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Efficacy of SGLT Activators on Water Absorption (public)

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September 11, 2025

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

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Paper search

Using your research question “How effective are sodium-glucose cotransport activators in improving water absorption?”, we searched across over 126 million academic papers from the Semantic Scholar corpus. We retrieved the 997 papers most relevant to the query.

Screening

We screened in sources based on their abstracts that met these criteria:

• SGLT Activators/Enhancers: Does this study investigate sodium-glucose cotransporter (SGLT) activators or enhancers (compounds that stimulate or enhance SGLT function)?
• Water Absorption Outcome: Does this study measure water absorption as a primary or secondary outcome (using methods such as perfusion techniques, balance studies, or biomarkers of water absorption)?
• In Vivo Studies: Is this an in vivo study (human studies or animal studies conducted in living systems)?
• Appropriate Study Design: Is this study one of the following designs: randomized controlled trial, controlled clinical trial, cohort study, case-control study, systematic review, or meta-analysis?
• SGLT Activators vs Inhibitors: Does this study focus on SGLT activators/enhancers rather than focusing solely on SGLT inhibitors (such as SGLT2 inhibitors like empagliflozin)?
• Beyond In Vitro Only: Does this study include in vivo components rather than being limited to in vitro studies only?
• Publication Quality: Is this study a peer-reviewed research article rather than a case report, case series, conference abstract, editorial, or opinion piece?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

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 Design

Clinical Condition

Intervention Type

Primary Outcome Measure

Full text retrieved

Wapnir et al., 1988

Animal experimental study

Osmotic diarrhea (rats)

L-alanine, protein hydrolysate in oral hydration solution

Water and sodium absorption

No

Rongione et al., 2001

Animal experimental; in vivo physiological

Normal dogs

Epidermal Growth Factor (EGF), Transforming Growth Factor (TGF)

Sodium, chloride, water, glucose absorption

No

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

No

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

No

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

No

Sundaram et al., “Corticosteroids Reverse Na-Glucose Cotransport”

Animal experimental; in vivo physiological

Chronic ileal inflammation (rabbits)

Methylprednisolone

SGLT1 activity

No

Wapnir et al., 1990

Animal experimental; in vivo physiological

Secretory diarrhea (rats)

L-alanine in oral hydration solution

Water and sodium absorption

No

Elliott et al., 1986

Animal experimental; in vivo physiological

Secretory diarrhea (rats)

Oral rehydration solution with varying glucose:sodium ratios

Water absorption

No

Laverty et al., 2001

Animal experimental

High/low salt diet (hens)

Aldosterone

SGLT activity, short-circuit current (Isc)

No

Summers and Schedl, 1968

In vivo physiological; animal experimental

Normal rats

Glucose, mannitol, varying tonicity

Sodium and water absorption

No

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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).
• Reporting of clinical outcomes:
  • Only one study (Khin-Maung-U and Greenough, 1991) used clinical outcomes (stool volume, duration) as the primary measure. Most studies used physiological absorption or transporter activity as the primary outcome.

Effects

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

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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.
• Statistical significance:
  • 10 studies reported p<0.05 (including p<0.01, p<0.001, p≤0.028).
  • 2 studies reported significant effects without a p-value.
  • 1 study reported no significant effect (p>0.05).
  • In 16 studies, we did not find mention of statistical significance.

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

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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.
• Effect size reporting:
  • Quantified effect sizes (numerical fold, percent, or absolute values) were reported in 6 studies.
  • Qualitative effect size descriptions (e.g., “very significant increase”, “significant”) were reported in 4 studies.
  • Unquantified effect size statements were found in 12 studies.
  • Effect size was not applicable or not reported in 7 studies.
• Statistical significance:
  • 4 studies reported p<0.05.
  • 3 studies reported p<0.001 or p<0.0001.
  • 3 studies reported statements of significance without a p-value.
  • 2 studies reported results as not significant.
  • In 13 studies, we did not find mention of statistical significance.
  • In 7 studies, statistical significance was not applicable.

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

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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.

References

J. Turner, David E. Cohen, R. Mrsny, J. Madara\ (2000).Noninvasive In vivo Analysis of Human Small Intestinal Paracellular Absorption: Regulation by Na+-Glucose Cotransport. Digestive Diseases and Sciences

Rong Lin, R. Murtazina, B. Cha, M. Chakraborty, Rafiquel I. Sarker, and 9 more\ (2011).D-glucose acts via sodium/glucose cotransporter 1 to increase NHE3 in mouse jejunal brush border by a Na+/H+ exchange regulatory factor 2-dependent process. Gastroenterology

P. Y. Pearson, Dahong Yu, M. Schwartz\ (2002).Transfection of the sodium/glucose cotransporter into colon mucosa: a novel treatment for short bowel syndrome. Journal of Pediatric Surgery

N. Bank, H. Aynedjian\ (1990).Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats. Journal of Clinical Investigation

R. Wapnir, M. Zdanowicz, S. Teichberg, F. Lifshitz\ (1990).Alanine Stimulation of Water and Sodium Absorption in a Model of Secretory Diarrhea. Journal of Pediatric Gastroenterology and Nutrition - JPGN

R. Wapnir, M. Wingertzahn, J. Moyse, S. Teichberg\ (1997).Gum arabic promotes rat jejunal sodium and water absorption from oral rehydration solutions in two models of diarrhea. Gastroenterology

