Effect of 1,25-dihydroxyvitamin D3, Treatment on Insulin Secretion and Muscle Strength in Pre-diabetic Persons
Phase: PHASE1
Conditions: Pre-Diabetic
Sponsor: Mayo Clinic

 
 
Effect of 1,25-dihydroxyvitamin D3, 
Treatment on Insulin Secretion and Muscle 
Strength in Pre-diabetic Persons 
 
NCT04286529 
 
March 17, 2000 

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v.4_CH 200317 
Title: Effect of 1,25-dihydroxyvitamin D3 treatment on insulin secretion and muscle strength in pre-
diabetic persons. 
 
Principal Investigator: Rajiv Kumar, MD 
Co-Investigators: Adrian Vella, MD, Kenton Kaufman, PhD. 
Participants: Christine Huyber, Kathie Bernhardt, Louis Losbanos. 
 
Abstract 
Pre-diabetes affects over 325 million adults worldwide. These individuals that are predisposed to 
developing type 2 diabetes mellitus have few options to prevent the progression of the disease other than 
diet and exercise. Emerging evidence suggests that the active from of vitamin D, 1,25-dihydroxyvitamin 
D3 (1,25(OH)2D3; also known as calcitriol), contributes to glucose metabolism partly by increasing insulin 
secretion and also by increasing muscle glucose utilization. We intend to investigate the effects of a low 
daily dose of 1,25(OH)2D3 on glucose tolerance and muscle function in persons who are susceptible to 
developing diabetes. This study could provide a new strategy for preventing the progression of type 2 
diabetes mellitus with a drug that is already approved for use by the US Food and Drug Administration. 
 
Research Plan 
A. Specific Aim 
The aim of this study is to assess the effects of 1,25(OH)2D3 on insulin secretion by the pancreas 
and glucose utilization by skeletal muscle as well as to determine the effects of 1,25(OH)2D3 on muscle 
strength in pre-diabetic subjects. 
 
Hypothesis: 1,25(OH)2D3 will increase the rate of insulin secretion by pancreatic beta cells and 
improve glucose uptake in muscle, resulting in improved glucose homeostasis. Secondarily, 1,25(OH)2D3 
will increase muscle strength.  
 
Approach: This will be a double blind randomized control trial in pre-diabetic persons. Each 
participant will be randomly assigned to receive an oral tablet containing 0.25 µg 1,25(OH)2D3 or a 
placebo tablet for 8 weeks. Identical assessments will be performed both before and after the 8-week 
intervention period. These assessments will include the 2-hour glucose tolerance test (GTT) and muscle 
strength testing. 
 
B. Background 
Impairments in insulin secretion and glucose disposal affect a third of adults living in the United 
States (84 million, (CDC 2017)) and approximately 325 million people worldwide (IDF 2017). Over time, 
these symptoms progress into type 2 diabetes mellitus and then lead to secondary complications such as 
microvascular (e.g. diabetic nephropathy, retinopathy and neuropathy) and macrovascular (e.g. peripheral 
vascular and coronary artery disease) diseases.  
Early investigations demonstrated a strong link between vitamin D and insulin secretion. In rats, 
studies had shown that vitamin D deficiency (diet induced) negatively affected insulin secretion 
(Kadowaki and Norman 1984; Norman et al. 1980). Later, 1,25(OH)2D3 was confirmed to increase insulin 

