# How effective are sodium-glucose cotransport activators in improving water absorption?

## Sodium-glucose cotransport activators effectively improve water absorption in both experimental models and human subjects, with amino acid-based and glucose-based formulations showing significant increases in water uptake rates.

# Abstract

Sodium‐glucose cotransport activators improve water absorption in both experimental models and human subjects. Many studies report that amino acid–based activators—most notably L‑alanine and leucine—increase water uptake, with one study noting a rise from 17.4 to 43.9 μL/min/g (p < 0.001). Glucose‐based formulations administered in carefully balanced oral rehydration solutions yield similarly positive results; for example, one report documented an increase of 98.6 ± 16 μL/min/g (p < 0.01), and glucose polymers increased absorption rates from 221–240 to 291–332 μL/min/g (p < 0.02 to p < 0.005). In addition, interventions such as stevia extract yielded a 1.8‐fold boost in SGLT1‐mediated glucose transport (p < 0.05), an effect linked to improved water uptake. In diarrheal or secretory models, these activators also lower net fluid secretion and reduce stool water content. Overall, the studies indicate that activators targeting the sodium‐glucose cotransport mechanism effectively enhance water absorption as measured by both quantitative fluid uptake and associated transporter activity.

## Methods

We analyzed 29 sources from an initial pool of 997, using 7 screening criteria. Each paper was reviewed for 5 key aspects that mattered most to the research question. More on methods

Papers identified with Elicit search

n = 997

Papers screened using: SGLT Activators/Enhancers, Water Absorption Outcome, In Vivo Studies, Appropriate Study Design, SGLT Activators vs Inhibitors, Beyond In Vitro Only, Publication Quality

n = 997

Papers screened out

n = 968

Papers included for extraction

n = 29

## Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

- **Study Design Type**:
Identify the specific type of study design used. Look in the methods section for details about the study approach. Possible types include:

- Animal experimental study
- Human intervention study
- In vivo physiological study
- Noninvasive experimental study

If multiple design elements are present, list all relevant types. If unclear, note “design not clearly specified”. Prioritize the most specific description of the study design.

- **Animal/Human Model Characteristics**:
Extract specific details about the study subjects:

- For animal studies: species, strain, number of animals, sex, age/weight range
- For human studies: number of participants, age range, sex distribution, health status

If multiple groups are studied, provide details for each group. Use exact numbers and ranges from the text. If any characteristics are not reported, write “not reported”.

- **Sodium-Glucose Cotransport Intervention Details**:
Identify and extract:

- Specific substances used to activate sodium-glucose cotransport
- Concentration of interventional substances
- Method of administration (oral, intravenous, etc.)
- Duration of intervention

If multiple interventions were tested, list all with their specific details. If no direct intervention was used, note the specific experimental conditions that examined cotransport activation.

- **Water and Electrolyte Absorption Outcomes**:
Extract quantitative outcomes related to water and electrolyte absorption:

- Specific absorption measurements (e.g., percentage, volume, rate)
- Measured substances (water, sodium, chloride, etc.)
- Statistical significance of results
- Measurement methods used

Prioritize primary outcomes directly addressing water absorption. Include numerical values with appropriate units when available.

- **Mechanism of Sodium-Glucose Cotransport**:
Identify and extract:

- Specific molecular or cellular mechanisms described
- Transporters or pathways involved (e.g., SGLT-1)
- Any inhibition or activation mechanisms observed

If multiple mechanisms are discussed, list all. If mechanisms are speculative, note this explicitly.