J. Reiner, Peggy Berlin, Jakob Wobar, H. Schäffler, K. Bannert, and 5 more\ (2020).Teduglutide Promotes Epithelial Tight Junction Pore Function in Murine Short Bowel Syndrome to Alleviate Intestinal Insufficiency. Digestive Diseases and Sciences

R. Wapnir, M. Zdanowicz, Saul Teichberg, Fima Lifshitz\ (1988).Oral hydration solutions in experimental osmotic diarrhea: enhancement by alanine and other amino acids and oligopeptides. American Journal of Clinical Nutrition

A. Rongione, A. Kusske, T. Newton, S. Ashley, M. Zinner, and 1 more\ (2001).EGF and TGF Stimulate Proabsorption of Glucose and Electrolytes by Na+/Glucose Cotransporter in Awake Canine Model. Digestive Diseases and Sciences

E. J. Elliott, J. Walker-smith, M. Farthing\ (1986).RELATIONSHIP BETWEEN GLUCOSE AND SODIUM IN ORAL REHYDRATION SOLUTIONS (ORS); STUDIES IN A MODEL OF SECRETORY DIARRHOEA. Pediatric Research

O. Hines, E. Whang, A. Bilchik, M. Zinner, M. Welton, and 3 more\ (2004).Role of Na+-Glucose Cotransport in Jejunal Meal-Induced Absorption. Digestive Diseases and Sciences

F. Artunc, R. Rexhepaj, H. Völkl, F. Grahammer, C. Remy, and 5 more\ (2006).Impaired intestinal and renal glucose transport in PDK-1 hypomorphic mice. American Journal of Physiology. Regulatory Integrative and Comparative Physiology

F. V. van Loon, A. Banik, S. K. Nath, F. C. Patra, M. Wahed, and 3 more\ (1996).The effect of L-glutamine on salt and water absorption: a jejunal perfusion study in cholera in humans. European Journal of Gastroenterology and Hepathology

A. Casselbrant, M. Malinauskas, H. Marschall, V. Wallenius, L. Fändriks\ (2015).Angiotensin II exerts dual actions on sodium-glucose transporter 1-mediated transport in the human jejunal mucosa. Scandinavian Journal of Gastroenterology

D. Rolston, V. Mathan\ (1990).Jejunal and ileal glucose-stimulated water and sodium absorption in tropical enteropathy: implications for oral rehydration therapy. Digestion

Gary Laverty, Sesselja Bjarnadóttir, Vibeke S. Elbrønd, S. Árnason\ (2001).Aldosterone suppresses expression of an avian colonic sodium-glucose cotransporter. American Journal of Physiology. Regulatory Integrative and Comparative Physiology

R. Summers, H. Schedl\ (1968).Effects of tonicity and glucose on intestinal sodium and water absorption in the rat. Scandinavian Journal of Gastroenterology

F. Grahammer, G. Henke, Ciprian Sandu, R. Rexhepaj, A. Hussain, and 8 more\ (2006).Intestinal function of gene-targeted mice lacking serum- and glucocorticoid-inducible kinase 1. American Journal of Physiology - Gastrointestinal and Liver Physiology

Khin-Maung-U, W. Greenough\ (1991).Cereal-based oral rehydration therapy. I. Clinical studies. Jornal de Pediatria

R. Rexhepaj, M. Dërmaku-Sopjani, Eva-Maria Gehring, M. Sopjani, Daniela S. Kempe, and 2 more\ (2010).Stimulation of Electrogenic Glucose Transport by Glycogen Synthase Kinase 3. Cellular Physiology and Biochemistry

A. Thillainayagam, J. A. Dias, A. F. Salim, F. Mourad, M. Clark, and 1 more\ (1994).Glucose polymer in the fluid therapy of acute diarrhoea: studies in a model of rotavirus infection in neonatal rats. Clinical science

A. Moran, M. Al-Rammahi, K. Daly, Emeline Grand, C. Ionescu, and 3 more\ (2019).Consumption of a Natural High-Intensity Sweetener Enhances Activity and Expression of Rabbit Intestinal Na+/Glucose Cotransporter 1 (SGLT1) and Improves Colibacillosis-Induced Enteric Disorders. Journal of Agricultural and Food Chemistry

Zhiwei Li, F. Sun, Yaohui Zhang, Hao Chen, Ningning He, and 5 more\ (2015).Tacrolimus Induces Insulin Resistance and Increases the Glucose Absorption in the Jejunum: A Potential Mechanism of the Diabetogenic Effects. PLoS ONE

B. Sandhu, C. Pillai, D. Burston, M. Brueton\ (1988).64 ORAL REDHYRATION SOLUTIONS – EXPERIMENTAL STUDIES OF NET WATER AN ELECTROLYTE ABSORPTION. Pediatric Research

M. E. T. Aguero, R. Vicich, E. Carmuega, A. O'donnell\ (1990).GLUTAMINE INCREASES SODIUM ABSORPTION IN WHO—ORS PREFUSED INTESTINE OF NORMAL AND DIARRHETIC RATS. Pediatric Research