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v.4_CH 200317 
secretion in the vitamin D-deficient rat model (Cade and Norman 1986). On the other hand, observational 
studies comparing serum 25(OH)D3 concentrations and diabetes, as well as randomized control trials with 
vitamin D3 supplementation, have not corroborated the link between vitamin D and insulin secretion 
(Mitri, Muraru, and Pittas 2011; Pittas et al. 2007, 2012, 2019; Wexler 2019). A recent longitudinal 
clinical trial, known as the Vitamin D and Type 2 Diabetes (D2d) Trial, studied the effects of 
supplementation with 4,000 IU of vitamin D3, the tolerable upper intake level (Ross et al. 2011), or 
placebo for 2.5 years in 2432 participants with pre-diabetes. The results of this trial indicated that vitamin 
D3 supplementation (n=1211) had no effect on the incidence of T2DM compared to the placebo group 
(n=1212) (Pittas et al. 2019). Many clinical trials have focused solely on the relationship between vitamin 
D3 intake or serum 25(OH)D3 and glucose metabolism and have established that vitamin D3 and 
25(OH)D3 do not have an effect on insulin secretion. However, Bonakdaran and colleagues studied 
patients with chronic renal deficiency and found that 0.5 µg 1,25(OH)2D3, (n=13) given daily for 4 weeks 
improved glucose utilization compared to placebo-treated controls (n=14) (Bonakdaran et al. 2008). Thus, 
1,25(OH)2D3 has been shown to positively affect insulin secretion in CKD patients and we believe that 
this benefit could be applied to persons with pre-diabetes. Based on these studies, we recognize that 
1,25(OH)2D3 itself has a direct hormonal effect on pancreatic beta cells and insulin secretion and that 
administration of 1,25(OH)2D3, rather than vitamin D3 or 25(OH)D3, may be a key factor in improving 
glucose homeostasis.     
Deficiency of vitamin D has been associated with muscle atrophy and poor diaphragm function 
(Dzik et al. 2019; Malinovschi et al. 2014). A recent study consisting of 4,157 older adults (>60 years) 
had shown that vitamin D deficiency (serum [25(OH)D] <30 nmol/L) was associated a three-fold 
increased incidence of impaired muscle performance and 2-fold increased incidence of impaired muscle 
strength compared to the vitamin D sufficient group (serum [25(OH)D] >50 nmol/L) (Aspell et al. 2019). 
Persons with diabetes are particularly susceptible to losses in muscle strength and endurance (Domaski 
and Ciechanowski 2012; Foley et al. 2007; Ijzerman et al. 2012). Poor muscle function not only 
accelerates deterioration of health and well-being, but it also impedes recovery following illness or 
hospitalization. In unpublished preliminary studies, Kumar and colleagues have found that a mouse model 
severely deficient in 1,25(OH)2D3 experiences a 30% reduction in both muscle strength and fatigue after 
merely 2 weeks without exogenous 1,25(OH)2D3. Furthermore, our laboratory has shown that human 
muscle responds to 1,25(OH)2D3 stimulation by increasing mitochondrial function (Ryan et al. 2016). 
Thus, we believe that 1,25(OH)2D3 in the pre-diabetic populations will offer benefits in muscle function 
that will reduce losses in mobility and pulmonary diaphragm function.  
The overall premise of this research is to investigate the action of a low daily dose of 
1,25(OH)2D3 in pre-diabetic persons. Assuming that our hypothesis is valid, these individuals are likely to 
observe benefits from 1,25(OH)2D3 for improvements in insulin secretion, glucose metabolism, and 
muscle strength.  
 
C. Significance of Proposed Research 
 
 
Insulin resistance is an early indication for the development of T2DM. The action of 1,25(OH)2D3 
on insulin secretion and glucose utilization may delay or prevent the onset of T2DM in pre-diabetic 
persons. Additionally, The action of 1,25(OH)2D3 on muscle may maintain and improve muscle function. 
 
 

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D. Design and Methods 
Study Design 
We will compare insulin secretion and glucose uptake and muscle function before and after 8 
weeks of treatment with 1,25(OH)2D3 or placebo in pre-diabetic participants. Men and women will be 
identified for recruitment to the study based on strict inclusion and exclusion criteria (Table 1 and 
Enrollment Criteria). After assignment to the study group, the participants will be randomly assigned on a 
first-come-first-serve basis to receive a daily oral table containing either 0.25 µg 1,25(OH)2D3 or placebo 
for 8 weeks. Before and after the intervention period, assessments will be made that will include a glucose 
tolerance test (GTT), knee flexor, and grip strength tests.  
 
