The integrative biology of type 2 diabetes
Open accessAbstract
Obesity and type 2 diabetes are the most frequent metabolic disorders, but their causes remain largely unclear. Insulin resistance, the common underlying abnormality, results from imbalance between energy intake and expenditure favouring nutrient-storage pathways, which evolved to maximize energy utilization and preserve adequate substrate supply to the brain. Initially, dysfunction of white adipose tissue and circulating metabolites modulate tissue communication and insulin signalling. However, when the energy imbalance is chronic, mechanisms such as inflammatory pathways accelerate these abnormalities. Here we summarize recent studies providing insights into insulin resistance and increased hepatic gluconeogenesis associated with obesity and type 2 diabetes, focusing on data from humans and relevant animal models.
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With increasing hepatic lipid accumulation, the generation of toxic lipid intermediates and altered hepatic mitochondrial respiration rates drive hepatic insulin resistance, inflammation and oxidative stress, all fueling pro-fibrotic pathways.
“With increasing hepatic lipid accumulation, the generation of toxic lipid intermediates (diacylglycerols, ceramides) and altered hepatic mitochondrial respiration rates drive hepatic insulin resistance, inflammation and oxidative stress -all of them fueling pro-fibrotic pathways (Fig. 1) [26,27].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [26]
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Experimental — accuracy not yet measuredDeposition of ectopic fat within pancreatic islets, possibly inside β cells themselves, contributes to progressive impairment of β-cell function (which is reversible with weight loss) in individuals who are genetically susceptible.
“Emerging evidence supports the concept that deposition of ectopic fat within pancreatic islets, possibly inside β cells themselves, contributes to progressive impairment of β-cell function (which is reversible with weight loss)115 in individuals who are genetically susceptible.116–118”
From Definition and diagnostic criteria of clinical obesity (2025) · cites this paper as [118]
The paper’s introductory discussion says that many type 2 diabetes-associated genetic variants relate to islet function, and its Outlook says acquired and inherited factors can impair insulin secretion. But the passages found do not link genetic susceptibility to fat deposition within islets or β cells; the weight-loss findings discussed concern liver fat and insulin resistance, not reversal of β-cell impairment. (LLM, conf=0.78)
Experimental — accuracy not yet measuredNEFA promote hepatic triglyceride storage and gluconeogenesis when the capacity of the liver to oxidize these substrates or export them as VLDL is depleted.
“Here, NEFA promote hepatic triglyceride storage and gluconeogenesis [26], when the capacity of the liver to oxidize these substrates or export them as very-low-density lipoproteins (VLDL) is depleted [19].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [26]
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Beyazal Polat, H., Beyazal, M., Arpa, M., Kızılkaya, B., Ayaz, T., Gündoğdu, Ö. L., Konur, K., Polat, Z., Beyazal Çeliker, F., & Atasoy, H. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14103513 · Cited by 13 · see citing works
- Authors
- Roden, M., & Shulman, G. I.
- Affiliations
- Deutsches Diabetes-Zentrum e.V. (DE)
- Yale University (US)
- Corresponding author
- Roden, Michael
- Shulman, Gerald I.
- Venue
- Nature
- Published
- 2019-12-04
- Volume
- 576
- Issue
- 7785
- Pages
- 51-60
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2992666626
- Cited by
- 1,167
- References
- 149
- Citations by year
- 2026: 141 · 2025: 184 · 2024: 188 · 2023: 209 · 2022: 189 · 2021: 163 · 2020: 90 · 2019: 2 · 2015: 1
- FWCI
- 16.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- AstraZeneca
- Sanofi
- Gilead Sciences
- Danone
- Bundesministerium für Bildung und Forschung (SFB 1116)
- Bundesministerium für Gesundheit
- National Institutes of Health (P30 DK, DK045735)
- European Regional Development Fund (E! 113230 DIA-PEP, EFRE-0400191)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119968, R01DK114793, R01DK116774, R01DK113984, P30DK045735)
- Janssen Research and Development
- Eurostars
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- type 2 diabetes, obesity, insulin resistance, energy balance, white adipose tissue, circulating metabolites, insulin signaling, inflammation, hepatic gluconeogenesis, nutrient storage
- MeSH terms
- Adipose Tissue, Animals, Diabetes Mellitus, Type 2, Eating, Humans, Hyperglycemia, Insulin Resistance, Liver
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