Naoto Fujii, Akira Sugihara, Kazuhito Watanabe, Takehiro Niwa, Akira Katagiri, and 4 more\ (2021).Carbohydrate hastens hypervolemia achieved through ingestion of aqueous sodium solution in resting euhydrated humans. European Journal of Applied Physiology

Brian M. Chung, Brian M. Chung, L. Wallace, R. Winkfein, E. O'Loughlin, and 2 more\ (2004).The Effect of Massive Small Bowel Resection and Oral Epidermal Growth Factor Therapy on SGLT-1 Distribution in Rabbit Distal Remnant. Pediatric Research

R. Wapnir, M. Zdanowicz, S. Teichberg, F. Lifshitz\ (1988).enhancement by alanine and other amino acids and oligopeptides13

U. Sundaram, S. Coon, S. Wisel, A. West\ (1998).Corticosteroids reverse the inhibition of Na-glucose cotransport in the chronically inflamed rabbit ileum

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Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats.

N. Bank, H. Aynedjian

Journal of Clinical Investigation·

1990·

99 citations

SourceDOI

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Study Design Type

Animal experimental study, In vivo physiological study

Animal/Human Model Characteristics

- Species: Sprague-Dawley rats - Number of animals: 47 - Sex: Male - Weight range: 275-325 g - Groups: Normal rats (32), Diabetic rats (15)

Sodium-Glucose Cotransport Intervention Details

- Specific substances used: Glucose, Alpha-methyl D-glucoside - Concentration of interventional substances: Glucose (100, 300, 500 mg%), Alpha-methyl D-glucoside (27.5 mM) - Method of administration: Microperfusion of proximal tubules - Duration of intervention: Not explicitly mentioned

Water and Electrolyte Absorption Outcomes

- Water absorption increased significantly with glucose addition in both normal and diabetic rats. - Sodium absorption increased significantly with glucose addition in both normal and diabetic rats. - Osmolality fell by 22 mosmol with glucose addition, indicating hypotonicity. - Statistical significance was determined using paired t-tests. - Specific absorption measurements are provided in Tables II and III.

Mechanism of Sodium-Glucose Cotransport

- Specific molecular or cellular mechanisms described: Brush border Na/glucose cotransport is the primary mechanism for sodium absorption stimulated by glucose. - Transporters or pathways involved: Na/glucose cotransporter (likely SGLT-1, though not explicitly mentioned). - Inhibition or activation mechanisms observed: Activation by glucose and a-methyl D-glucoside; inhibition by substitution of bicarbonate and acetate for chloride in the perfusion fluid.

The effect of progressive increases in intraluminal glucose concentration on proximal tubule sodium absorption was studied in normal and streptozotocin diabetic rats by microperfusion. Each tubule was perfused twice, with and without glucose added to the perfusion fluid. Net sodium and water absorption were markedly enhanced by 300-500 mg% intraluminal glucose in both normal and diabetic rats. Substituting the transported but nonmetabolized glucose analogue, alpha-methyl D-glucoside for glucose also resulted in marked stimulation of sodium absorption, whereas substituting bicarbonate and acetate for chloride in the perfusion solution inhibited the effect of glucose. These observations suggest that the stimulation of sodium absorption by glucose was mediated by the brush border Na/glucose cotransporter. Sodium concentration and osmolality were found to fall markedly to hypotonic levels when high glucose concentrations were in the perfusion fluid. This luminal hypotonicity may be an important driving force for proximal fluid absorption. In poorly controlled diabetes, high filtered glucose concentrations may lead to enhanced proximal sodium and water absorption, which could in turn contribute to volume expansion, hypertension, and renal hypertrophy.

Introduction

There is substantial although not unanimous evidence that glucose stimulates fluid and sodium absorption by the normal kidney. In isolated perfused rat kidneys, addition ofglucose to the perfusion fluid results in an increase in both sodium and water reabsorption (1)(2)(3)(4)(5). In isolated perfused rabbit proximal tubules, glucose added to the luminal fluid, but not to the bath fluid, increases fluid absorption and the transepithelial electri- cal potential (6). However, in several free-flow micropuncture studies in normal rats (7)(8)(9)(10) and dogs (1 1), glucose infusion was found to inhibit proximal sodium and water absorption (1 1), to increase absorption (7), or to have no specific effect (8, 10). The reasons for these disparate results are not certain, but variations in GFR, which alter the delivery ofboth glucose and sodium to the tubule, and changes in extracellular volume, are two possibilities. No previous study of the effect of glucose on Address reprint requests to Dr. Bank, Department of Medicine, Mon- tefiore Medical Center, 110 East 210th Street, Bronx, NY 10467. Receivedfor publication 15 September 1989 and in revisedform 29 December 1989. proximal tubule sodium reabsorption has been reported in diabetic animals.

The present experiments were undertaken to examine the effects of increasing concentrations of luminal D-glucose on proximal tubule sodium absorption in both normal and insu- lin-deficient diabetic rats. The in vivo reperfusion technique was used in which each tubule serves as its own control (12). This experimental approach obviates variations in GFR and allows precise control of delivery rate and perfused glucose concentrations. The findings indicate that in both normal and diabetic rats, progressive increases in luminal D-glucose stimu- late net sodium and water absorption markedly. This was ac- companied by a fall in sodium and glucose concentrations in the collected fluid, and a decrease in osmolality to frankly hypotonic levels. The enhancement of net sodium transport was presumably due to brush border Na/glucose cotransport since the nonmetabolized analogue a-methyl D-glucoside also stimulated absorption. The findings are consistent with the hypothesis that in poorly controlled diabetes, high concentra- tions of filtered glucose may increase prqximal sodium and water absorption, contributing to volume expansion, hyper- tension, and renal hypertrophy.

