Diabetes Mellitus, Type 1
Conditions
Keywords
brain, fMRI, carbohydrate, insulin clamp, intake regulation, overweight, glycemic index
Brief summary
Processed carbohydrates cause rapid changes in blood sugar and have been associated with overeating and obesity. We have shown that test meals high in processed carbohydrate affect brain areas involved in addiction, craving and overeating. It is unknown whether the changes in blood sugar or the associated higher insulin levels mediate this brain activation and its likely adverse effects. Answering this question is important for patients with type 1 diabetes who have elevated risks of obesity and disordered eating: If blood sugar is the causal mechanism, optimal insulin coverage should be protective. If insulin is the causal mechanism, however, a diet high in processed carbohydrate could predispose to overeating and weight gain, as this diet requires higher insulin doses. To disentangle these factors, we will study brain activation and relevant blood markers in 15 men with diabetes. In 4 sessions, we will examine meals with differential carbohydrate properties while giving insulin infusions.
Detailed description
A total of 15 male participants (age 18-45) with T1DM will be recruited. Participants will be enrolled in the study for a total of 1-3 months, and participate in a pre-test visit and three test visits, each after a 10-12-hr overnight fast. Participants will be instructed to consume their regular, weight maintaining diet between visits. At the pre-test visit, the study director or PI will meet participants, confirm eligibility and obtain informed consent. Participants will receive a low glycemic index (GI) meal with optimal iv insulin coverage using a negative feedback algorithm to maintain euglycemia (euglycemic clamp). Insulin requirement will be quantified. At some time during the visit, participants will present to the BIDMC research imaging facility for a practice MRI session, during which they will undergo a brief imaging sequence to get accustomed to the scanning process and eliminate anxiety as a confounder of imaging data. At each of 3 test visits, one of the following experimental conditions will be applied in a randomized, blinded cross-over design: (a) high GI meal with euglycemic clamp, (b) low GI meal with euglycemic clamp, (c) high GI meal with primed-variable insulin infusion at the rate established during the pre-test visit. After steady state is established, baseline laboratory evaluation and MRI imaging will be obtained, followed by the test meal. Imaging will be repeated at 1 and 4 hours postprandial. Blood samples for pertinent metabolic and hormonal parameters will be obtained every 30 minutes. Each test-visit concludes with a standard weighed meal to quantify ad-libitum intake.
Interventions
OTHERhigh GI meal
High and low GI liquid test meals are matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals will provide 25% of individual daily energy requirements as estimated by the Harris Benedict equation. A high glycemic index of \ 90 is achieved by using corn syrup as a carbohydrate source.
OTHERlow GI meal
High and low GI liquid test meals are matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals will provide 25% of individual daily energy requirements as estimated by the Harris Benedict equation. A low glycemic index of \ 40 is achieved by using uncooked corn starch as a carbohydrate source.
DRUGeuglycemic insulin clamp
Insulin will be given intravenously for 5 hours. During the entire clamp protocol, glucose levels will be measured every 5 minutes. A basal insulin infusion will be started at 80% of the patients insulin pump basal rate, and will be adjusted between 0.1 and 2.5 mU/kg•min, depending upon the patient's plasma glucose level in relation to the target range target of 90-100 mg/dl.
DRUGprimed-variable insulin infusion
A primed-variable infusion of insulin will be administered at the rate established to achieve euglycemia after a low glycemic index meal. This is expected to result in moderate hyperglycemia as the high GI meal is associated with higher insulin requirements. For patient safety, glucose levels will be measured every 30 minutes. If glucose levels are \> 400 mg/dl or \< 60 mg/dl, insulin infusion will be adjusted to maintain glucose levels target of 60-400 mg/dl.
