Lipotoxicity in the Pathogenesis of Obesity-Dependent NIDDM: Genetic and Clinical Implications
Abstract
We review evidence that increased tissue levels of fatty acyl CoA cause the β-cell abnormalities of nondiabetic obesity and ultimately result in obesity-dependent diabetes. Nondiabetic obesity in Zucker rats is characterized by hypersecretion of insulin at normal fasting and subfasting glucose concentrations. This is a result of β-cell hyperplasia and increased low Km glucose usage and oxidation. These abnormalities, the hyperinsulinemia, the hyperplasia of β-cells, i.e., its in vitro equivalent, enhanced bromodeoxyuridine incorporation, and the increased low Km glucose usage can be induced by culturing normal islets with 2 mmol/l free fatty acids (FFAs). Once obese Zucker diabetic fatty rats become diabetic, glucose-stimulated insulin secretion (GSIS) is absent and β-cell GLUT2 reduced. Islet triglyceride (TG) content is increased 10-fold, probably reflecting increased FFA delivery (plasma FFA levels > 1.5 mmol/l) beginning about 2 weeks before the onset of diabetes. These β-cell abnormalities, GSIS loss, GLUT2 loss, and TG accumulation, are prevented by reducing plasma FFAs by caloric restriction and by nicotinamide injection. The loss of GSIS and the accumulation of TGs, but not the GLUT2 loss, can be induced in vitro in normal islets cultured in a 2 mmol/l FFA-containing medium, but prediabetic islets seem far more vulnerable to FFA-induced functional impairment and TG accumulation. It is proposed that in uncomplicated obesity, increased lipid availability (FFA levels <1.5 mmol/1) induces both hyperinsulinemia and insulin resistance in parallel fashion, thereby maintaining normoglycemia. A further increase in substrate overload impairs β-cell compensation for insulin resistance and hyperglycemia appears.
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Elevated plasma free fatty acid levels have a causative role in the pathogenesis of skeletal muscle insulin resistance, a phenomenon referred to as lipotoxicity.
“Collectively, these results support a causative role of elevated plasma FFA levels in the pathogenesis of insulin resistance in skeletal muscle and have been referred to as “lipotoxicity” [73].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [73]
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- Authors
- Unger, R. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Unger, Roger H
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1995-08-01
- Volume
- 44
- Issue
- 8
- Pages
- 863-870
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2002711503
- Cited by
- 1,100
- References
- 0
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 24 · 2023: 23 · 2022: 20 · 2021: 27 · 2020: 40 · 2019: 22 · 2018: 34 · 2017: 36 · 2016: 32 · 2015: 28 · 2014: 33 · 2013: 37 · 2012: 45
- FWCI
- 25.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01dk042582-04)
- National Institute of Diabetes and Digestive and Kidney Diseases (1-P01-DK42582, DK 02700)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- lipotoxicity, obesity, type 2 diabetes, fatty acyl-CoA, free fatty acids, beta-cell dysfunction, hyperinsulinemia, beta-cell hyperplasia, glucose-stimulated insulin secretion, GLUT2, Zucker rats, caloric restriction, nicotinamide, insulin resistance, islet culture
- MeSH terms
- Insulin Secretion, Acyl Coenzyme A, Animals, Blood Glucose, Diabetes Mellitus, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Glucose, Humans, Insulin, Islets of Langerhans, Niacinamide, Obesity, Rats, Zucker, Adipocytes, Rats
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