The DOI matches its Crossref record; 323 of the 328 references it cites were found in a registry or an index.
Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance in liver and muscle and impaired insulin secretion. Considerable evidence also implicates deranged adipocyte metabolism and altered fat topography in the pathogenesis of glucose intolerance in T2DM. 1) Fat cells are resistant to insulin’s antilipolytic effect, leading to day-long elevated plasma FFA levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic/muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. 2) Dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory, and atherosclerotic-provoking cytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines. 3) Enlarged fat cells are insulin resistant and have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid “overflows” into muscle, liver, and perhaps β-cells, causing muscle/hepatic insulin resistance and impaired insulin secretion. Thiazolidinediones enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA, and favorably influence the production of adipocytokines. Thiazolidinediones also redistribute fat within the body (decreased visceral and hepatic fat; increased sc fat) and decrease intracellular concentrations of triglyceride metabolites in muscle, liver, and β-cells, contributing to improvements in muscle/hepatic insulin sensitivity and pancreatic function in type 2 diabetics.
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“an increased intramyocellar fat content and fatty acid metabolites have been shown to play a pivotal role in the development of insulin resistance in skeletal muscle [11–15].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [14]
In the citing paper
“Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [14]
In the citing paper
“Considerable data implicate a causative role for elevated plasma FFA level in insulin resistance in skeletal muscle.”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [14]
In the citing paper
“It is well established that chronically elevated plasma FFA levels cause insulin resistance in skeletal muscle [1, 12, 14, 62–65].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [14]
In the citing paper
“The important role of elevated plasma FFA in the pathogenesis of insulin resistance is now well established [12, 14, 57].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [14]
In the citing paper
“Insulin resistance, in combination with b cell dysfunction, contributes to the development of type 2 diabetes (T2D) 4 (1).”
From A Lower-Carbohydrate, Higher-Fat Diet Reduces Abdominal and Intermuscular Fat and Increases Insulin Sensitivity in Adults at Risk of Type 2 Diabetes (2015) · cites this paper as [1]
In the citing paper
“Obesity, particularly visceral and ectopic adiposity, increases the risk of type 2 diabetes.”
From A Lower-Carbohydrate, Higher-Fat Diet Reduces Abdominal and Intermuscular Fat and Increases Insulin Sensitivity in Adults at Risk of Type 2 Diabetes (2015) · cites this paper as [1]
Citations
Cites
1 retracted
Insulin Binding to Monocytes and Insulin Action in Human Obesity, Starvation, and Refeeding
Defronzo, R. A., Soman, V., Sherwin, R. S., Hendler, R., & Felig, P. (1978) · Journal of Clinical Investigation · doi:10.1172/jci109108 · Cited by 252
Self-citationRetractedPositional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419
Role of Insulin Resistance in Human Disease
Reaven, G. M. (1988) · Diabetes · doi:10.2337/diab.37.12.1595 · Cited by 12,154
Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance
Hotamisligil, G. S., Shargill, N. S., & Spiegelman, B. M. (1993) · Science · doi:10.1126/science.7678183 · Cited by 7,518
Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963) · The Lancet · doi:10.1016/s0140-6736(63)91500-9 · Cited by 5,093
Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., et al. (2001) · Nature Medicine · doi:10.1038/90984 · Cited by 4,915
Paradoxical Decrease of an Adipose-Specific Protein, Adiponectin, in Obesity
Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J.-I., Hotta, K., Shimomura, I., Nakamura, T., Miyaoka, K., et al. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0255 · Cited by 4,856
The hormone resistin links obesity to diabetes
Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S., & Lazar, M. A. (2001) · Nature · doi:10.1038/35053000 · Cited by 4,755
DeFronzo, R. A., & Ferrannini, E. (1991) · Diabetes Care · doi:10.2337/diacare.14.3.173 · Cited by 4,555
