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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Increased intramyocellular fat content and fatty acid metabolites have a pivotal role in the development of skeletal muscle insulin resistance.
“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]
Dysregulation of fatty acid metabolism has a central role in the development of insulin resistance in skeletal muscle.
“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]
Elevated plasma free fatty acid levels have a causative role in skeletal muscle insulin resistance.
“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]
Chronically elevated plasma free fatty acid levels cause insulin resistance in skeletal muscle.
“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]
Elevated plasma free fatty acid levels have an important role in the pathogenesis of insulin resistance.
“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]
Insulin resistance, in combination with beta cell dysfunction, contributes to the development of type 2 diabetes.
“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]
Obesity, particularly visceral and ectopic adiposity, increases the risk of type 2 diabetes.
“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]
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- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › 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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