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“In individuals with T2DM, there is a daily rhythm in insulin sensitivity, with decreasing insulin sensitivity and increasing hepatic glucose production across the night (Boden et al., 1996), which leads to a fasting/morning hyperglycemia (Radziuk and Pye, 2006).”
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“In the present study, careful research was conducted, in which we modified the model structure based on the results of our research, and new mechanisms (circadian rhythm [12, 13] and food effect [11]) were addressed and confirmed from other studies.”
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“Many years ago, Jarrett and others (11, 14, 15, 27) reported that the normal diurnal rhythm in glucose tolerance was lost as humans progress toward non-insulin-dependent diabetes mellitus.”
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“Changes in insulin sensitivity of up to 50% have been experimentally observed [14].”
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Échec des antidiabétiques oraux à doses maximales tolérées : Quels traitements injectables?
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“ing higher during the day [17], and this cycle seems to be regulated by melatonin through the receptor encoded by MTNR1B, expressed in beta cells [18].”
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Diabète de type2: insulinothérapie basale, « flat insulin for flat sugar »
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Monnier, L., Colette, C., Azrak, A. E., & Rochd, D. (2017) · doi:10.1016/b978-2-294-74646-8.00041-9
Chapitre 15 – Diabète de type 2 : forte insulinorésistance
Monnier, L., RABASA-LHORET, R. P. R., & Colette, C. (2017)
Metadata
- Authors
- Boden, G., Chen, X., & Urbain, J. L.
- Affiliations
- Divisions of Endocrinology, Diabetes and Metabolism and Nuclear Medicine Philadelphia, Pennsylvania
- Temple University (US)
- Corresponding author
- Boden, Guenther
- ORCID
- Chen, Xinhua
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1996-08-01
- Volume
- 45
- Issue
- 8
- Pages
- 1044-1050
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2138487775
- Cited by
- 228
- References
- 0
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 15 · 2019: 4 · 2018: 9 · 2017: 12 · 2016: 10 · 2015: 15 · 2014: 18 · 2013: 10 · 2012: 7
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health (5r01ag007988-10, 5r01aa010221-03)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA-10221)
- National Institute on Aging (R01-AG07988)
- National Center for Research Resources (RR-349)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin sensitivity, circadian rhythm, type 2 diabetes, hepatic glucose production, glucose infusion rate, glucose disappearance rate, free fatty acids, cortisol, insulin secretion, insulin clearance
- MeSH terms
- Alanine, Circadian Rhythm, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Female, Glucagon, Glucose, Humans, Hydrocortisone, Insulin, Lactates, Liver, Male, Middle Aged, Sleep, Growth Hormone
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