Self-citationWeight-Reducing Effects of the Plasma Protein Encoded by the obese Gene
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K., & Friedman, J. M. (1995) · Science · doi:10.1126/science.7624777 · Cited by 4,451
Research works printed but not linked: 16
- Kelley, 1995, Effects of weight loss on glucose homeostasis in NIDDM., Diabetes Rev, 3, 366
- Schneider, 1995, Effects of fitness and physical training on carbohydrate metabolism and associated cardiovascular risk factors in patients with diabetes., Diabetes Rev, 3, 378
- Kashyap, 2002, Chronic elevation in plasma free fatty acids impairs insulin secretion in non-diabetic offspring with a strong family history of T2DM, Diabetes, 51, A12
- 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
- Kashyap, 2002, A chronic physiologic increase in FFA in healthy subjects causes insulin signaling defects similar to those of insulin-resistant non-diabetic subjects with a strong family history of T2DM, Diabetes, 51, A24
- Seppala-Lindroos, 2002, Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men., J Clin Endocrinol Metab, 87, 3023, 10.1210/jcem.87.7.8638 · DOI · Paper page
- McTernan, 2002, Depot-specific expression of resistin in human adipose tissue and regulation of resistin secretion by insulin and rosiglitazone in human subcutaneous adipocytes in vitro, Diabetologia, 45, A66
- Groop, 1992, Effect of insulin on oxidative and non-oxidative pathways of glucose and free fatty acid metabolism in human obesity, Am J Physiol, 263, E79
- Krssak, 1999, Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study., Diabetologia, 42, 113, 10.1007/s001250051123 · DOI · Paper page
- Stein, 1999, Increasing intramyocellular triglyceride stores are associated with impaired glucose tolerance and NIDDM, Diabetes, 48, A287
- Greco, 2002, Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion., Diabetes, 51, 144, 10.2337/diabetes.51.1.144 · DOI · Paper page
- Kahsyap, 2003, Effect of sustained reduction in plasma FFA concentration on insulin secretion in non-diabetic subjects with a strong family history of T2DM, Diabetes, 52, A336
- Chilcott, 2001, A systematic review of the effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus., Clin Ther, 23, 1792, 10.1016/S0149-2918(00)80078-8 · DOI
- Finegood, 2001, β-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
- Lupi, 2002, PPARγ ligand-specificity in the modulation of insulin release from isolated human islets in response to fatty acid incubation, Diabetologia, 45, A161
- Marselli, 2002, Rosiglitazone partially prevents free fatty acid-induced cytotoxicity of human pancreatic islet cells, Diabetologia, 45, A161
Cited by
Sorted by citations
DeFronzo, R. A. (2009) · Diabetes · doi:10.2337/db09-9028 · Cited by 3,016
Self-citationDeFronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.19 · Cited by 2,611
Self-citationPathogenesis of type 2 diabetes mellitus
DeFronzo, R. A. (2004) · Medical Clinics of North America · doi:10.1016/j.mcna.2004.04.013 · Cited by 1,342
Self-citationAMP-activated protein kinase signaling in metabolic regulation
Long, Y. C. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29044 · Cited by 1,125
International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors
Michalik, L., Auwerx, J. H., Berger, J. P., Chatterjee, K., Glass, C. K., Gonzalez, F. J., Grimaldi, P. A., Kadowaki, T., Lazar, M. A., O’Rahilly, S., et al. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.4.5 · Cited by 1,022
Metadata
- Authors
- Bays, H., Mandarino, L., & DeFronzo, R. A.
- Affiliations
- Louisville Metabolic and Atherosclerosis Research Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-02-01
- Volume
- 89
- Issue
- 2
- Pages
- 463-478
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2151025367
- Cited by
- 664
- References
- 328
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 20 · 2023: 13 · 2022: 27 · 2021: 12 · 2020: 14 · 2019: 22 · 2018: 24 · 2017: 20 · 2016: 24 · 2015: 31 · 2014: 42 · 2013: 48 · 2012: 28
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- type 2 diabetes, free fatty acids, lipotoxicity, ectopic fat, thiazolidinediones, adipokines, insulin secretion, hepatic insulin resistance, muscle insulin resistance, adipocyte lipolysis, fat redistribution, impaired glucose tolerance
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Humans, Obesity, Transcription Factors, Adipocytes, Receptors, Cytoplasmic and Nuclear, Lipid Metabolism
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