Methods 47 male Sprague-Dawley rats, weighing 275-325 g were studied. 15 rats were made diabetic by injection of streptozotocin 65 mg/kg body wt i.v. 10-14 d before study. These animals were provided with a regular rat pellet diet and unlimited amounts of drinking water, but they received no insulin. The remaining 32 rats were normal animals.

On the day of micropuncture study, all animals were anesthetized with inactin, 100 mg/kg body wt, the trachea was intubated, and a jugular vein was cannulated with PE 50 tubing for constant infusion of Ringer's lactate solution. The left kidney was surgically exposed, cleaned of perirenal fat tissue, and immobilized in a lucite cup, as previously described (12)(13)(14). Group 1. In 18 normal and 15 diabetic rats, microperfusion of surface proximal convoluted tubules was carried out under direct visu- alization via a dissecting stereomicroscope. The technique of reperfu- sion was used (12), in which each segment oftubule was perfused twice, once with an electrolyte solution devoid of glucose and once with the same solution containing 100, 300, or 500 mg% n-glucose. Both col- lected perfusates were measured for volume, ['4C]inulin concentration and sodium concentration. The technique was as follows: an intrave- nous bolus injection of FD and C green dye (Keystone Aniline and Chemical, Chicago, IL) was given, and an early proximal convolution was identified by direct visualization of appearance of the dye. A mi- cropipette filled with stained castor oil, but with a small amount ofF D and C green-colored saline in the tip, was inserted into an early proximal convolution. The colored saline was injected into the lumen, and convolutions ofthe same tubule were identified by following the dye. A short column of castor oil was then injected into the lumen from the same pipette, after which this pipette was withdrawn and used to puncture several holes proximal to the oil block to allow escape of fluid coming from the glomerulus. Microinfusion of the tubule was begun by inserting a second pipette just distal to this oil block. The pipette contained the basic perfusion solution, the composition of which was as follows: sodium, 140 mM; bicarbonate 25 mM; chloride 118 mM; potassium 5 mM; calcium 1.5 mM; phosphate 2.5 mM. ['4C]Inulin was added in trace amounts. Osmolality was 275 mosmol/kg H20. The rate of microinfusion was controlled by a Sage pump which was cali- brated to deliver 20 nl/min. After 1-2 min of microinfusion, allowing the fluid to flow through the nephron, a second oil-filled (collecting) pipette was inserted into a segment of the tubule several convolutions distal to the proximal pipette. A second (distal) oil block was injected from this pipette. The flow of perfusion fluid was unavoidably inter- rupted for 5-10 s during injection of the distal oil block. A timed collection ofthe perfusion fluid was then made into the second pipette. After the collection was completed, the perfusion and collection pipettes were withdrawn. When several tubules had been perfused with the same solution, and their location on the surface of the kidney drawn, the perfusion pipette was filled with the same solution to which 100, 300, or 500 mg% n-glucose had been added. Each tubule was then reperfused with this solution, using the same technique. Proximal and distal oil blocks were reinjected if necessary. In each animal, three or four tubules were each perfused twice. In two normal and seven dia- betic rats the sequence of microperfusion was reversed, i.e., the first solution contained glucose and the second was devoid of glucose. The following calculations were carried out: perfusion rate = (C/I)N X collected volume/min (1) where (C/I)1,, is the concentration ratio of ['4Clinulin in the collected/ infused solutions.

absolute H20 absorbed = perfusion rate X [1 -(I/C)Q].

(2) Sodium concentration in the collected perfusion solution was mea- sured in triplicate by a helium glow photometer. ['4C]Inulin concen- tration was measured by liquid scintillation counting. Absolute net sodium absorption was calculated by the equation Na' abs = Perfusion rate X [Naj+] -collection rate X [Na:]

(3) where (NaJl is the concentration in the initial perfusion fluid and [Naf] is the concentration in the collected fluid. Because each tubule served as its own control, the length of tubule for each paired perfusion was constant, and therefore microdissection oftubules to determine length was not carried out.

In the experiments in normal rats in which either 300 mg% or 500 mg% D-glucose was used in the second ofthe paired tubular perfusions, blood glucose of the animals was raised by intravenous bolus infusion of 0.4 to 0.6 ml of a hypertonic glucose solution (500 mg/ml) before starting the second perfusion of the tubules. This was followed by continuous intravenous infusion of either 300 mg% or 500 mg% glu- cose in Ringer's solution at 2.5 ml/h. The purpose was to raise blood glucose to a level approximately the same as the intraluminal glucose concentration in order to minimize transepithelial osmotic gradients. However, in the two normal rats in which the order of microperfusion of the tubules was reversed, glucose was not administered intravenously. Also, in the diabetic animals, no attempt was made to modify the blood glucose concentration. Group 2: quantitative glucose vs. sodium absorption. In three addi- tional normal rats, sodium and glucose reabsorption were measured simultaneously in the same nephron segments with the reperfusion technique. In these experiments, the tubules were perfused first with the electrolyte solution containing 100 mg% n-glucose, and then they were reperfused with the same solution containing 500 mg% n-glucose.

