Milk for Diabetes Prevention

Not Applicable

Not yet recruiting

• Conditions: Lactose Intolerant; Pre-Diabetes; Lactose Intolerance; Lactase Persistence; Diabetes Mellitus, Type 2
• Interventions: Dietary Supplement: Lactose-Free Milk; Dietary Supplement: Lactose-Containing Milk

• Registration Number: NCT06513026
• Lead Sponsor: Albert Einstein College of Medicine

Brief Summary

Individuals with lactase non-persistence (LNP; determined by a functional variant in the LCT gene \[rs4988235, GG genotype\]) are susceptible to lactose intolerance in adulthood due to deficiency of lactase, the enzyme which digests milk lactose sugars. However, many LNP individuals still drink ≥1 cup of milk daily. Recent analysis in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) found that consumption of 1 serving (cup) of milk/day was associated with \~30% lower risk of type 2 diabetes among LNP individuals, but not among individuals with lactase persistence (LP). This beneficial effect might be partially explained by favorable alterations in gut microbiota and related metabolites associated with higher milk consumption among LNP individuals. Based on these observational study findings, the investigator team proposes to conduct a randomized, controlled trial of lactose-containing vs. lactose-free milk in LNP individuals with pre-diabetes, to comprehensively investigate the effects of milk intake on the gut microbiome and glycemic outcomes.

Detailed Description

The trial will feature a 2-week milk washout period, followed by 1:1 randomization to lactose-containing or lactose-free milk for 12 weeks (4 weeks each of ½ cup, 1 cup, and 2 cups milk). Before and after the 12 weeks, visits will entail lactose challenge hydrogen breath tests (HBT; i.e., lactose tolerance tests) and blood tests for fasting glucose, hemoglobin A1c, and metabolomics; while stool samples and continuous glucose monitoring (CGM) data will be collected at home using provided kits/devices.

Specific aims of the study are to: (1) establish feasibility and tolerability of a randomized trial of lactose-containing vs. lactose-free milk; (2) to examine the effect of lactose-containing milk on gut microbiome species, functions, and metabolites in LNP individuals with pre-diabetes; and (3) to examine the effect of lactose-containing milk on glycemic outcomes in LNP individuals with pre-diabetes.

Study Timeline

• Study First Submitted: 2024-07-16
• Study First Submitted QC: 2024-07-19
• Study First Posted: 2024-07-22
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-27
• Last Update Posted: 2025-03-25
• Study Start: 2025-05
• Primary Completion: 2027-05
• Study Completion: 2027-05

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• Age ≥18
• LNP genotype (LCT gene rs4988235, GG genotype)
• History of pre-diabetes, defined as fasting blood glucose 100-125 mg/dL and/or hemoglobin A1c (HbA1c) 5.7-6.4% and have not been diagnosed with diabetes nor take diabetes medication. If blood test over 3 years ago, pre-diabetes will be confirmed using finger-stick HbA1c.
• Drink ≤1 cup milk/day
• Basic computer or smartphone skills
• English or Spanish speaking

Exclusion Criteria

• No diabetes diagnosis
• No anti-diabetes medication
• Blood test with history of pre-diabetes conducted >3 years ago and finger-stick HbA1c is normal (≤5.6%).
• No cancer, cardiovascular disease (CVD), or life-threatening illness
• No known milk allergy
• Does not have severe GI symptoms after drinking milk
• No history of GI surgery
• No smoking
• ≤1 alcoholic beverage/day
• Not pregnant or breastfeeding
• No colonoscopy in last 2 weeks
• No antibiotics in last 3 months
• Not taking probiotics or fiber supplements (or can stop taking during study)
• Not taking laxatives, stool softeners, anti-diarrheal (or can stop taking during study)
• Not participating in any extreme dieting programs

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lactose-Free Milk	Lactose-Free Milk	Participants will be randomized to lactose-free milk in strata of age (\<60, ≥60) and sex (female, male). Within each age and sex stratum, 10 participants will be randomized into two intervention groups in a 1:1 ratio
Lactose-Containing Milk	Lactose-Containing Milk	Participants will be randomized to lactose-containing milk in strata of age (\<60, ≥60) and sex (female, male). Within each age and sex stratum, 10 participants will be randomized into two intervention groups in a 1:1 ratio

