Exercise and Intranasal Insulin in Type 2 Diabetes
Effects of Intranasal Insulin Plus Exercise Training on Brain Blood Flow, Neuronal Insulin Signaling, and Cognition in Adults With Type 2 Diabetes
About 6.5 million adults in the United States who are 65 or older have dementia.
While the exact cause of dementia is not known, it may be due to changes in the brain. Further, risk may be higher when the brain does not respond to insulin. Indeed, brain insulin resistance has emerged as a pathologic factor affecting memory, executive function as well as systemic glucose control. Regular aerobic exercise may help reduce the risk of dementia by increased blood flow to the brain and help the brain respond better to insulin. In addition, giving insulin through a nose spray (called intranasal insulin) may also help with thinking and memory. However, it is unknown if using both exercise and intranasal insulin is best for the brain.
研究概览
地位
条件
详细说明
研究类型
注册 (估计的)
阶段
- 阶段2
- 第三阶段
联系人和位置
学习联系方式
- 姓名：Steven K Malin, PhD
- 电话号码：848-932-7540
- 邮箱：steven.malin@rutgers.edu
研究联系人备份
- 姓名：Emily M Heiston, PhD
- 电话号码：848-932-7540
- 邮箱：emily.heiston@rutgers.edu
学习地点
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New Jersey
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New Brunswick、New Jersey、美国、08901
- 招聘中
- Rutgers University Loree Gymnasium
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接触：
- Steven Malin, PhD
- 电话号码：848-932-7540
- 邮箱：steven.malin@rutgers.edu
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New Brunswick、New Jersey、美国、08901
- 招聘中
- Institute for Food, Nutrition, and Health
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接触：
- Sue Shapses, PhD
- 邮箱：shapses@rutgers.edu
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New Brunswick、New Jersey、美国、08091
- 招聘中
- Robert Wood Johnson University Hospital Clinical Research Center
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接触：
- Fei Chen
- 电话号码：732-235-5966
- 邮箱：chenf2@rwjms.rutgers.edu
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Piscataway、New Jersey、美国、08854
- 招聘中
- Center for Advanced Human Brain Imaging Research
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接触：
- David Zald, PhD
- 电话号码：732-235-7211
- 邮箱：dz268@rbhs.rutgers.edu
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参与标准
资格标准
适合学习的年龄
- 成人
- 年长者
接受健康志愿者
描述
Inclusion Criteria:
- Male or female 55-80 years old
- Type 2 diabetes diagnosis or confirmation HbA1c >6.5% and fasting glucose >126 mg/dl
- Individuals prescribed metformin, GLP-1 agonists (oral/injectable), TZDs, DPP-IV inhibitors, Acarbose, SGLT-2 inhibitors >6 months.
- MOCA ≥26
- Body mass index (BMI) ≥25 and ≤40 kg/m2
- Not diagnosed with Type 1 diabetes
- Not currently engaged in <90 min/wk of exercise
Exclusion Criteria:
- A diagnosis of dementia
- Neurologic disease (e.g. Parkinson's, autonomic neuropathy, etc.)
- Intolerance to insulin
- Morbidly obese patients (BMI >40 kg/m2) and lean patients (BMI <25 kg/m2)
- >2 kg weight change in past 6 months
- Participants who have been recently active (>90 min of moderate/high intensity exercise)
- Individuals who are smokers or who have quit smoking (<2 years)
- Hypertriglyceridemia (400 mg/dl) and hypercholesterolemic (>260 mg/dl) subjects
- Uncontrolled Hypertensive (>160/100 mmHg)
- Participants with a history of significant metabolic, cardiac, cerebrovascular, hematological, pulmonary, gastrointestinal, liver, renal, or endocrine disease or cancer that in the investigator's opinion would interfere with or alter the outcome measures, or impact subject safety
- Pregnant (as evidenced by positive pregnancy test) or nursing women
- Participants with contraindications to participation in an exercise training program
- Major psychiatric disorders (e.g. psychosis, bipolar disorder, major depression, alcohol/substance abuse)
- History of head trauma or loss of consciousness in last 5 years.
Known contraindications for MR imaging:
- History of head trauma or neurosurgery, or neurological disorder (other than headaches or peripheral nerve disease) as these may impact neuroimaging results.
- Ferrous material implanted in or on the body, including flakes or filings, surgical clips, bullets, or electrical devices such as a pacemaker, or nonremovable ferrous jewelry (fillings in teeth and permanent retainers are permitted).