Sponsors
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Boston Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetes for a minimum of 3 years * BMI 20-35 kg/m2 * Use of insulin pump * Willing and able to: Maintain weight and document for duration of the study
Exclusion criteria
* Insulin resistance (current insulin requirement \> 1.5 U/kg/d) * Insulin requirement \< 0.5 unit/kg/day (cut-off for preserved beta-cell function) * HbA1C ≥ 8.0% * DKA within 2 months * Frequent hypoglycemia (BG \<50 mg/dl), \> 3 times per week * Fluctuations in body weight \>10% over preceding year * Smoking or illicit substance abuse * High levels of physical activity (≥60 minutes per day, ≥ 4 days per week) * Current weight loss diet * Medical problems, medications or dietary supplements that may affect metabolism, insulin action, body weight, appetite, energy expenditure, or gastrointestinal absorption (e.g. celiac disease) * Allergies to compounds or intolerance of the liquid meals * MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nucleus Accumbens Blood Flow | 4 hrs postprandial | Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nucleus Accumbens Blood Flow | 1 hr postprandial | Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan. |
| Blood Flow in Other Brain Areas Involved in Intake Regulation - Dorsal Caudate | 4 hrs postprandial | Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right dorsal caudate, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan. |
| Blood Flow in Other Brain Areas Involved in Intake Regulation - Ventrolateral Striatum | 1 hr postprandial | Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right ventrolateral striatum, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan. |
| Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation | 4 hrs postprandial | Cerebral blood oxygen concentration level was measured by resting state functional MRI (rs-fMRI). Seed based analysis was performed with the seed on the right Nucleus Accumbens. Functional connectivity between Nucleus Accumbens and Hypothalamus was assessed through extraction of temporal correlation measures. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Plasma PYY | 0-4.5 hrs postprandial | blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel |
| Plasma CCK | 0-4.5 hrs postprandial | analyzed as part of a metabolic hormone panel |
| Plasma Glucose Level | 0-4.5 hrs postprandial | blood samples will be obtained every 30 minutes |
| Plasma Leptin | 0-4.5 hrs postprandial | analyzed as part of a metabolic hormone panel |
| Metabolomics | 0, 1 and 4 hrs postprandial | LC-MS/MS methodology using several chromatographic stationary phases for \> 400 metabolites |
| Plasma Glucagon | 0-4.5 hrs postprandial | blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel |
| Serum Insulin Level | 0-4.5 hrs postprandial | blood samples will be obtained every 30 minutes |
| Serum Fatty Acids | 0-4.5 hrs postprandial | blood samples will be obtained every 30 minutes |
| Plasma Ghrelin | 0-4.5 hrs postprandial | blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel |
| Plasma GLP-1 | 0-4.5 hrs postprandial | blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Boston Children's Hospital Diabetes Program and via postings in the surrounding medical area.
Pre-assignment details
Participants underwent a 5 hour pre-randomization visit to establish IV insulin requirement for a low GI test meal. Participants were positioned in the MRI scanner for a brief test sequence. Participants were excluded if they were unable to finish these pre-randomization procedures, or if they decided to not continue.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants In a randomized cross-over design, a nutritional shake with high GI vs low GI was consumed with differential insulin coverage:
* High GI meal covered with IV insulin to to achieve euglycemia, resulting in hyperinsulinemia (experimental condition A); 1 day.
* 1-week wash-out
* Low GI meal covered with IV insulin to achieve euglycemia (comparison condition B); 1 day.
* 1-week wash-out
* High GI meal with IV insulin matching the low GI meal, resulting in hyperglycemia (experimental condition A); 1 day.
The order of experimental conditions A and B was randomized.
High and low GI liquid test meals were matched for macronutrient composition (60% carbohydrate, 15% protein, 25% fat), micronutrient profiles, physical properties, palatability and sweetness. Meals provided 25% of individual daily energy requirements.
Insulin was given intravenously for 5 hours. Glucose levels were measured every 5 minutes for insulin titration.
Because all participants completed all interventions, results are presented in aggregate for the entire study group. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 21 years STANDARD_DEVIATION 1.6 |
| BMI | 21 kg/m^2 STANDARD_DEVIATION 1.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 15 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 1 / 15 | 0 / 15 | 1 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Nucleus Accumbens Blood Flow
Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time frame: 4 hrs postprandial
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| High GI With Matched to Low GI Glucose (HGI HI) | Nucleus Accumbens Blood Flow | right | 1.13 ml/g/min per ml/g/min | Standard Error 0.02 |
| High GI With Matched to Low GI Glucose (HGI HI) | Nucleus Accumbens Blood Flow | left | 1.21 ml/g/min per ml/g/min | Standard Error 0.02 |
| Low GI (LGI) | Nucleus Accumbens Blood Flow | right | 1.16 ml/g/min per ml/g/min | Standard Error 0.02 |
| Low GI (LGI) | Nucleus Accumbens Blood Flow | left | 1.18 ml/g/min per ml/g/min | Standard Error 0.02 |
| High GI With Matched to Low GI Insulin (HGI LI) | Nucleus Accumbens Blood Flow | right | 1.15 ml/g/min per ml/g/min | Standard Error 0.02 |
| High GI With Matched to Low GI Insulin (HGI LI) | Nucleus Accumbens Blood Flow | left | 1.18 ml/g/min per ml/g/min | Standard Error 0.02 |
Secondary
Blood Flow in Other Brain Areas Involved in Intake Regulation - Dorsal Caudate
Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right dorsal caudate, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time frame: 4 hrs postprandial
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High GI With Matched to Low GI Glucose (HGI HI) | Blood Flow in Other Brain Areas Involved in Intake Regulation - Dorsal Caudate | 0.60 ml/g/min per ml/g/min | Standard Error 0.01 |
| Low GI (LGI) | Blood Flow in Other Brain Areas Involved in Intake Regulation - Dorsal Caudate | 0.59 ml/g/min per ml/g/min | Standard Error 0.01 |
| High GI With Matched to Low GI Insulin (HGI LI) | Blood Flow in Other Brain Areas Involved in Intake Regulation - Dorsal Caudate | 0.64 ml/g/min per ml/g/min | Standard Error 0.01 |
Secondary
Blood Flow in Other Brain Areas Involved in Intake Regulation - Ventrolateral Striatum
Cerebral blood flow was measured by arterial spin labeling (MRI). Grouped MRI data was visually inspected for postprandial differences between conditions. Blood flow from a cluster contracting the conditions in the right ventrolateral striatum, just lateral to the nucleus accumbent, was extracted, normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time frame: 1 hr postprandial
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High GI With Matched to Low GI Glucose (HGI HI) | Blood Flow in Other Brain Areas Involved in Intake Regulation - Ventrolateral Striatum | 0.60 ml/g/min per ml/g/min | Standard Error 0.01 |
| Low GI (LGI) | Blood Flow in Other Brain Areas Involved in Intake Regulation - Ventrolateral Striatum | 0.61 ml/g/min per ml/g/min | Standard Error 0.01 |
| High GI With Matched to Low GI Insulin (HGI LI) | Blood Flow in Other Brain Areas Involved in Intake Regulation - Ventrolateral Striatum | 0.60 ml/g/min per ml/g/min | Standard Error 0.01 |
Secondary
Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation
Cerebral blood oxygen concentration level was measured by resting state functional MRI (rs-fMRI). Seed based analysis was performed with the seed on the right Nucleus Accumbens. Functional connectivity between Nucleus Accumbens and Hypothalamus was assessed through extraction of temporal correlation measures.