Primary Outcome Measures

Name	Time	Method
Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) mean glucose	From Screening visit to Week 14 visit	During screening visit participants will have a 2-week continuous glucose monitor (CGM) applied to the skin on the upper arm in advance of the 2-week milk washout period. The CGM will be returned during the baseline visit 2 weeks later. After the 12 week visit, another 2-week CGM will be applied during which time participants will continue drinking milk concurrent with the 2-week CGM (i.e., until 14 weeks). Change in mean glucose (mg/dL) from screening to week 14 will be summarized using descriptive statistics (means and standard deviations) and compared between the treatment groups.
Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) glycemic variability	From Screening visit to Week 14 visit	During screening visit participants will have a 2-week continuous glucose monitor (CGM) applied to the skin on the upper arm in advance of the 2-week milk washout period. The CGM will be returned during the baseline visit 2 weeks later. After the 12 week visit, another 2-week CGM will be applied during which time participants will continue drinking milk concurrent with the 2-week CGM (i.e., until 14 weeks). Change in glycemic variability (%CV) from screening to week 14 will be summarized using descriptive statistics (means and standard deviations) and compared between the treatment groups.
Change in gut microbiome features - Relative Abundance of Species	From Baseline to Week 12	Stool samples will be collected using home stool microbiome kits at baseline, 4-, 8-, and 12-week timepoints. Shotgun sequencing will be conducted. Change in relative abundance of species (with \>1% mean relative abundance) from baseline will summarized, using basic descriptive statistics (group means and standard deviations). Change in relative abundance of species from baseline will be compared between the treatment groups.
Change in gut microbiome features - Functional Pathway Relative Abundance	From Baseline to Week 12	Stool samples will be collected using home stool microbiome kits at baseline, 4-, 8-, and 12-week timepoints. Shotgun sequencing will be conducted. Change in relative abundance of functional pathways (with \>1% mean relative abundance) from baseline will summarized, using basic descriptive statistics (group means and standard deviations). Change in relative abundance of functional pathways from baseline will be compared between the treatment groups.
Change in glycemic outcomes - Hemoglobin A1c (HbA1c)	From Baseline to Week 12	Whole blood samples for HbA1c will be collected at baseline and Week 12. HbA1c, used to measure the amount of hemoglobin with attached glucose and reflects average blood glucose levels over the past several months, will be analyzed via standard analytical chemistry approaches. Ranges vary, however, a 'normal' HbA1c is generally \<5.7%, 5.7-6.4% is in the 'pre-diabetic' range and a value of 6.5% or greater is in the 'diabetic' range. Change in HbA1c from baseline will be summarized using descriptive statistics (means and standard deviations) and compared between the treatment groups.
Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) time in range	From Screening visit to Week 14 visit	During screening visit participants will have a 2-week continuous glucose monitor (CGM) applied to the skin on the upper arm in advance of the 2-week milk washout period. The CGM will be returned during the baseline visit 2 weeks later. After the 12 week visit, another 2-week CGM will be applied during which time participants will continue drinking milk concurrent with the 2-week CGM (i.e., until 14 weeks). Change in time in range (%) from screening to week 14 will be summarized using descriptive statistics (means and standard deviations) and compared between the treatment groups.
Change in Expired Breath Hydrogen	From Baseline to Week 12	Expired breath hydrogen after lactose challenge will be measured during the baseline visit and after 12 weeks of milk intervention at the time of the follow-up visit using Hydrogen Breath Test (HBT) kits. Breath tubes will be mailed to an external laboratory where stable isotope analysis for expired breath hydrogen will be conducted. Expired breath hydrogen will be expressed as incremental Area Under the Curve (iAUC). Change in iAUC from baseline to week 12 will be summarized using basic descriptive statistics (group means and standard deviations), and change in iAUC will be compared between treatment groups.
Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) time below range	From Screening visit to Week 14 visit	During screening visit participants will have a 2-week continuous glucose monitor (CGM) applied to the skin on the upper arm in advance of the 2-week milk washout period. The CGM will be returned during the baseline visit 2 weeks later. After the 12 week visit, another 2-week CGM will be applied during which time participants will continue drinking milk concurrent with the 2-week CGM (i.e., until 14 weeks). Change in time below range (%) from screening to week 14 will be summarized using descriptive statistics (means and standard deviations) and compared between the treatment groups.
Gastrointestinal symptoms	Daily From Baseline to Week 12	Gastrointestinal symptoms, specifically abdominal pain, bloating, flatulence, and diarrhea, will be recorded daily through 12 weeks of milk intervention. The occurrence and severity of these four adverse events will be summarized and reported by study arm. Average frequencies of none-mild vs. moderate-severe symptoms will be compared between treatment groups by week of study, as well as for specific time intervals corresponding to milk doses (weeks 1-4, 5-8, 9-12).
Change in gut microbiome features - Metabolomics	From Baseline to Week 12	Targeted metabolic profiling will be performed on serum and stool samples (baseline and week 12) using LC-MS/MS methods for absolute quantitation of 70 metabolites associated with gut bacterial metabolism. Change in stool and serum metabolites from baseline will be summarized using basic descriptive statistics (group means and standard deviations). Change in stool and serum metabolites from baseline will be compared between the treatment groups.
Change in glycemic outcomes - Fasting glucose	From Baseline to Week 12	Blood sera samples for fasting glucose will be collected at baseline and Week 12. Fasting glucose, i.e., blood sugar levels following an 8-hour fast, will be analyzed via standard analytical chemistry approaches and reported in mg/dL or mmol/L units. Ranges vary but a fasting glucose level \<99 mg/dL is considered 'normal', between 100-125 mg/dL is within the 'pre-diabetic' range, \>126 mg/dL is within the 'diabetic' range. Change in fasting glucose from baseline will be summarized using descriptive statistics (means and standard deviations) and compared between the treatment groups.
Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) time above range	From Screening visit to Week 14 visit	During screening visit participants will have a 2-week continuous glucose monitor (CGM) applied to the skin on the upper arm in advance of the 2-week milk washout period. The CGM will be returned during the baseline visit 2 weeks later. After the 12 week visit, another 2-week CGM will be applied during which time participants will continue drinking milk concurrent with the 2-week CGM (i.e., until 14 weeks). Change in time above range (%) from screening to week 14 will be summarized using descriptive statistics (means and standard deviations) and compared between the treatment groups.

Trial Locations

Locations (1)

HCHS/SOL Bronx Field Center; 🇺🇸 Bronx, New York, United States