- Fillings and permanent retainers do not provide a safety risk and are not general exclusions. However, upper retainers may cause artifacts in ventral frontal regions and therefore may be an exclusion for some studies.
- Individuals with surgical pins or plates above the neck are excluded. Surgical pins or plates below the neck are exclusions, except when the material is fixed to bone, and considered acceptable by the Reference Manual for Magnetic Resonance Safety. Implants and Devices, 2020 Edition. Almost all recent orthopedic implants are made of materials that are not ferromagnetic and therefore are safe for scanning, and even though some screws are still made of ferromagnetic materials these are firmly screwed into bone. In cases where the material is unknown or deemed unsafe for scanning by the Reference Manual for Magnetic Resonance Safety. Implants and Devices the participant will be excluded.
- History of eye injury involving metallic materials, shavings in eyes, or welding without a face mask
- Lead/iron tattoos
- Claustrophobia (history of significant anxiety in closed places).
- Back problem that would prevent the subject from laying still comfortably for up to 90 minutes.
- Deafness
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：随机化
- 介入模型：并行分配
- 屏蔽：四人间
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
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安慰剂比较：HiEx with Intranasal Placebo
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Saline will be administered twice daily (20 seconds in each nostril) using the Kurve Technology intranasal insulin device.
High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate.
Supervised exercised will occur on a treadmill 3d/wk.
The duration of each exercise session will be adjusted based on fitness level so that ~300 kcal will be expended per training session during weeks 1-2, 350 kcal per training session during weeks 3-4, and 400 kcal per training session during weeks 5-16.
This usually equals ~60 minutes per session but can vary from person to person.
Each session will start with a 5-minute warm-up and end with a 5-minute cool down.
During each exercise session, individuals will wear a heart rate monitor rating of perceived exertion will be recorded.
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有源比较器：HiEx with Intranasal Insulin
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High intensity exercise will consist of 16 weeks of walking at ~85% of each participant's predetermined VO2max and monitored via heart rate.
Supervised exercised will occur on a treadmill 3d/wk.
The duration of each exercise session will be adjusted based on fitness level so that ~300 kcal will be expended per training session during weeks 1-2, 350 kcal per training session during weeks 3-4, and 400 kcal per training session during weeks 5-16.
This usually equals ~60 minutes per session but can vary from person to person.
Each session will start with a 5-minute warm-up and end with a 5-minute cool down.
During each exercise session, individuals will wear a heart rate monitor rating of perceived exertion will be recorded.
Dosage will be 20 IU of INI twice per day (40 IU in total/day).
The study will use the Kurve Technology intranasal device, which delivers a 20 second stream of insulin through a nose piece into a nostril, after which the device switches off.
The process will then be repeated in the other nostril.
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研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
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Cerebrovascular Insulin Sensitivity
大体时间：Change from baseline to the end of the intervention at 16 weeks
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People will undergo a motion corrected diffusion weighted gradient-and spin echo pseudo-Continuous Arterial Spin Labeling (pCASL) sequence with 5 post labelling delays. This provides 3.5 mm3 resolution for whole brain coverage for CBF. CBF will be determined via the hippocampus. Participants will then be administrated INI at a dose of 40 IU of human insulin (0.4 ml, Humulin, Eli Lilly & Co., Indianapolis, IN). Single puffs of 0.1ml will occur 4 times (twice each nostril) over 2 minutes via the VianaseTM electronic atomizers (Kurve Technology Inc., Lynnwood, WA). After 30 minutes, scanning will be repeated to determine CBF changes to indicate brain insulin sensitivity. Brain insulin sensitivity will be defined as the change from fasting to INI (e.g. CBFINI - CBFfast). |
Change from baseline to the end of the intervention at 16 weeks
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
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Blood Brain Barrier Integrity
大体时间：Change from baseline to the end of the intervention at 16 weeks
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People will undergo a motion corrected diffusion weighted gradient-and spin echo pseudo-Continuous Arterial Spin Labeling (pCASL) sequence with 5 post labelling delays. This provides 3.5 mm3 resolution for whole brain coverage for BBB water exchange (Kw). Kw will serve as primary index of BBB integrity. Participants will then be administrated INI at a dose of 40 IU of human insulin (0.4 ml, Humulin, Eli Lilly & Co., Indianapolis, IN). Single puffs of 0.1ml will occur 4 times (twice each nostril) over 2 minutes via the VianaseTM electronic atomizers (Kurve Technology Inc., Lynnwood, WA). After 30 minutes, scanning will be repeated to determine BBB changes from fasting to INI (e.g. KwINI - Kwfast). |
Change from baseline to the end of the intervention at 16 weeks
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Insulin Signaling Proteins
大体时间：Change from baseline to the end of the intervention at 16 weeks
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Insulin signaling proteins pIRS-1Ser636 and pAktSer473, derived from neuronal extracellular vesicles (nEVs) will be measured before and 30 minutes after intranasal insulin (e.g. nEVsINI - nEVsfast). nEVs will be isolated from plasma samples through a 2-step method: 1) isolating total plasma nEVs via Size Exclusion Chromatography (SEC) and selective immunocapture targeting three neuronal-specific epitopes on intact EVs (L1CAM, NLGN3, and GAP43). Isolated nEVs concentration and size distribution will be assessed by nanoparticle tracking analysis (NTA). nEV concentration will be used to normalize protein biomarker values to account for differential recovery. |
Change from baseline to the end of the intervention at 16 weeks
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Augmentation Index
大体时间：Change from baseline to the end of the intervention at 16 weeks
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Brachial artery augmentation index (AIx75) will be tested in the semi-supine position using the SphygmoCor device to depict arterial stiffness before and after INI (e.g.
