Brain Function, Cognition, and Hypoglycemia Tolerance in Patients With Type 1 Diabetes Mellitus in the Setting of Nutritional Ketosis Versus Standard Carbohydrate Diet
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Glycemic threshold for hypothalamic activation
研究概览
简要总结
The scientific goal of this study is to examine the effects of a ketogenic diet on hypoglycemia tolerance and brain function in people with type 1 diabetes mellitus (T1D) and to clarify the mechanistic role of ketones in this process. Glycemic management of T1D is typified by alternating periods of hyper- and hypo-glycemia. Because brain metabolism under usual conditions depends on glucose, acute hypoglycemia leads to immediate complications including impaired cognitive function and a counter-regulatory hormone response. Recurrent hypoglycemia is associated with functional and structural changes in the brain and contributes to the cognitive decline observed in individuals with diabetes. The state of nutritional ketosis (as it occurs during fasting or when following a ketogenic [very low carbohydrate] diet) may protect against these acute and chronic complications. As the body relies on fat metabolism, ketone bodies build up and provide an alternative fuel for the brain. Studies during hypoglycemia have shown better cognitive function and less hypoglycemia symptoms in the setting of nutritional ketosis or with ketone administration. This physiological benefit may have special relevance for people with T1D who experience hypoglycemia frequently. To date, no mechanistic studies have examined brain effects of nutritional ketosis in T1D; nor have any trials explored the potential relevance of this for diabetes care.
详细描述
To test the hypothesis that a ketogenic diet increases hypoglycemia tolerance and improves brain function and cognitive performance during hypoglycemia, the researchers propose a randomized mechanistic study using insulin infusions and neuroimaging. The study will leverage an existing randomized controlled trial (RCT) in 32 young adults with T1D who will receive a ketogenic vs a standard carbohydrate diet for 12 weeks. Researchers will conduct a euglycemic-hypoglycemic insulin clamp using a continuous infusion of insulin, along with a glucose infusion that is adjusted to keep blood glucose levels normal (90 mg/dL), followed by a slow drop to hypoglycemia (50 mg/dL). Researchers will assess activation and connectivity of relevant brain areas by magnetic resonance imaging (MRI). Using continuous imaging during the gradual glycemic descent from 90 mg/dL to 50 mg/dL, the researchers will establish the glycemic threshold at which the hypothalamus becomes activated. Using a combination of MRI modalities, they will assess brain activation and connectivity changes during hypoglycemia versus euglycemia, both during rest and in relation to a cognitive task. Brain findings will be integrated with physiologic (blood levels of glucose, ketones, free fatty acids, counter-regulatory hormones) and behavioral (reaction time, cognitive task performance, hypoglycemia symptoms scale) parameters. In additional studies, researchers will give an oral ketone drink to raise blood ketone levels in participants in the standard carbohydrate diet arm. They will perform the same insulin infusion and MRI investigations to clarify the mechanistic role of ketones in mediating brain activation patterns. Comparison will be between nutritional vs no ketosis, exogenous vs no ketosis, and nutritional vs exogenous ketosis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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).
结局指标
主要结局
Glycemic threshold for hypothalamic activation
时间窗: Diet week 5-12
The blood glucose level at which hypothalamic activation is detected by continuous BOLD functional MRI during a 40 min glycemic descent from 90 to 50 mg/dL
次要结局
- Response time changes during hypoglycemia(Diet week 5-12)
- Blood glucose level at which participant reports symptoms of hypoglycemia.(Diet week 5-12)
- Functional connectivity changes in brain areas related to cognition during hypoglycemia(Diet week 5-12)
- Cognitive performance during hypoglycemia(Diet week 5-12)
- Hypoglycemia symptoms(Diet week 5-12)
- Task-related brain activation changes during hypoglycemia in brain areas related to cognition(Diet week 5-12)
- Resting brain activation changes in brain areas related to cognition during hypoglycemia(Diet week 5-12)
研究者
Belinda Lennerz
Instructor in Pediatric Endocrinology
Boston Children's Hospital