D-Allulose in carbohydrate and fat metabolism

Due to changing living conditions, the incidence of obesity and obesity-related endocrine diseases has increased.

In addition to lifestyle changes, they also began to look for other treatment options to prevent these diseases.

D-Allulose is the third carbon epimer of fructose and is rarely found in nature.

Allulose exerts its effects through various mechanisms, including potent antioxidant effects, inhibitory activity against intestinal digestive enzymes, translocation of glucokinase from the liver nucleus to the cytoplasm, and competitive transport of glucose across the intestinal mucosa.

It also has antihyperlipidemic and antihypertriglyceridemic effects on fat metabolism.

Toxicity studies on rats with D-allulose did not show any adverse effects and it is considered safe.

Because it reduces monosaccharide absorption, enhances fatty acid oxidation, and suppresses glucose oxidation when administered orally, it can be considered an alternative treatment method in addition to lifestyle changes in the treatment of obesity and related diseases.

D-Allulose in carbohydrate and fat metabolism

Introduction

AD-allulose (also known as D-psicose) is a rare monosaccharide that occurs naturally in small amounts in dried fruits, brown sugar, and maple syrup.

It has the same chemical structure as fructose, differing only in the configuration of one of the hydroxyl groups, which fundamentally changes its metabolic pathways and energy content.

Unlike traditional sugar, D-allulose is largely not metabolized into glucose in the body, so its energy content is only about 0.4 kcal/g, compared to 4 kcal/g for sucrose.

Over the past decade, numerous studies have examined how this “calorie-free sugar” affects human carbohydrate and fat metabolism, body weight control, and insulin sensitivity.

Biochemical properties

AD-allulose is an epimer of fructose at the C-3 position, which gives it special properties in enzymatic interactions.

The glucotransporter system (GLUT5) is able to absorb it from the intestine, but allulose is not converted to glucose by the liver due to the lack of further metabolism initiated by fructokinase.

This results in D-allulose entering the bloodstream being excreted unchanged in the urine after a short time.

Through this mechanism, D-allulose is able to modulate carbohydrate metabolism without functioning as an actual energy carrier.

Its effect on blood sugar levels and insulin response is clinically demonstrably negligible.

Effects on carbohydrate metabolism

Regulating blood sugar and insulin levels

AD-allulose inhibits intestinal glucose absorption and promotes hepatic glycogen synthesis while reducing hepatic gluconeogenesis.

Animal studies have shown that D-allulose supplementation increases insulin sensitivity and reduces postprandial blood sugar spikes.

This is particularly relevant among adjunctive therapeutic strategies for type 2 diabetes.

Enzymatic mechanisms

At the biochemical level, D-allulose activates the PI3K/Akt pathway involved in the insulin signaling pathway, which promotes the translocation of GLUT4 glucose transporters to the cell membrane.

This effect facilitates glucose uptake into muscle and fat cells without triggering insulin secretion.

Furthermore, some studies suggest that allulose can inhibit the enzyme alpha-glucosidase, thereby slowing the breakdown of complex carbohydrates in the intestine — an effect that further reduces postprandial blood sugar spikes.

Effects on fat metabolism

Lipid profile and visceral fat

Clinical and preclinical studies have shown that D-allulose significantly reduces visceral fat, a key factor in metabolic syndrome and insulin resistance. Allulose inhibits key enzymes of lipogenesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), while stimulating fatty acid oxidation in the liver.

Mitochondrial oxidation and energy balance

AD-allulose enhances the activity of AMP-activated protein kinase (AMPK), the main regulatory enzyme of fatty acid oxidation.

At the same time, activation of AMPK inhibits the formation of new fatty acids and promotes mitochondrial energy use.

Through this process, allulose also plays a role in maintaining energy homeostasis: the body spends more energy on breaking down fat stores while optimizing carbohydrate oxidation.

Thermogenesis and weight control

Animal model experiments have shown that consuming D-allulose promotes the activation of brown adipose tissue and increases thermogenesis.

The increased energy expenditure is partly related to increased expression of UCP1 (uncoupling protein-1), which is key to thermogenesis and fat oxidation.

In human studies, daily intake of 5–10 g of D-allulose was associated with lower body mass index (BMI) and a more favorable lipid profile.

The effect results from an improvement in the efficiency of fat oxidation, in addition to a moderate reduction in calorie intake.

The relationship between liver and intestinal metabolism

A significant portion of AD-allulose temporarily accumulates in the liver and is then excreted without being converted to glucose.

This “metabolically inert” cycle reduces hepatic glucose output, which supports blood sugar stability.

At the level of the gut microbiota, allulose has a beneficial effect on bacterial composition: it promotes the growth of Bacteroidetes-type strains, which reduce the efficiency of energy absorption and act against fat storage.

Oxidative stress and anti-inflammatory effects

AD-allulose has antioxidant properties as it can reduce the levels of reactive oxygen radicals (ROS) in liver and fat cells.

This effect is mediated in part through the AMPK-dependent signaling pathway and contributes to protection against insulin resistance.

Some animal studies have also shown that allulose reduces the expression of inflammatory cytokines (e.g. TNF-α, IL-6) in the liver, thereby reducing the progression of non-alcoholic fatty liver disease (NAFLD).

D-Allulose in the prevention of obesity and metabolic syndrome

In addition to reducing visceral fat, long-term consumption of allulose improves leptin and adiponectin balance, which is key to appetite and energy homeostasis.

By restoring leptin sensitivity, allulose may support long-term weight control.

Based on human studies, allulose can be safely consumed up to a daily dose of 0.4 g/kg body weight, with only mild, transient gastrointestinal complaints (bloating, mild diarrhea) reported as side effects at higher doses.

Overview of cellular metabolism

The metabolic effects of allulose at the cellular level occur through the following mechanisms:

• Activation of AMPK – promotes fatty acid oxidation and inhibits lipogenesis.
• Modulation of PI3K‑Akt signaling – improves insulin sensitivity.
• GLUT4 translocation – enhances glucose uptake in muscles.
• Alpha-glucosidase inhibition – slows down the breakdown of carbohydrates.
• Increasing UCP1 expression – enhances thermogenesis and energy expenditure.

These molecular effects collectively promote optimal metabolic balance, in which glucose and lipid oxidation are effectively regulated.

Clinical application perspectives

Future applications of AD-allulose could include a number of areas:

• Functional foods – development of low glycemic index products.
• Diabetes prevention – as a dietary supplement for insulin-resistant or prediabetic individuals.
• Fatty liver therapy – through favorable modulation of liver lipid metabolism.
• Sports nutrition – body fat optimization without excess calories.

Summary

AD-allulose occupies a special place among the “rare sugars” because it is able to influence carbohydrate and fat metabolism without providing an actual source of energy.

Its effects are mediated by several mechanisms: it inhibits gluconeogenesis, improves insulin sensitivity, activates the AMPK pathway, reduces lipogenesis, and promotes fatty acid oxidation.

These properties make D-allulose a promising tool for maintaining metabolic health, preventing obesity, and reducing the risk of type 2 diabetes.