AIx75INI - AIx75fast).
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Change from baseline to the end of the intervention at 16 weeks
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Peripheral Insulin Sensitivity
大体时间：Change from baseline to the end of the intervention at 16 weeks
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A 120 minute 75g OGTT will be used to depict insulin sensitivity.
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Change from baseline to the end of the intervention at 16 weeks
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Cognitive Function
大体时间：Change from baseline to the end of the intervention at 16 weeks
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Cognitive function will be assessed via the NIH toolbox.
The NIH toolbox is an iPad application that consists of cognitive, emotional, motor, and sensory function assessments.
Specific measurements will include: Flanker Inhibitory Control and Attention Test, List Sorting Working Memory Test, Pattern Comparison Processing Speed Test, and Picture Sequence Memory Test.
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Change from baseline to the end of the intervention at 16 weeks
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Pulse Wave Velocity
大体时间：Change from baseline to the end of the intervention at 16 weeks
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Pulse Wave Velocity (PWV) will be tested in the semi-supine position using the SphygmoCor device to depict arterial stiffness before and after INI (i.e.
PWV-INI - PWV-fast).
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Change from baseline to the end of the intervention at 16 weeks
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Insulin Secretion
大体时间：Change from baseline to the end of the intervention at 16 weeks
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A 120 minute 75g OGTT will be used to depict insulin secretion.
Using the oral c-peptide minimal model (OMM), an estimate of 3 insulin secretion patterns will be be obtained: 1) one that is proportional to glucose rate change (i.e.
early phase); 2) another proportional to plasma glucose above a threshold after a delay (i.e. late phase); and 3) total responsivity index, (total phase).
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Change from baseline to the end of the intervention at 16 weeks
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合作者和调查者
调查人员
- 首席研究员：Steven K Malin, PhD、Rutgers University - New Brunswick
出版物和有用的链接
一般刊物
- Malin SK, Battillo DJ, Beeri MS, Mustapic M, Kapogiannis D. A Single Bout of Aerobic Exercise Increases Neuronal Extracellular Vesicle-Derived Insulin Signaling Biomarkers in Adults With Cardiometabolic Risk. Compr Physiol. 2026 Apr;16(2):e70131. doi: 10.1002/cph4.70131.
- Malin SK, Battillo DJ, Zald DH, Ramirez J. Appetite Perception and Cerebral Blood Flow in Aging Adults Following a Single Bout of Exercise. Nutrients. 2026 Mar 27;18(7):1072. doi: 10.3390/nu18071072.
- Malin SK, Zald DH, Battillo D. Acute Exercise Reduces Intranasal Insulin-Mediated Elevations in Blood Pressure in Aging Adults with Cardiometabolic Risk. Am J Physiol Regul Integr Comp Physiol. 2026 Jun 15. doi: 10.1152/ajpregu.00119.2026. Online ahead of print.
- Malin SK, Battillo DJ, Beeri MS, Mustapic M, Delgado-Peraza F, Kapogiannis D. Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes. Aging Cell. 2025 Jan;24(1):e14369. doi: 10.1111/acel.14369. Epub 2024 Oct 18.
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
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