Intravenous glucose was not administered in these experiments, but rather blood glucose remained constant during both periods of the experiments. Trace amounts of [3H]methoxy inulin and ['4C]D-glucose were added to the perfusion solutions. Sodium concentration in the collected perfsion solution was measured by the helium glow photometer method, and absolute rates of sodium absorption were calculated by Eq. 3. Absolute net glucose absorption was calculated by the equation:

Glucose absorption (pmol/min) = [Perfusion rate X glucose concentration] X [I -(C/Il4c/C/I3H)J (4) where C/I14, is the ratio of ['4C]glucose in collected fluid/injected fluid, and C/I3H is the ratio of [3H]inulin in the collected/injected fluid. The glucose concentration in the perfusion fluid is expressed in pmol/nl, and the calculated glucose absorption is expressed as pmol/min. The molar concentration of radiolabeled glucose added to the perfusion solution was < 0.15 mM in all experiments and this amount has been ignored in the calculations of unlabeled glucose absorption.

Group 3: effect ofintraluminal anions. To study the effect of intra- luminal anions on quantitative sodium and glucose absorption, paired microperfusions were carried out in four normal rats with a solution devoid ofchloride and ofthe following composition: sodium 140 mM, bicarbonate 74 mM, acetate 70 mM, potassium 4 mM, calcium phosphate 2.5 mM, osmolality 275 mosmol. Since both bicarbonate and acetate are largely converted to non-ionic forms before traversing the brush border membrane, this perfusion fluid provided little or no permeant anions to accompany the absorbed sodium (15). The first of the paired perfusion solution contained 100 mg% D-glucose and the second solution contained 500 mg% D-glucose. As in group 2, glucose was not administered intravenously during the second period of the experiments, allowing blood glucose to remain constant. ['4C]Glucose and [3H]inulin were added to the perfusion solutions in trace amounts, as described above. The technique of microperfusion was the same as in the preceding groups.

Group 4: a methyl D-glucoside. In three normal rats, reperfusion of proximal tubules was carried out with the same electrolyte solution used above to which 27.5 mM a-methyl D-glucoside (Sigma Chemical Co., St. Louis, MO) was added, instead of D-glucose. In these experi- ments the first perfusion solution contained no sugar, and the second contained the a-methyl D-glucoside. Water absorption was measured with ['4Clinulin and sodium concentration in the collected fluid was measured by helium glow photometry, as described above. No glucose was administered intravenously.

Group 5: osmolality measurements. In four animals, osmolality of plasma, perfusion solutions, and collected perfusates was measured by the freezing point method of Ramsay and Brown, as described previously (16,17). The accuracy of this method is ±2 mosmol (16). Two different perfusion solutions were used: (a) the basic electrolyte solu- tion + 500 mg% D-glucose; (b) NaCl 155 mM. The rate of perfusion was 20 nI/min, as in the preceding experiments. A total of21 proximal tubules were studied.

In all experiments, blood glucose was measured enzymatically with a glucose meter (Beckman Instrument Co., Inc., Fullerton, CA). Sta- tistical analysis was by paired Student's t test for the reperfusion sam- ples, and by unpaired t test for other comparisons.

Results

In Table I are shown the data for blood glucose concentrations in the normal and diabetic rats, comparing these values with the concentration ofglucose in the various perfusion solutions. In the normal rats when either 300 or 500 mgO glucose was in the second of the paired perfusion solutions, i.e., the second half of the experiment, blood glucose was raised by intrave- nous infusion of hypertonic glucose. In the diabetic rats, no attempt was made to alter blood glucose. As can be seen, the transepithelial gradients ofglucose varied considerably among the various experiments. In the normal rats, there were rela- tively small glucose gradients during perfusion with glucose- containing fluid, and thus transepithelial osmotic gradients due to glucose were minimized. However, each tubule was also perfused with a glucose-free solution, which was lower in os- molality, and under these circumstances plasma osmolality was higher than luminal osmolality. In the diabetic rats, blood glucose was considerably higher than luminal glucose in two of the three experimental conditions. Moreover, when these tu- bules were perfused with fluid devoid ofglucose, an even larger osmotic gradient existed across the tubular epithelium. Thus, although an attempt was made to minimize transepithelial glucose gradients during perfusion with glucose containing so- lutions, a large osmotic gradient usually existed during the first perfusion when no glucose was in the lumen. This gradient was diminished during the second perfusion by addition ofglucose to the perfusion solution. Group 1: water and sodium absorption (Tables II and III , Figs. 1 2 3 ). The data for proximal water absorption are pre- sented in Table II , in which the paired microperfusions are grouped according to the concentration ofglucose added to the perfusion solution. The data have been analyzed by paired t test for individual tubules. As can be seen, in both the normal and the diabetic animals, water absorption increased signifi- cantly when glucose was added to the perfusion fluid. This was observed in every tubule studied. Since the transepithelial os- motic gradient favoring fluid absorption was less during the glucose perfusion than during the control perfusion, the enhanced fluid absorption cannot be attributed to a more favor- able osmotic gradient. The increments in fluid absorption are shown in Fig. 1 . Although these increments appear to be greater in the diabetic rats, a statistical comparison with the normals is not justified because tubular lengths were not de- termined, and renal hypertrophy with increased tubular length and diameter had most likely occurred (13).