Table 1: Enrollment Groups  
Group 
Criteria 
1 
Men 
2 
Pre-menopausal Women 
 
Enrollment Criteria  
Inclusion criteria: 
• 
Adults, 20 - 45 years old 
• 
Body mass index (BMI) of >24 kg/m2 
• 
Fasting serum glucose <126 mg/dl 
 
Exclusion criteria:  
• 
BMI ≤24 kg/m2 
• 
Fasting serum glucose ≥126 mg/dl  
• 
Currently taking calcium and/or vitamin D supplements and unwilling to stop for study duration 
• 
Serum total calcium >10.2 mg/dL 
• 
Serum inorganic phosphorus >4.5 mg/dL 
• 
Pregnancy or breastfeeding 
• 
Diagnosis of Diabetes Mellitus 
• 
Diagnosis of Rheumatoid Arthritis 
• 
Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) 
• 
Renal insufficiency/failure (serum creatinine >1.5 mg/dl men, >1.3 mg/dl women) 
• 
Chronic active liver disease (bilirubin > 1.2 mg/dL, AST >144 IU/L, or ALT >165 IU/L) 
• 
History of chronic hepatitis 
• 
History of depression, anxiety or psychiatric disease 
• 
Active coronary artery disease (unstable angina, myocardial infarction, stroke, and 
revascularization of coronary, peripheral or carotid artery within 3 months of recruitment) 
• 
Oral warfarin or history of blood clotting disorders 
• 
Platelet count < 100,000 per uL within the last 7 days 
• 
Alcohol consumption greater than 2 glasses/day or other substance abuse 
• 
Untreated or uncontrolled thyroid disorders (outside a TSH range of 0.5 to 10 mIU/L) 
• 
Debilitating chronic disease (at the discretion of the investigators) 

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v.4_CH 200317 
• 
The presence of infections, highly communicable diseases (AIDS, active tuberculosis, venereal 
disease, hepatitis) 
• 
Any malignancy 
 
 
Recruitment  
A study coordinator will work closely with Dr. Kumar to identify potential candidates for this 
study. Participants will be recruited from the Research Studies section of the Mayo Classifieds website, 
and from participants who completed other research studies and agreed to be contacted again for other 
studies. While most of the information will be provided to potential participants in person, participants 
may also be contacted by telephone with a brief description of the study and to determine if they are 
interested in participating. The study coordinator will perform a brief screening questionnaire to 
determine eligibility to proceed with enrollment. The information gathered from the screening 
questionnaire will not be stored or used for data analysis if participants do not qualify for the study. 
 
Consent and Screening 
Potential participants will report to the Clinical Research and Trials Unit at the Charlton Building 
or St. Mary’s Hospital. A member of the study team will meet the potential participant and then the 
consent form will be read and discussed in a private area. After receiving consent, the participant will 
have a urine pregnancy test (if applicable) and screening blood work (fasted). Screening blood work will 
be processed in a clinical lab and will include: Basic Metabolic Panel (sodium, potassium, bicarbonate, 
creatinine, BUN, calcium, phosphorous, and albumin), ALT (alanine transaminase), AST (aspartate 
aminotransaminase), BILIT (total bilirubin), TSH (thyroid stimulating hormone), CBC with differential 
count including platelets, APT (activated partial thromboplastin time), PT (prothrombin time), GLUCF 
(glucose fasting) and CDHVD (1,25(OH)2D3, 25(OH)D3). Participants will have a nursing assessment that 
will include vital signs and a brief physical exam by a study MD.  
 
Study Intervention Agent: 1,25-Dihydroxyvitamin D3 
As per DrugBank, this agent is used to treat refractory rickets (vitamin D resistant rickets), 
familial hypophosphatemia, hypoparathyroidism, and in the management of hypocalcemia and renal 
osteodystrophy in patients with chronic renal failure undergoing dialysis. This protocol will use doses that 
are identical to those used for these other clinical indications.  
The Mayo Clinic Pharmacy will prepare 1,25(OH)2D3 tablets containing 0.25 µg of 1,25(OH)2D3  
as well as an identical placebo tablet containing 0 µg of 1,25(OH)2D3. Assignment will remain blinded to 
participant, healthcare providers and members of the study team who have direct participant contact.  
 
Intervention instructions: During screening and prior to receiving the intervention, caloric intake 
and vitamin and mineral analysis will be estimated by having participants complete the VIOCare Food 
Frequency questionnaire, with the dieticians in the clinical research unit. A dietician will instruct the 
participant to adhere to a diet of 400 mg calcium and 800-1000 mg phosphorus while taking 
1,25(OH)2D3/placebo agent intervention. These instructions are included to prevent potential development 
of hypercalcemia and/or hyperphosphatemia as a direct result of 1,25(OH)2D3. After completing 
screening and baseline assessments, participants will be instructed to take 1 tablet (containing 0.25 µg 
1,25(OH)2D3 or placebo) per day for 8 weeks following the completion of Day 3 of baseline assessments 
(Table 2). 