# Results

## Characteristics of Included Studies

Study

| Study | Study Design | Clinical Condition | Intervention Type | Primary Outcome Measure |
|----------|----------------|-----------------|------------------|------------------------|
| Wapnir et al., 1988 | Animal experimental study | Osmotic diarrhea (rats) | L-alanine, protein hydrolysate in oral hydration solution | Water and sodium absorption |
| Rongione et al., 2001 | Animal experimental; in vivo physiological | Normal dogs | Epidermal Growth Factor (EGF), Transforming Growth Factor (TGF) | Sodium, chloride, water, glucose absorption |
| Grahammer et al., 2006 | Animal experimental; in vivo physiological | Normal and dexamethasone-treated mice | Dexamethasone | Sodium-glucose cotransporter 1 (SGLT1) / Sodium-hydrogen exchanger 3 (NHE3) activity, sodium absorption |
| Aguero et al., 1990 | Animal experimental; in vivo physiological | Normal and diarrheic Wistar rats | Glutamine in World Health Organization Oral Rehydration Solution (WHO-ORS) | Sodium and water absorption |
| Wapnir et al., “Enhancement by Alanine” | Animal experimental; in vivo physiological | Chronic diarrhea (rats) | L-alanine, protein hydrolysate in oral hydration solution | Water and sodium absorption |
| Sundaram et al., “Corticosteroids Reverse Na-Glucose Cotransport” | Animal experimental; in vivo physiological | Chronic ileal inflammation (rabbits) | Methylprednisolone | SGLT1 activity |
| Wapnir et al., 1990 | Animal experimental; in vivo physiological | Secretory diarrhea (rats) | L-alanine in oral hydration solution | Water and sodium absorption |
| Elliott et al., 1986 | Animal experimental; in vivo physiological | Secretory diarrhea (rats) | Oral rehydration solution with varying glucose:sodium ratios | Water absorption |
| Laverty et al., 2001 | Animal experimental | High/low salt diet (hens) | Aldosterone | SGLT activity, short-circuit current (Isc) |
| Summers and Schedl, 1968 | In vivo physiological; animal experimental | Normal rats | Glucose, mannitol, varying tonicity | Sodium and water absorption |

## Summary of study characteristics:

- **Study design**:
  - 23 studies were animal experimental (including in vivo physiological models).
  - 6 studies were human intervention studies (including in vivo physiological and noninvasive designs).
- **Clinical condition and species**:
  - 12 studies used diarrhea models (including cholera, rotavirus, Escherichia coli, secretory, and osmotic diarrhea).
  - 7 studies used normal (healthy) animals or humans.
  - 3 studies used short bowel syndrome models.
  - 2 studies used inflammation or enteropathy models.
  - 1 study used a diabetes model.
  - 2 studies used genetic models (PDK-1, SGLT1).
  - 2 studies used other models (high/low salt diet, tacrolimus treatment).
  - 11 studies used rats, 6 used mice, 3 used rabbits, 2 used dogs, 1 used hens, and 6 used humans (one study used oocytes with mice).
- **Intervention type**:
  - 6 studies tested amino acids or protein hydrolysate (including glutamine and alanine).
  - 6 studies tested oral rehydration solution composition (glucose:sodium ratio, cereal-based, glucose polymer, dextrin).
  - 3 studies tested hormones (aldosterone, Angiotensin II, Teduglutide).
  - 2 studies tested growth factors (Epidermal Growth Factor, Transforming Growth Factor).
  - 2 studies tested steroids (dexamethasone, methylprednisolone).
  - 2 studies tested plant extracts (stevia, gum arabic).
  - 2 studies tested glucose analogs (alpha-methyl-D-glucoside, alpha-methyl D-glucoside).
  - 2 studies tested gene therapy or genetic modification (SGLT1 transfection, PDK-1 reduction).
  - 1 study tested an immunosuppressant (tacrolimus).
  - 1 study tested kinase modulation (GSK3β).
  - 3 studies tested dietary or meal ingestion interventions.
- **Primary outcome measures**:
  - 15 studies measured water and sodium absorption.
  - 10 studies measured SGLT1 or NHE3 activity or expression.
  - 3 studies measured water absorption alone.
  - 3 studies measured glucose or galactose absorption or transport.
  - 1 study measured clinical outcomes (stool volume, duration; Khin-Maung-U and Greenough, 1991).
  - 1 study measured fluid balance (plasma/urine volume).
  - 2 studies measured other outcomes (paracellular absorption, hormonal measures).

----

## Water Absorption Outcomes

| Study | Activator Type | Water Absorption Effect | Effect Size | Statistical Significance |
|------|---------------|---------------------|-------------|-------------------|
| Wapnir et al., 1988 | L-alanine, protein hydrolysate | Increased water absorption | “Very significant increase” | No mention found |
| Rongione et al., 2001 | Epidermal Growth Factor, Transforming Growth Factor | Increased water absorption | Not quantified | Significant vs. mixed meal (no further details in abstract) |
| Grahammer et al., 2006 | Dexamethasone | No mention found | N/A | N/A |
| Aguero et al., 1990 | Glutamine | Increased water absorption | Not quantified | Not significant (p>0.05) |
| Wapnir et al., “Enhancement by Alanine” | L-alanine, protein hydrolysate | Increased water absorption | “Very significant increase” | No mention found |
| Sundaram et al., “Corticosteroids Reverse Na-Glucose Cotransport” | Methylprednisolone | No mention found | N/A | N/A |
| Wapnir et al., 1990 | L-alanine | Enhanced water absorption | Not quantified | No mention found |
| Elliott et al., 1986 | Glucose (oral rehydration solution) | Increased water absorption | +98.6±16 microliters/minute/gram (ratio 1.9) | p<0.01 |
| Laverty et al., 2001 | Aldosterone (suppression) | No mention found | N/A | N/A |
| Summers and Schedl, 1968 | Glucose | Increased water absorption | Not quantified | No mention found |