The concentrations of sodium in the collected perfusates are shown in Fig. 2 . In the normal rats, addition of increasing amounts ofglucose to the perfusion fluid resulted in a progres- sive fall in intraluminal sodium concentration to a nadir of 112 meq/liter reached with the 300 mg% solution. No further fall in [Na+] was observed with the 500 mgO glucose solution.

In the diabetic rats, intraluminal [Na+] also fell with increasing perfusion fluid glucose concentrations. The average sodium concentrations tended to be slightly higher in the diabetic rats than in the normals, even though tubular diameters and lengths were most likely greater. A larger luminal surface area for sodium transport would be expected in the diabetic ani- mals. The fact that the average sodium concentrations in the collected perfusates tended to be higher than in the normals is consistent with some impairment in establishing a transepithelial sodium gradient in the diabetic animals.

The measured rates of sodium absorption are shown in Table III . In both the normal and diabetic rats, proximal so- dium absorption increased strikingly when each of the three D-glucose concentrations was added to the perfusion solution. This occurred in every nephron studied in both the normal and diabetic rats. The increment in sodium absorption with addition of glucose is shown in Fig. 3 . It appears that a maxi- mum stimulation ofsodium absorption was achieved with 300 mg% D-glucose in the normal rats, but in the diabetics 500 mg% D-glucose seemed to cause a slightly greater stimulus than 300 mg%. However, as noted above, sodium transport in the diabetic rats might be impaired if expressed in terms of luminal surface area, as hypertrophy of the tubules was most likely present. It is important to note that the increment in sodium absorption occurred in spite of the higher luminal osmolality due to added glucose, and thus the stimulation of sodium transport cannot be attributed to osmotically induced fluid transfer. In the diabetic rats, blood glucose was in a hy- perglycemic range and remained relatively constant through- out each experiment. Our observations on enhanced sodium absorption in normal rats are in accord with the derived values for sodium absorption during hyperglycemia calculated by Von Baeyer et al. (18). Group 2: simultaneous quantitative sodium and glucose absorption (Figs. 4 and 5 ). The reperfusion technique was used to compare the effect of increasing glucose concentration on absolute rates of net glucose and sodium absorption simulta- neously in the same proximal convoluted tubules. In these experiments, the first perfusion solution contained 100 mg%/6 D-glucose and the second perfusion fluid contained 500 mgO D-glucose. [3Hjmethoxy inulin and ["4C]glucose were added in trace amounts. It is clear from the results shown in Fig. 4 that both glucose and sodium absorption increased in every tubule 140. when the perfusion fluid glucose concentration was raised from 100 to 500 mg%. Previous studies have shown that net glucose absorption by the proximal tubule can be accounted for by an active efflux mechanism and a small passive backflux (19, 20), the passive backflux being dependent upon the blood/lumen concentration gradient. Since in our experi- ments, the transepithelial glucose gradient usually favored ef- flux (Table I ), especially when large amounts of glucose were added to the lumen, the reabsorption of glucose most likely reflects principally active efflux with little or no passive influx. As shown in Fig. 4 , the increment in net sodium absorption appeared to be much greater than the increment in glucose absorption. In order to examine this relationship more closely, the increment in absorption in each tubule, i.e., A glucose vs.

A sodium, has been plotted in Fig. 5 . Each closed circle repre- sents a single tubule, microperfused twice. The solid line is the line of identity, i.e., points would fall along this line if sodium and glucose absorption increased by equal amounts. It is evi-

Intraluminal Glucose(mg%) Figure 4 . Paired absolute rates of sodium and glucose absorption with 100 or 500 mg% glucose in perfusion solution. Sodium and glucose absorption measured in same tubules. Glucose Absorption (picomoleu/min) Figure 5 . Increment in sodium and glucose absorption with 500 vs. 100 mg% glucose in perfusion solution. Each point represents a sin- gle tubule perfused twice. Closed and open circles reflect anion com- position of perfusion solution.

dent that in individual tubules, sodium absorption increased considerably more than glucose absorption. The relationship varied from 2:1 to 8:1 in different tubules. There was no statistically significant linear correlation of the data (r = 0.1). Group 3: effect of intraluminal anions (Table IV , Fig. 5 ). Studies of Na/glucose cotransport in isolated brush border membrane vesicles have shown that a permeant anion is neces- sary in the bathing medium in order for the transporter to operate (15, 21). Bicarbonate and acetate in the bathing media severely reduce the rapid entry of sodium into the vesicles when glucose is added (15, 21). In the group 3 animals, we examined the effect of substituting bicarbonate and acetate for chloride in the luminal perfusion fluid. As shown in Table IV , net absorption of both sodium and water were much lower in these experiments than in group 1 in which chloride was the major anion in the perfusion fluid (Tables II and III ). The concentration of sodium in the collected perfusate fell from 130±1.1 with 100 mg% glucose to 118±1.2 meq/liter when 500 mg% D-glucose was in the perfusion solution (P < 0.001).

