Current Environment:


Despite major technological advances, management of type one diabetes mellitus (T1D) remains suboptimal, putting millions of people at risk for immediate and long-term complications. After meals, a mismatch between carbohydrate absorption rate and insulin action typically leads to alternating periods of hyper- and hypoglycemia. A conceptually promising approach to control both problems is dietary carbohydrate restriction to reduce postprandial blood glucose changes and insulin needs. In a prior survey study, the investigators documented exceptional glycemic control (HbA1c 5.67%) and low acute complication rates among 316 children and adults with T1D consuming a very-low-carbohydrate (VLC) diet. Despite these promising preliminary results, the use of VLC diets for T1D remain controversial, because of their restrictive nature and theoretical concerns regarding growth, ketoacidosis and hypoglycemia risks and efficiency of glucagon treatment for hypoglycemia. Glucagon is used as a rescue medication during severe hypoglycemia and increases blood glucose levels by mobilizing liver glycogen stores. If these stores are depleted during carbohydrate restriction, glucagon response may be inadequate and put individuals at risk for refractory hypoglycemia. A physiologic study has shown a blunted but still adequate response to glucagon in n=10 participants after following a VLCD for 1 week. Longer-term studies have not been done. To test the hypotheses that glucagon response remains adequate while following a VLC diet in the longer term, the investigators will conduct a glucagon challenge in participants who are assigned to the VLC arm of a randomized-controlled feeding study in 32 young adults with T1D who will receive a VLC vs a standard diet for 12 weeks. After an overnight fast, twelve participants in the VLC arm will receive IV insulin to lower blood glucose levels to 60 mg/dL, followed by a glucagon injection and monitoring of blood glucose levels and other metabolic fuels.



Recruitment Status


Eligibility Criteria

Inclusion Criteria:

Males and females with T1D for at least 1 year
Age 18 to 40 years
Tanner stage ≥ IV
BMI 18.5-35 kg/m2
Stable glycemic control (HbA1c 6.5-9%)
Use of a continuous glucose monitor (CGM)
Use of an insulin pump
Attendance of at least 1 diabetes care visit over the past 12 months (including virtual)

Exclusion Criteria:

Ketoacidosis or severe hypoglycemia with seizure or coma in the past 6 months
Dietary restrictions or intolerances that are incompatible with the planned food deliveries, e.g. celiac disease, gastroparesis, certain food allergies
Following a weight-loss or otherwise restrictive diet
Vigorous exercise >2 hours on >3 days a week
History of an eating disorder or at risk for eating disorder, assessed by the Eating Disorders Diagnostic Scale (EDDS)
Major medical illness or use of medications other than insulin and metformin that could interfere with metabolic or glycemic variables
Significant psychiatric illness
Smoking, use of recreational drugs, or excessive alcohol consumption
Pregnancy or breastfeeding

For participants who undergo MRI:

Standard MRI exclusion criteria
Irregular menses
Use of psychotropic medication other than SSRIs or other mild antidepressant or anxiety medications (unless these medications are safe to be held for several days to allow for the acquisition of MRI data).


Intervention Type

Intervention Name


Very low carbohydrate diet


Not Applicable



Min Age

18 Years

Max Age

40 Years

Download Date

July 3, 2023

Principal Investigator

Belinda Lennerz

Primary Contact Information

Belinda S Lennerz, MD, PhD


Svetlana Azova, MD


For more information on this trial, visit


For more information and to contact the study team:

Very Low Carbohydrate Diets and Glucagon Response in T1DM NCT04200391 Belinda S Lennerz, MD, PhD 8572183896 Svetlana Azova, MD 617-919-6675