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v.4_CH 200317 
 
E. Assessments 
 
Participants will undergo a series of assessments for initial baseline measurements and post-
intervention measurements (Table 2). Both baseline and post-intervention evaluations will include a 
questionnaire, glucose tolerance, lower extremity strength testing (knee flexor), and upper extremity 
strength testing (grip strength). During the intervention phase, serum calcium and phosphorus levels will 
be monitored at every two weeks.  
 
Questionnaire: The NIH-funded Patient-Reported Outcomes Measurement Information System 
Global-10 (PROMIS 10) is a brief, 10-question, multiple-choice survey that approximates a person’s 
perceived physical and mental health (Hays et al. 2009). The questionnaire will be delivered as a written 
survey or in electronic format on a handheld tablet at the consent and screening visit as well as at the final 
visit for post-intervention assessments. 
 
Glucose Tolerance Test (GTT): After an overnight fast, subjects will present to the Clinical 
Research and Trials Unit (CRTU). The subjects will ingest a drink containing 75g glucose. Venous blood 
will be obtained for measurement of glucose, insulin, and C-peptide concentrations over a 120 min period 
at 0, 10, 20, 30, 60, 90 and 120 minutes (Dalla Man et al. 2005; Sathananthan et al. 2012). All blood will 
be immediately placed on ice, centrifuged at 4oC, separated, and stored at -80oC until assay. Glucose will 
be measured using a Yellow Springs glucose analyzer, C-Peptide will be measured by ELISA assay using 
EMD Millipore (Billerica, MA) reagents, and insulin will be measured using a chemiluminescence assay 
with reagents obtained from Beckman (Chaska, MN). At the time of study, glucose values at 0 and 120 
minutes will be used to categorize glucose tolerance status and exclude subjects with T2DM. Data 
obtained from GTT will provide fasting, peak, and nadir insulin concentrations. Additional calculations 
will be used to determine area above basal (AAB) or area under the curve (AUC) during the postprandial 
period using the trapezoidal rule as previously described (Vella et al. 2007). Insulin action (Si) and β-Cell 
responsivity indices (φ) will be calculated (Cobelli et al. 2014) from the plasma glucose, insulin and C-
peptide concentrations observed during the experiments using the appropriate minimal model (Breda et al. 
2001), incorporating age-associated changes in C-peptide kinetics (Cauter et al. 1992). The disposition 
index (DI) will be calculated as DI = φ·Si, which determines if β-cell function is appropriate for the 
prevailing insulin action. 
  
Lower Extremity Strength Test: Participants will undergo measurements at the Motion Analysis 
Laboratory. Dominant knee flexor musculature strength will be assessed via a computerized multi-joint 
testing system (Humac Norm System; CSMi Medical Solutions Stoughton, MA). Subjects will be 
positioned and stabilized on the testing apparatus using standardized protocols. The axis of the knee joint 
will be aligned with the center of rotation of the dynamometer arm and the lower leg will be strapped to 
the lever arm just proximal to the angle. Participants will be buckled in at the waist, shoulders and the 
distal part of the thigh. Peak torque will be assessed at a knee angle of 60o flexion. Participants will be 
verbally encouraged to perform at their maximum. Torque generated by the subject in an isometric 
contraction will be measured and recorded. Three isometric strength testing repetitions will be performed 
for each muscle group. Each isometric muscle contraction will be held for 5s and a 30s rest period will be 
observed between contractions. The largest value from three trials will be used. 

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v.4_CH 200317 
Upper Extremity Strength Test: Isometric handgrip strength will be measured in the Motion 
Analysis Laboratory. Dominant hand grip strength will be tested using a custom designed digital grip 
dynamometer (NK Biotechnical Engineering Co., Minneapolis, MN). The measurements will be 
performed with participants sitting upright, feet flat on the floor, elbow flexed to 90o, and forearm in 
neutral position. Standardized verbal encouragement will be given for each contraction. Three maximal 
repetitions (30s rest between attempts) will be recorded. The largest value from three trials will be used.  
 
