Medical Biochemistry - Carbohydrates

Carbohydrates are central to human metabolism, serving as primary fuels, structural constituents and signalling molecules. Dietary starches and sugars are digested to glucose, which enters cells via specific transporters and is metabolised through glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation to generate ATP. Excess glucose can be stored as glycogen in liver and muscle or diverted into the pentose phosphate pathway for reductive biosynthesis and antioxidant defence. In states of increased nutrient supply, hepatocytes engage in de novo lipogenesis, converting acetyl-CoA into fatty acids for triglyceride assembly. Conversely, during fasting, gluconeogenesis in liver and kidney maintains blood glucose. Balanced carbohydrate flux is essential for energy homeostasis, while dysregulation underlies conditions such as insulin resistance, type 2 diabetes and nonalcoholic fatty liver disease.

Research from Nature Portfolio

A human iPSC-based co-culture model has been developed to recapitulate inflammation-induced hepatic insulin resistance. In this system, hepatocytes exposed to cytokine-activated macrophages exhibit impaired insulin-mediated suppression of gluconeogenesis. Tumour necrosis factor α and interleukin-1β were shown to act via NF-κB and JNK pathways to disrupt insulin receptor signalling, and combined cytokine neutralisation restored insulin sensitivity more effectively than single-cytokine blockade.

An advanced mass-spectrometry approach now resolves deuterium and carbon-13 isotopomers of fatty acids using high-resolution Orbitrap instruments. This allows de novo lipogenesis to be quantified in hours rather than days and with lower tracer doses. In mice, nocturnal activation of lipogenesis was captured in real time, and in human volunteers post-prandial and post-fasting fluxes were measured within a four-hour window, enabling minimally invasive clinical studies of hepatic lipid synthesis.

Mechanistic studies in murine models of insulin resistance have identified WD40 repeat-containing protein 6 (WDR6) as a driver of persistent hepatic lipogenesis. WDR6 interacts with the catalytic subunit of protein phosphatase 1 (PPP1CB), promoting its dephosphorylation and enhancing transcription of fatty acid synthase via DNA-dependent protein kinase and USF1. A natural compound was shown to disrupt the WDR6–PPP1CB interaction, reducing lipid accumulation in insulin-resistant liver, and offering a new target for steatosis therapy.

Medical Biochemistry - Carbohydrates publication trend

The graph below shows the total number of articles in medical biochemistry - carbohydrates across all publications each year (not limited to Nature Index journals).

Technical terms

De novo lipogenesis (DNL): The metabolic pathway by which acetyl-CoA is converted into fatty acids, typically upregulated in hyperinsulinaemia.

Metabolic flux analysis: Quantitative measurement of pathway reaction rates using isotope tracers to determine substrate contributions to metabolic products.

Induced pluripotent stem cells (iPSCs): Somatic cells reprogrammed to a pluripotent state, used to model human hepatocyte function in vitro.

Insulin resistance: A condition in which target tissues fail to respond adequately to insulin, resulting in impaired suppression of hepatic glucose output and altered lipid metabolism.

Orbitrap mass spectrometry: A high-resolution mass analyser capable of distinguishing closely spaced isotopic peaks, improving sensitivity in tracer-based studies.

References

1. Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages. Nature Communications (2023).
2. Measurement of lipogenic flux by deuterium resolved mass spectrometry. Nature Communications (2021).
3. Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice. Nature Metabolism (2023).
4. The Effects of Long-Term High Fat and/or High Sugar Feeding on Sources of Postprandial Hepatic Glycogen and Triglyceride Synthesis in Mice. Nutrients (2024).
5. A high-fat diet suppresses de novo lipogenesis and desaturation but not elongation and triglyceride synthesis in mice[S]. Journal of Lipid Research (2014).
6. Carbohydrate Metabolism.