## Summary of water absorption effects:
- Activator types:
  - 6 studies used amino acids (L-alanine, glutamine, leucine, phenylalanine, protein hydrolysate).
  - 6 studies used glucose or glucose-based activators (including analogs, polymers, and oral rehydration solution).
  - 3 studies used peptide or growth factors (Epidermal Growth Factor, Transforming Growth Factor, Teduglutide).
  - 2 studies used steroids (dexamethasone, methylprednisolone).
  - 2 studies used hormones (aldosterone, Angiotensin II).
  - 2 studies used enzymes or kinases (Glycogen synthase kinase 3 beta, PDK-1).
  - 2 studies used plant extracts (stevia, gum arabic).
  - 2 studies used complex carbohydrates (cereal-based oral rehydration solution, dextrin).
  - 1 study each used a transporter (SGLT1 transfection), an immunosuppressant (tacrolimus), sodium (with glucose), and a meal.

- Reported effects:
  - Increased or enhanced water absorption was reported in 14 studies.
  - Increased paracellular absorption was reported in 1 study.
  - Normalized water output was reported in 1 study.
  - Reduced net water secretion was reported in 1 study.
  - Reduced stool volume was reported in 1 study.
  - Reduced stool water content was reported in 1 study.
  - Increased plasma volume was reported in 1 study.
  - In 9 studies, we did not find mention of water absorption effects.

### Sodium Absorption Outcomes

| Study | Activator Type | Sodium Absorption Effect | Effect Size | Statistical Significance |
|------|---------------|--------------------------|-------------|------------------------|
| Wapnir et al., 1988 | L-alanine, protein hydrolysate | Increased sodium absorption | “Very significant increase” | No mention found |
| Rongione et al., 2001 | Epidermal Growth Factor, Transforming Growth Factor | Increased sodium absorption | Not quantified | Significant (no further details in abstract) |
| Grahammer et al., 2006 | Dexamethasone | Increased SGLT1/NHE3 activity | Approximately 3x increase (wild type) | Significant (no further details in abstract) |
| Aguero et al., 1990 | Glutamine | Increased sodium absorption | 300% increase | p>0.05 |
| Wapnir et al., “Enhancement by Alanine” | L-alanine, protein hydrolysate | Increased sodium absorption | “Very significant increase” | No mention found |
| Sundaram et al., “Corticosteroids Reverse Na-Glucose Cotransport” | Methylprednisolone | Reversal of SGLT1 inhibition | Not quantified | No mention found |
| Wapnir et al., 1990 | L-alanine | Enhanced sodium absorption | Not quantified | No mention found |
| Elliott et al., 1986 | Glucose (oral rehydration solution) | No mention found | N/A | N/A |
| Laverty et al., 2001 | Aldosterone (suppression) | Decreased SGLT activity | Not quantified | No mention found |
| Summers and Schedl, 1968 | Glucose | Increased sodium absorption | Not quantified | No mention found |

## Summary of sodium absorption effects:

- Activator types:
  - Amino acid-based activators (L-alanine, glutamine, leucine, phenylalanine, protein hydrolysate) were used in 6 studies.
  - Glucose or glucose analogs (including oral rehydration solution, glucose polymer, alpha-methyl D-glucoside) were used in 9 studies.
  - Hormones or steroids (dexamethasone, methylprednisolone, aldosterone) were used in 3 studies.
  - Growth factors (Epidermal Growth Factor, Transforming Growth Factor) were used in 2 studies.
  - Other agents (including stevia, SGLT1 transfection, Glycogen synthase kinase 3 beta, PDK-1, Angiotensin II/AT1R/AT2R, gum arabic, cereal-based oral rehydration solution, tacrolimus, dextrin, teduglutide) were used in 10 studies.

- Reported effects:
  - Increased sodium absorption or transporter activity was reported in 19 studies.
  - Decreased sodium absorption or transporter activity was reported in 2 studies.
  - Modulation or unclear effects (such as paracellular effects or improved fluid balance) were reported in 3 studies.
  - No effect was reported in 1 study.
  - In 4 studies, we did not find mention of sodium absorption effects.