Table 2: Timeline of the study 
Consent, Screening, and Baseline Assessments (complete within 5 days) 
Day 1 
Consent and Screening 
Completion of the  PROMIS 10 Questionnaire 
Food Frequency Questionnaire 
Nutrition Consult with Dietitian 
Urinalysis (women only) 
• 
HCG 
Fasting Blood Draw 
• 
Basic Metabolic Panel, ALT, AST, BILIT, TSH, CBC, APT, PT, GLUCF, PTH, 
CDHVD (1,25(OH)2D3, 25(OH)D3), calcium, and phosphorus 
Day 2 
Glucose Tolerance Test 
• 
Glucose, insulin, glucagon and C-peptide, at fasting and at 10, 20, 30, 60, 90 and 
120 minutes following oral glucose bolus 
Knee Flexor Strength Test 
Grip Strength Test  
Physical Exam with Physician 
Begin Intervention with 1,25(OH)2D3 or Placebo 
Intervention 
Week 2 
Blood Draw: calcium and phosphorus 
Week 4 
Blood Draw: calcium and phosphorus 
Week 6 
Blood Draw: calcium and phosphorus 
Week 8 
Begin Post-Intervention Assessments 
Post-Intervention Assessments (complete within 2 days of taking last tablet ) 
Day 1 
Fasting Blood Draw 
• 
CDHVD (1,25(OH)2D3), calcium, and phosphorus 
Glucose Tolerance Test 
• 
Glucose, insulin, glucagon and C-peptide, at fasting and at 10, 20, 30, 60, 90 and 
120 minutes following oral glucose bolus 
Knee Flexor Strength Test 
Grip Strength Test 
Completion of PROMIS 10 Questionnaire 
 
F. Statistics and Analyses 
Power calculations for determining sample sizes were performed in JMP Pro 14 by using 
previously published variances on DI and φ that describe beta cell function in pre-diabetic persons 
(Sathananthan et al. 2012) (Table 3).   
 

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Table 3: Power calculations for determining sample size 
Parameter 
Expected Outcome (mean ± sd) 
Total 
Sample Size 
DI 
1920 ± 321 (10-14dl/kg/min2 per pmol/l) 
28 
φ 
63.8 ± 7.5 (10-9 min-1) 
15 
 
 
47 
* Total N to detect a 20% difference with 85% power between two groups of N/2. 
 
Analysis: Data will be analyzed as a repeated measures analysis of variance (ANOVA) with the 
independent variable as 1,25(OH)2D3 or placebo and the dependent variable as assessments made before 
and after intervention. The main effect will be an analysis of the study groups pooled across gender and 
hormonal status to compare intervention with placebo. Additional co-variables to be considered in the 
analyses will be sex and menopausal stage per study group affiliation, as well as age, race, and others as 
post-hoc analyses. 
G. Endpoints 
Primary: Completion of final blood collection and GTT. 
Secondary: Completion of PROMIS 10 Questionnaire. 
 
Human Subjects 
Risks to the subjects 
Human Subjects Involvement and Characteristics: All protocols and all techniques to be used will be 
approved by the Mayo Clinic Institutional Review Board (IRB) prior to initiation of any studies. Subject 
characteristics and inclusion/exclusion criteria have been clearly specified above. Our plan is to complete 
the study on 50 participants with 25 in each group. We are anticipating a target accrual of 75 subjects to 
account for anticipated dropout in order to have 50 participants complete the study. 
 
Sources of Materials. Samples of blood and urine obtained during the study will be used exclusively for 
research purposes. No use will be made of pre-existing specimens.  
 
Urine: Urine samples will be collected from women for pregnancy testing. 
Blood: One blood draw will occur during the screening visit (approximately 15 mL). A glucose tolerance 
test will be performed at baseline that will include seven blood draws (approximately 1 mL of blood from 
each draw) periodically over the course of 2 hours. Every 2 weeks during the intervention, a small sample 
of blood (1 mL) will be collected to monitor calcium and phosphorus levels. At completion of 8 weeks of 
intervention, another GTT will be performed and 5 mL of blood will be collected for post-intervention 
analysis. This analysis will include calcium, phosphorus, 25(OH)D3, 25(OH)D2, 1,25(OH)2D3, and 
1,25(OH)2D2. All specimens will be processed internally and stored in the study team laboratory. 
 