It should be noted that fluid absorption was not stimulated by the higher glucose concentration, and in fact the mean value was lower (P = NS). The quantitative increments of sodium and glucose absorption in individual tubules is shown in Fig. 5 as open circles. As can be seen, very little stimulation of so- dium or glucose absorption occurred when glucose was raised from 100 to 500 mg%, in contrast to the experiments in which chloride was the major intraluminal anion. Thus, the Na/glu- cose cotransporter in the intact proximal tubule appeared to behave similarly to that in isolated brush border membrane vesicles with regard to requiring a permeant charge-carrying anion.

Group 4: effect ofa-methyl D-glucoside. In additional nor- mal rats, reperfusion of proximal tubules was carried out with 0 or 27.5 mM a-methyl D-glucoside added to the basic perfusion solution. Sodium concentration in the collected perfusion fluid fell to 110 meq/liter when 27.5 M a-methyl D-glucoside was in the perfusion fluid, similar to the effect of D-glucose. Sodium absorption rose markedly from 320±15 pmol/min (zero sugar) to 725±30 pmol/min, yielding an increment of 405 pmol/min. This appears to be a somewhat smaller incre- ment than that observed with D-glucose in the normal and diabetic rats (Fig. 3 ), but a statistical comparison between the groups cannot be made because tubular lengths and surface areas were not evaluated. Nevertheless, the observations with a-methyl D-glucoside support the role of the Na/glucose co- transporter in the enhanced sodium absorption. A smaller stimulus with this glucose analogue is consistent with its lower affinity for the transporter (22, 23).

Group 5: osmolality measurements. In Fig. 6 are shown the osmolality data for initial perfusion fluid, and collected perfus- ate when two different perfusion solutions were used. One solution was the basic electrolyte perfusion solution with 500 mg% D-glucose added. The other was a solution of 155 mM NaCl, devoid of glucose. Plasma osmolality in these experiments is also shown. The initial osmolality ofthe glucose-con- taining solution was 299 mosmol, close to that of plasma. The osmolality of the NaCl solution was 288 mosmol, significantly lower than plasma. The osmolality of the glucose-containing solution fell to 277.5±1.5 mosmol (A 22 mosmol) when per- fused into the proximal tubule. In contrast, the osmolality of 300 the NaCl solution fell by only 4.7 mosmol, to 283.3±1.3 mos- mol. The difference in final osmolality of the two collected fluids was statistically significant (P < 0.02), as was the fall in osmolality.

Discussion

The present microperfusion experiments demonstrate that in both normal and diabetic rats, stepwise increases in luminal glucose concentration markedly stimulate sodium and water absorption. This was accompanied by a striking fall in intraluminal sodium concentration, and a 22 mosmol fall in osmolal- ity to a level frankly hypotonic to plasma. In contrast, perfu- sion with a NaCl solution devoid ofglucose resulted in a small but significant fall in osmolality of 4 mosmol. Several mechanisms have been proposed to explain the effect of glucose to enhance renal sodium absorption (24): stimulation ofNa/glucose cotransport, solvent drag, and meta- bolic energy provided by absorbed glucose. We carried out experiments to examine these various mechanisms. Solvent drag did not seem to play a significant role, since sodium absorption increased whether transepithelial glucose gradients favored influx or efflux of glucose. In fact, in the group 1 experiments, no glucose was present in the first perfusion, and glucose was added to the second of the paired perfusions. Thus, whatever the plasma glucose concentration, the gradient across the tubular epithelium was diminished during the sec- ond perfusion. In spite of this, both sodium and water absorption were increased by the addition of intraluminal glucose. In addition, in groups 2-5, glucose was not administered intrave- nously but rather plasma glucose remained constant through- out both periods ofthe experiment. In the diabetic rats, plasma glucose was also constant throughout the experiment, yet so- dium and water absorption were markedly increased when glucose was added to the luminal perfusion solution. It seems highly unlikely that passive diffusion ofglucose from lumen to blood can account for the observed increase in fluid and so- dium absorption, since the rat proximal tubule has a low per- meability to glucose (25). Our observations strongly suggest therefore that the effect of glucose in these experiments was mediated from the luminal side of the tubule by stimulating transport. In agreement with this conclusion, Burg et al. (6) found in isolated perfused rabbit proximal tubules that addi- tion of glucose to the bathing media had no effect on fluid absorption, whereas addition to the luminal fluid stimulated fluid absorption. Finally, the fact that osmolality of the lu- minal fluid fell with addition of glucose to the perfusion fluid suggests that the primary event was active transport of solute out of the lumen.

We examined the role of the Na/glucose cotransporter in two protocols. Substitution of a-methyl D-glucoside, a glucose analogue which substitutes for glucose on the sodium/glucose co-transporter but is not metabolized (22,24), stimulated sodium absorption markedly, almost to the same degree as D- glucose. These observations are in agreement with those of Burg et al. (6), and provide evidence for Na/glucose cotrans- port and against a metabolic effect of glucose.

