Cited by 236Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismPeroxisome Proliferator-Activated Receptors

The DOI matches its Crossref record; 230 of the 230 references it cites were found in a registry or an index.

Dysfunctional fat cells, lipotoxicity and type 2 diabetes

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Defronzo, R. A.·2004·International Journal of Clinical Practice

Abstract

Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion. Considerable evidence implicates altered fat topography and defects in adipocyte metabolism in the pathogenesis of type 2 diabetes. In individuals who develop type 2 diabetes, fat cells tend to be enlarged. Enlarged fat cells are resistant to the antilipolytic effects of insulin, leading to day-long elevated plasma free fatty acid (FFA) levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic and muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. Enlarged fat cells also have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid 'overflows' into muscle and liver, and possibly the beta-cells of the pancreas, exacerbating insulin resistance and further impairing insulin secretion. In addition, dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory and atherosclerosis-provoking cytokines, and fail to secrete normal amounts of insulin-sensitizing cytokines. As more evidence emerges, there is a stronger case for targeting adipose tissue in the treatment of type 2 diabetes. Peroxisome-proliferator activated receptor gamma (PPARgamma) agonists, for example the thiazolidinediones, redistribute fat within the body (decrease visceral and hepatic fat; increase subcutaneous fat) and have been shown to enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA and favourably influence the production of adipocytokines. This article examines in detail the role of adipose tissue in the pathogenesis of type 2 diabetes and highlights the potential of PPAR agonists to improve the management of patients with the condition.

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Crossref · 10.1111/j.1368-504x.2004.00389.x

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Citations

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Research works printed but not linked: 11

  1. Kelley, 1995, Effects of weight loss on glucose homeostasis in NIDDM, Diabetes Rev, 3, 366
  2. Schneider, 1995, Effects of fitness and physical training on carbohydrate metabolism and associated cardiovascular risk factors in patients with diabetes, Diabetes Rev, 3, 378
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  4. Miyazaki, 2002, Effect of pioglitazone on liver fat content, abdominal fat distribution, and insulin sensitivity in patients with type 2 diabetes mellitus, Diabetes, 51, A69
  5. Kashyap, 2002, A chronic physiologic increase in FFA in healthy subjects causes insulin signaling defects similar to those of insulin-resistant nondiabetic subjects with a strong family history of T2DM, Diabetes, 51, A24
  6. Stein, 1999, Increasing intramyocellular triglyceride stores are associated with impaired glucose tolerance and NIDDM, Diabetes, 48, A287
  7. Greco, 2002, Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion, Diabetes, 51, 144, 10.2337/diabetes.51.1.144 · DOI · Paper page
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  9. Finegood, 2001, Beta-Cell mass dynamics in Zucker diabetic fatty rats: rosiglitazone prevents the rise in net cell death, Diabetes, 50, 1021, 10.2337/diabetes.50.5.1021 · DOI
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  11. Marselli, 2002, Rosiglitazone partially prevents free fatty acid-induced cytotoxicity of human pancreatic islet cells, Diabetologia, 45, A161

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Metadata

Authors
Defronzo, R. A.
Affiliations
The University of Texas at San Antonio Health Science Center (US)
Corresponding author
Defronzo, R. A.
Venue
International Journal of Clinical Practice
Publisher
Wiley
Published
2004-09-27
Volume
58
Issue
143
Pages
9-21
ISSN
1368-5031 (ISSN-L)
OpenAlex
W1548248963
Cited by
236
References
230
Citations by year
2026: 6 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 23 · 2021: 9 · 2020: 8 · 2019: 16 · 2018: 13 · 2017: 10 · 2016: 8 · 2015: 16 · 2014: 5 · 2013: 15 · 2012: 10
FWCI
0.99
Type
journal article
Language
en
Open access
Locations
  • International Journal of Clinical Practice (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
type 2 diabetes, adipocyte dysfunction, lipotoxicity, insulin resistance, free fatty acids, adipocyte hypertrophy, body fat distribution, lipolysis, adipokines, PPARγ agonists, thiazolidinediones, insulin secretion, hepatic insulin resistance, visceral fat
MeSH terms
Adipose Tissue, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Humans, Insulin, Insulin Resistance, Adipocytes, Peroxisome Proliferator-Activated Receptors

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