Potential Risks: 
The following are potential risks for this study 

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a) Blood will be withdrawn. The total blood withdrawn throughout the 8-week study will be 
approximately 40 mL. 
b) The study agent, 1,25(OH)2D3, has potential risks that are considered rare at the dosage in use. 
These risks include hypercalcemia, hyperphosphatemia, weakness, headache, nausea, vomiting, 
sleepiness, dry mouth, constipation, muscle pain, bone pain, or a metallic taste. 
Adequacy of Protection Against Risks 
Feasibility, Recruitment, and Informed Consent: Volunteers will be initially recruited from individuals 
who have previously indicated a desire to participate in research. Each willing participant will meet one 
of the investigators who will explain the scientific rationale, the procedures and the potential risks 
involved in the study. The consent form will be approved by the Mayo Clinic IRB prior to use. Informed 
written consent from the participant will be obtained by one of the investigators prior to participation. An 
electronic note will be entered in each participant’s medical record regarding the consent and a copy of 
the consent will be electronically kept with the participant’s medical record. A copy of the consent will be 
offered to the subject and the original kept with the investigators records. 
 
Protection against risk: All protocols and all techniques to be used will be approved by the Mayo Clinic 
IRB  prior to initiation of any studies. All participants will have the Mayo Clinic paging operator 
available to them 24 hours a day to contact the investigators for any problems. The Clinical Research and 
Trials Unit (CRTU) also has an on-call physician available 24 hours a day to contact for problems or 
concerns in the event that the study MD does not respond to calls or pages. The following protection will 
be taken for the risks identified above: 
a) The amount of blood drawn is within the amounts acceptable by the institution. There is an 
institutional electronic tracking system to ensure that a patient is not in more than one study at a 
time. 
b) A Data Safety and Monitoring Plan (DSMP) will be utilized for patient safety. Investigators and 
the CRTU have had extensive experience in all procedures and aspects of the study. The 
investigative team will review any participant safety issues as delineated in the DSMP. 
c) Subject protection is as listed in the above section. Confidentiality of all medical records is 
strictly maintained by established procedures. The original study data are kept in the Principal 
Investigator’s laboratory/office and are entered into a secure Mayo firewall allocated for use by 
only the study team. All data are reviewed by the Principal Investigator. All investigators carry 
pagers. Volunteers have access to the Mayo Clinic paging operator 24 hours a day. 
d) The risks to the subjects are small being primarily those of blood withdrawal. 
e) Participants will have their serum calcium and phosphorus levels repeatedly checked following 
administration of 1,25(OH)2D3 or placebo. Participants who develop an increase in their calcium 
or phosphorus level above the institutional upper limit of normal (defined values) will be taken 
off the intervention, referred to their primary healthcare provide, and have their blood calcium 
and phosphorus reassessed after two weeks or until the concentrations return to within normal 
limits.  
 
Potential Benefits of Proposed Research to the Subjects and Others 
Evidence for the impact of 1,25(OH)2D3 on glucose metabolism and muscle function is steadily 
increasing. When administered in low doses, this treatment may be a reliable option that is currently 

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v.4_CH 200317 
approved by the US Food and Drug Administration, for improving glucose metabolism in persons who 
are prone to T2DM. Participants included in this study may experience benefits that could enhance their 
general health and fitness and prevent development of T2DM.  
Protection of Human Research Participants 
The personnel identified in the application have completed the required education on the protection of 
human research participants. The institution has established a formal program entitled the Mayo 
Investigator Training Program (MITP). The MITP is a web-based educational course designed to provide 
all personnel involved in human subjects research with training about human subject protection. All Mayo 
personnel engaged in human subject research are required to complete the course and recertify themselves 
every two years. The primary objectives of the course are to provide the historical framework for current 
human subject protection regulations and to explore the evolving issues related to human subject research. 
The course is divided into four sections: 
1. Course introduction and general overview 
2. History section which explores examples of unethical behavior in human subject research 
3. Review of major human subject protection issues 
4. Discussion of the various roles and responsibilities of individuals involved in human subject 
research. 
At the conclusion of the instruction, individuals are required to complete a thirty-question assessment.  
 
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