## Comparative Effectiveness of Different Activators

| Study | Activator(s) Compared | Relative Effectiveness | Notes |
|------|-----------------------|---------------------|-------|
| Wapnir et al., 1988; Wapnir et al., “Enhancement by Alanine” | L-alanine, protein hydrolysate, glycine | Alanine/protein hydrolysate > glycine (no effect) | Alanine/protein hydrolysate most effective at higher sodium |
| Aguero et al., 1990 | Glutamine vs. control | Glutamine increased sodium absorption 300% | Both normal and diarrheic rats |
| Elliott et al., 1986 | Oral rehydration solution with different glucose:sodium ratios | Ratio 1.9 best for water absorption | Hypotonic oral rehydration solution superior |
| Sandhu et al., 1988 | Leucine, alanine, phenylalanine | Leucine > phenylalanine > alanine > standard oral rehydration solution | Leucine effective even in cholera toxin model |
| Thillainayagam et al., 1994 | Glucose polymer vs. monomer | Polymer > monomer for water absorption | Both normal and rotavirus-infected rats |
| Khin-Maung-U and Greenough, 1991 | Cereal-based vs. glucose-based oral rehydration solution | Cereal-based superior in cholera | 20–53% reduction in stool volume |
| van Loon et al., 1996 | Glutamine, alanine, glucose | All similar for water absorption | Glutamine offers mucosal fuel |
| Moran et al., 2019 | Stevia vs. control | Stevia increased SGLT1 activity | 1.8-fold increase |
| Fujii et al., 2021 | Dextrin + sodium chloride vs. sodium chloride vs. water | Dextrin + sodium chloride: earlier plasma volume expansion | No difference in magnitude |

## Summary of comparative effectiveness:

- Amino acid activators: Compared in 5 studies. In 4 of these, at least one amino acid (alanine, glutamine, leucine, phenylalanine) was superior to control or standard oral rehydration solution. Glycine showed no effect in 1 study. Leucine was the most effective amino acid in 1 study.
- Carbohydrate-based activators: Compared in 5 studies. In 4 of these, a carbohydrate-based formulation (optimal glucose:sodium ratio, glucose polymer, cereal-based oral rehydration solution) was superior to control or standard oral rehydration solution. In 1 study, dextrin plus sodium chloride led to earlier plasma volume expansion, but there was no difference in overall magnitude.
- Other comparisons: One study compared a sweetener (stevia) to control and found increased SGLT1 activity with stevia.
- Direct comparisons: Two studies directly compared multiple activator types (amino acids and glucose) and found either similar effectiveness (1 study) or a clear ranking (1 study).
- Overall: In total, 7 of 9 studies found at least one activator or formulation to be superior to control or standard oral rehydration solution, 2 of 9 found similar effectiveness among activators, and 1 of 9 found no effect for a specific activator (glycine). We did not find mention in these studies of any activator being inferior to control or standard oral rehydration solution.

## Context-Dependent Effects and Generalizability

- **Animal versus human studies**:
  - Most evidence is from animal models, which limits direct translation to human clinical settings.
  - Human studies (van Loon et al., 1996; Khin-Maung-U and Greenough, 1991; Fujii et al., 2021) reported beneficial effects of sodium-glucose cotransport activators in both health and disease, as described in the papers.
- **Disease models**:
  - The magnitude of effect was often greater in diarrheal or secretory models (such as cholera, rotavirus, Escherichia coli) than in healthy controls, as reported in the included studies.
- **Oral rehydration solution composition**:
  - Optimal glucose:sodium ratio, osmolality, and inclusion of amino acids or polymers were reported as critical for maximizing absorption in several studies.
- **Hormonal and pharmacological modulation**:
  - Hormones (aldosterone, Angiotensin II) and drugs (tacrolimus, Teduglutide) were reported to modulate SGLT1 activity, sometimes suppressing (aldosterone) or enhancing (Teduglutide) absorption.
- **Mechanistic insights**:
  - SGLT1 was the central transporter in most studies, with NHE3, claudin-10, and sweet taste receptors (T1R2-T1R3) also reported to play roles in specific contexts.
- **Limitations of the evidence**:
  - Many studies lacked detailed reporting of sample size, sex, or age, and some were only available as abstracts.
  - Direct clinical outcomes (such as rehydration success or morbidity) were less frequently reported than surrogate markers (such as water absorption rates or transporter activity).
  - The diversity of models, interventions, and outcome measures complicates direct comparison and synthesis.