Time frame: 4 hrs postprandial
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High GI With Matched to Low GI Glucose (HGI HI) | Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation | 0.26 unite-less correlation | Standard Error 0.08 |
| Low GI (LGI) | Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation | 0.24 unite-less correlation | Standard Error 0.08 |
| High GI With Matched to Low GI Insulin (HGI LI) | Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation | 0.25 unite-less correlation | Standard Error 0.08 |
Secondary
Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation
Cerebral blood oxygen concentration level was measured by resting state functional MRI (rs-fMRI). Seed based analysis was performed with the seed on the right Nucleus Accumbens. Functional connectivity between Nucleus Accumbens and Hypothalamus was assessed through extraction of temporal correlation measures. Functional connectivity between Nucleus Accumbens and other brain areas was visually assessed.
Time frame: 1 hr postprandial
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| High GI With Matched to Low GI Glucose (HGI HI) | Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation | 0.36 unite-less correlation | Standard Error 0.09 |
| Low GI (LGI) | Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation | 0.15 unite-less correlation | Standard Error 0.09 |
| High GI With Matched to Low GI Insulin (HGI LI) | Functional Connectivity of Nucleus Accumbens, Hypothalamus and Other Brain Areas Involved in Intake Regulation | 0.15 unite-less correlation | Standard Error 0.09 |
Secondary
Nucleus Accumbens Blood Flow
Cerebral blood flow in the right and left nucleus accumbent was measured by arterial spin labeling (MRI). Blood flow was normalized for whole brain perfusion and corrected for baseline perfusion in the respective brain area and meal order, as per our a priori statistical analysis plan.
Time frame: 1 hr postprandial
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| High GI With Matched to Low GI Glucose (HGI HI) | Nucleus Accumbens Blood Flow | left | 1.20 ml/g/min per ml/g/min | Standard Error 0.02 |
| High GI With Matched to Low GI Glucose (HGI HI) | Nucleus Accumbens Blood Flow | right | 1.12 ml/g/min per ml/g/min | Standard Error 0.02 |
| Low GI (LGI) | Nucleus Accumbens Blood Flow | right | 1.16 ml/g/min per ml/g/min | Standard Error 0.02 |
| Low GI (LGI) | Nucleus Accumbens Blood Flow | left | 1.19 ml/g/min per ml/g/min | Standard Error 0.02 |
| High GI With Matched to Low GI Insulin (HGI LI) | Nucleus Accumbens Blood Flow | right | 1.11 ml/g/min per ml/g/min | Standard Error 0.02 |
| High GI With Matched to Low GI Insulin (HGI LI) | Nucleus Accumbens Blood Flow | left | 1.14 ml/g/min per ml/g/min | Standard Error 0.02 |
Other Pre-specified
Metabolomics
LC-MS/MS methodology using several chromatographic stationary phases for \> 400 metabolites
Time frame: 0, 1 and 4 hrs postprandial
Other Pre-specified
Plasma CCK
analyzed as part of a metabolic hormone panel
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Plasma Ghrelin
blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Plasma GLP-1
blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Plasma Glucagon
blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Plasma Glucose Level
blood samples will be obtained every 30 minutes
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Plasma Leptin
analyzed as part of a metabolic hormone panel
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Plasma PYY
blood samples will be obtained every 30 minutes and analyzed as part of a metabolic hormone panel
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Serum Fatty Acids
blood samples will be obtained every 30 minutes
Time frame: 0-4.5 hrs postprandial
Other Pre-specified
Serum Insulin Level
blood samples will be obtained every 30 minutes
Time frame: 0-4.5 hrs postprandial