Exercise and Intranasal Insulin in Type 2 Diabetes

This goal of this study is to find out if exercise plus an insulin nose spray works better than exercise alone for brain blood flow in older adults with Type 2 Diabetes. This study will also look at how the brain uses insulin and thinking skills. Individuals will be randomized to one of two groups. One group will exercise and use an insulin nose spray. The other group will exercise and use a saline (placebo) nose spray. Exercise training will be supervised and consist of walking or light jogging 3 times per week for 16 weeks. Brain imaging, cognition, and blood tests will be conducted before and after the intervention. Other measures include fitness tests and body composition scans.

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