Interval training 'rewires' the liver and reduces insulin resistance in type 2 diabetes

Scientific Reports presents a preclinical study: eight weeks of high-intensity interval training (HIIT) in rats with induced type 2 diabetes reduced insulin resistance and “improved” liver metabolism. The key player is the relatively new adipokine spexin (SPX): its level in the serum and liver increased during HIIT, and along with it, liver expression of the GALR2 receptor and metabolic regulators associated with lipolysis and mitochondrial function increased. The authors formulate it carefully: these are associations, but they fit well with the idea that part of the benefit of training in diabetes is mediated by the spexin → liver axis.

Background of the study

Insulin resistance in the liver is one of the central “drivers” of type 2 diabetes: the liver continues to produce glucose (gluconeogenesis) and synthesize fat (lipogenesis) even when the insulin signal says “stop.” To model this condition in preclinical studies, the high-fat diet + low-dose streptozotocin (HFD+STZ) rat regimen is often used: obesity and inflammation from the HFD shift metabolism, and STZ partially “hook” β-cells, bringing the phenotype closer to the late stages of T2DM. This is an established and widely used model, although its exact similarity to human T2DM depends on the residual β-cell mass and the induction regimen.

Physical activity is one of the non-drug ways to “reset” insulin sensitivity. High-intensity interval training (HIIT) has attracted a lot of attention: in a number of studies, it improved glycemic control and liver/fat insulin resistance, not only due to weight loss, but also through molecular pathways of energy (AMPK, SIRT-1, PGC-1α) and mitochondrial biogenesis; in humans, fast intervals increase nuclear PGC-1α after an acute session. Against this background, it is logical to check whether HIIT also affects the liver nodes of gluconeogenesis/lipid metabolism.

A separate “new variable” is spexin (SPX), a 14-amino acid peptide/adipokine associated with the regulation of energy, appetite, and lipid metabolism via GALR2/3 receptors. Its expression has been described in the liver, adipose tissue, skeletal muscle, and other organs; in humans, low SPX is associated with obesity and T2DM, while exercise training increases circulating SPX (shown in both aerobic/resistance protocols and in the elderly). In cellular and animal models, SPX suppresses gluconeogenesis and lipogenesis, and supports lipolysis and mitochondrial programs (PPARα/PGC-1α/CPT1A), making it a candidate mediator of training benefits.

A new paper in Scientific Reports brings these lines together: using the HFD+STZ model, the authors test whether 8 weeks of HIIT reduces insulin resistance and adverse liver fluxes (gluconeogenesis, lipogenesis), and whether this is accompanied by activation of the SPX→GALR2 axis and metabolic regulators (AMPK/SIRT-1/PGC-1α/PPARα/CPT1A). This design helps to understand whether the increase in SPX during training is simply a marker of improvement or part of a mechanistic “chain” linking HIIT to improved liver metabolism.

How the study was conducted

The experiment involved 28 male Wistar rats, dividing them into 4 groups: healthy control, diabetes without training, HIIT in healthy and HIIT in diabetes (after the HFD + low-dose streptozotocin model). The HIIT protocol lasted 8 weeks: 4-10 intervals per session - 2 minutes at 80-100% of individual Vmax and 1 minute at low speed; Vmax was determined by step runs and recalculated every two weeks. Fasting glucose, insulin, HOMA-IR/HOMA-β and QUICKI indices, inflammation/oxidative stress indices were assessed, and in the liver, the levels of SPX, GALR2, AMPK, SIRT-1, PPARα, PGC-1α, CPT1A (lipolysis/mitochondria) and PEPCK, G6Pase (gluconeogenesis), ACC, FAS, SREBP-1c (lipogenesis) were measured.

What they found: metabolic “restructuring” for the better

Diabetic rats that performed HIIT, compared to non-training diabetic animals, showed:

• Better glycemic indices: lower HOMA-IR, higher HOMA-β and QUICKI; fasting glucose decreased.
• Shift in liver expression towards “fat burning”: higher SPX and GALR2, AMPK, SIRT-1, PPARα, PGC-1α, CPT1A; lower gluconeogenesis enzymes PEPCK, G6Pase and lipogenesis enzymes ACC, FAS, SREBP-1c.
• Anti-inflammatory and antioxidant profile: decreased inflammatory markers and increased antioxidant activity in the liver. The authors describe a “general health-promoting effect” on liver tissue.

In other words, HIIT in diabetic rats simultaneously inhibits gluconeogenesis and lipogenesis and upregulates lipolysis and mitochondria, which is consistent with a reduction in insulin resistance. On a molecular level, this is accompanied by an increase in specxin signaling.

Why is specxin involved and what does the liver have to do with it?

Spexin is a peptide from adipose tissue that binds to galanin receptors 2/3. In clinical observations, low SPX is associated with obesity, IR, and T2DM; physical activity increases its levels. Mechanistically, SPX can reduce gluconeogenesis and lipogenesis and maintain lipolysis, as well as increase the expression of CPT1A, PPARα, PGC-1α. In the new work, it was against the background of HIIT in diabetic rats that SPX and GALR2 increased in the liver - this is consistent with improvements in metabolism and insulin sensitivity, although the cause-and-effect relationship requires direct interventions in SPX signaling.

How this changes the picture of the benefits of HIIT in diabetes

It has long been known that interval protocols are often more effective than moderate cardio for glycemic control. The new detail is the liver component of this benefit: HIIT not only trains the muscle, but also “teaches” the liver to produce less glucose and fat and to oxidize fatty acids more actively, in part through the SPX→GALR2 axis and AMPK/SIRT-1/PGC-1α nodes. This helps to link the classic improvements in HOMA/QUICKI indices to specific liver targets.

Where is the practical sense (and caution) here?

This is preclinical work, but it provides guidance for future translational steps.

• What to look for in the clinic: SPX in the blood as a potential marker of response to training; liver AMPK/SIRT-1/PGC-1α pathways as points of pharmacological synergy with exercise therapy.
• What type of load was studied: short intervals of 2 min "fast" / 1 min "slow" at 80-100% of individual maximum speed - these are the "peaks" that could shift SPX the most. (This is a description of the protocol in rats, not a ready-made program for people.)
• Limitations: rats ≠ humans; sample size n=7 per group; no direct blockade of SPX/GALR2, so SPX is still a co-marker rather than a proven cause. RCTs in humans with objective liver markers and stratification by exercise type are needed.

What to check next

• Conduct SPX interventions (antagonists/agonists, knockout/overexpression) during HIIT to clarify causality.
• To carry out a hypothesis in small clinical pilots: HIIT vs moderate aerobics, dynamics of SPX, insulin resistance and liver fat (MR spectroscopy/elastography).
• To evaluate the long-term effect and “dosage” of HIIT (frequency/intensity), as well as possible differences by gender/age and concomitant therapy.

Briefly - the main points from the article

• HIIT in type 2 diabetes in rats reduced insulin resistance and re-shifted liver metabolism toward lipid oxidation, while increasing specxin and its liver signaling.
• Improvements affected gluconeogenesis (↓PEPCK, G6Pase), lipogenesis (↓ACC, FAS, SREBP-1c) and energy (↑AMPK, SIRT-1, PPARα, PGC-1α, CPT1A).
• These are preclinical associations; mechanistic and clinical confirmation are needed to translate them into recommendations for humans.

Source: Khoramipour K. et al. High intensity interval training attenuate insulin resistance in diabetic rats accompanied by improvements in liver metabolism and spexin signaling. Scientific Reports, August 21, 2025. DOI: https://doi.org/10.1038/s41598-025-15432-8