A second protocol examined the effect ofanions on glucose stimulated sodium and water absorption. A characteristic in vitro property of the Na/glucose cotransporter is that rapid uptake of sodium or glucose from the medium (overshoot) requires the presence ofan anion in the bathing solution which readily permeates the transporting membrane (15,21). Non- permeating anions such as sulfate or ferrocyanide prevent the rapid uptake of either sodium or glucose. Similarly, anions that are converted into non-ionic forms before permeating membranes, such as bicarbonate and acetate, markedly impede Na/glucose cotransport, presumably via a membrane po- tential effect (15). In the group 4 experiments (Table IV , Fig. 5 ), chloride was replaced by bicarbonate and acetate in the perfusion fluid. It is clear that both sodium and glucose ab- sorption were markedly reduced under these experimental conditions. Raising glucose to 500 mg% in the perfusion fluid had only a small effect on sodium and glucose absorption (Fig. 5 ). Measurements ofmembrane potentials in proximal tubules have shown that when glucose is added to the lumen, depolarization of the luminal membrane occurs, most likely due to sodium entry via Na/glucose cotransport (26,27). Ordinarily, this depolarization would be minimized by entry of an anion from the lumen which would tend to restore intracellular elec- tronegativity. In the absence of a permeant anion, sodium entry via Na/glucose cotransport would be expected to cause more marked depolarization of the brush border membrane. This in turn could severely reduce the electrochemical driving force for further passive sodium entry across the brush border membrane. Thus, the observations made in the group 4 animals are in accord with the in vitro data from isolated brush border membrane vesicles, and add further support to the view that Na/glucose cotransport was largely responsible for our observations.

From the above considerations, we conclude that the main mechanism responsible for the stimulation of sodium absorption by glucose was the Na/glucose cotransporter. However, in apparent discord with this conclusion is the fact that in isolated brush border membrane preparations of cortical tubules, the cotransporter operates in a 1:1 stoichiometry (28). In the outer medulla of the kidney, the co-transporter has been found to have a stoichiometry of 2:1 (29). As shown in Figs. 4 and 5, addition of glucose to the lumen stimulated sodium absorption considerably more than glucose absorption, and further- more no consistent ratio between these two was observed. In these normal rats, insulin may have acted to stimulate baso- lateral sodium transport (30,31), independent of the effect of intraluminal glucose on the brush border Na/glucose cotrans- porter. However, since glucose was not administered intrave- nously in these experiments, it seems unlikely that endogenous insulin was stimulated to higher than fasting levels. A discrepancy appears to exist between the intact nephron and isolated brush border membrane experiments with regard to the stoichiometry. The reason for this disagreement is not clear.

Recently, several investigators have reported that significant degrees of luminal hypotonicity can be generated and sustained by the rat proximal tubule (32-34). Hypotonicity of approximately -2 to -20 mosmol was measured under free- flow and microperfusion experimental conditions. Liu et al. (33) found an average decrease in osmolality along the length of the proximal tubule of 1 mosmol/mm length under freeflow conditions. It has been postulated that proximal fluid absorption depends upon the development of intraluminal hy- potonicity, relative to plasma (32-34), in that the critical osmotic force for fluid absorption is due to luminal hypotonicity, rather than hypertonicity developing in the basolateral interspaces (32). In the present study, we found that addition of high concentrations of glucose to the perfusion fluid, resulted in the development of striking hypotonicity of the luminal fluid, due to enhanced sodium (anion) absorption. Presum- ably, this hypotonicity provided the driving force which in- creased absolute fluid absorption in both the normal and dia- betic rats (Table II ). An important role for glucose (and amino acids) in generating luminal hypotonicity was predicted by Green and Giebisch (32), although the degree of hypotonicity that developed with hyperglycemic levels of glucose is remark- able.

It should be noted that in the group 3 experiments in which bicarbonate and acetate were substituted for chloride in the perfusion solution, luminal [Na'] fell markedly, and presum- ably the fluid became hypotonic. However, this was not ac- companied by enhanced fluid absorption (Table IV vs. Table II ). In these experiments, sodium absorption was also much less than it was when chloride was in the perfusion solution. Thus, the effectiveness of intraluminal hypotonicity as a driv- ing force for fluid absorption appears to be influenced by the anion composition of the luminal fluid and the rate of sodium absorption. As discussed above, Na/glucose cotransport is markedly constrained in the absence of a permeant anion (15), and this may have prevented fluid absorption in spite of lu- minal hypotonicity. Alternatively, high reflection coefficients for bicarbonate and acetate may have limited both sodium and water absorption.

Our observations suggest that high proximal tubular glucose concentrations in poorly controlled diabetes may lead to excessive reabsorption of sodium and water. This, in turn, could contribute to ECF volume expansion, hypertension, and renal hypertrophy (35,36). It is clear, however, that enhanced proximal sodium and fluid absorption would have to be offset by decreased reabsorption at a more distal site to allow a steady state to be achieved. Atrial natriuretic peptide, which is ele- vated in diabetes (37,38), would be a likely candidate for mediating decreased absorption distally.

In conclusion, our studies demonstrate that stepwise in- creases in intraluminal glucose concentration markedly stimu- late net sodium absorption in both normal and diabetic proximal tubules. Luminal hypotonicity is generated by the presence of glucose, due to enhanced sodium absorption, and this presumably provides an important transepithelial osmotic driving force for reabsorption of fluid by the proximal tubule. In poorly controlled diabetes, high concentrations of glucose in the glomerular filtrate may lead to increased renal sodium and water absorption which in turn could contribute to vol- ume expansion, hypertension, and renal hypertrophy.

Acknowledgements

AcknowledamentsThis work was supported by a grant from the U. S. Public Health Service (DK 32469).

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