The main purpose of this study is to find the long-term effects of daily administration of 40 IU of intranasal insulin (INI) as compared to placebo (sterile saline) on cognition and memory in people with type 2 diabetes mellitus (DM), and non-diabetic controls over 24 weeks with a follow-up period for 24 weeks. Four groups will be tested: DM group treated with INI; DM group treated with placebo; control group treated with INI and the control group treated with placebo. The INI or placebo will be delivered into the nose. The investigators are interested to see whether INI can improve memory and cognition and blood flow in the brain in the type 2 DM group as compared to placebo and to the non-diabetic group over a long-term period.

The investigators propose a randomized controlled trial determining the long-term effects of intranasal insulin (INI) on cognition and memory in type 2 diabetes (DM) and non-DM groups. The investigators hypothesize that: 1) INI-treated adults with DM have better memory and functioning of specific cognitive domains and faster walking during a dual task than those treated with placebo and the control group; 2) Glycemic and insulin resistance and genetic markers for Alzheimer's disease (Apolipoprotein E4 [ApoE4]) may serve as predictors of positive responses to INI therapy; 3) INI treatment neither adversely affects systemic glycemic levels or the cardiovascular system nor causes weight gain.

Aim 1: To determine whether INI-treated type 2 DM adults have a) better memory and functioning of specific cognitive domains and b) faster dual-task gait speed and better daily living functioning than the placebo-treated and non-DM groups. Four groups will be tested: 60 DM subjects treated with insulin; 60 DM subjects treated with placebo; 45 control subjects treated with INI and 45 control subjects treated with placebo. These 210 patients are expected to complete treatment and 168 are expected to complete study by the study completion anticipated date.

The investigators will conduct a randomized, double-blind, placebo-controlled study in 120 older adults with type 2 DM and 90 non-DM controls examining whether 40 IU INI once daily over a 24-week period improves:

• Specific domains of visuospatial attention and memory, verbal learning (primary outcomes);
• Gait speed during a dual task (which is an excellent predictor of overall health), daily living functionality, and depression as compared to the DM group receiving sterile saline and the non-DM groups. The non-DM groups will provide reference of INI effects in a clinical phenotype of cognitive decline and insulin resistance that occurs with normal aging.

Aim 2: To identify a phenotype and long-term trajectory predicting clinically relevant response to INI therapy based on glycemic control, insulin resistance, endothelial and genetic markers.

1. The investigators will determine a phenotype predicting a clinically relevant response to INI therapy and identify time-dependent trajectories of INI effects on cognition in the DM group vs. the placebo and the non-DM groups. Clinical predictors will be based on associations between cognitive function and/or gait and demographic, glycemic control, insulin resistance, endothelial and genetic (ApoE4) measures.
2. The investigators will evaluate the dose-escalating trajectory of cognition, gait speed, and functionality during the 24 weeks of therapy and 24 weeks post-treatment and their dependence on the above-mentioned factors, and determine the time point when maximum effect was reached. INI therapy response is defined as a clinically relevant improvement on cognitive tests or in gait speed (as a continuous variable) or as responders vs. non-responders as compared to placebo within DM and non-DM groups (as a categorical variable).
3. MRI substudy: The investigators will explore the long-term INI effects on regional perfusion, vasodilatation, and resting functional connectivity in 40 DM subjects pre- and post- INI/placebo administration at the beginning and at the end of intervention and their relationships to cognitive outcomes. Regional perfusion and vasodilatation will be measured by pseudo-continuous arterial spin labeling (PCASL) MRI at 3 Tesla, and resting-state functional connectivity will be quantified from low-frequency (0.01-0.08 Hz) fluctuations (LFF) of the whole-brain blood-oxygen-level dependent (BOLD) functional Magnetic Resonance Imaging (fMRI).

Aim 3: To determine the long-term safety of INI vs. placebo with regard to glycemic control (fasting glucose, hemoglobin A1c [HbA1c], hypoglycemic episodes), vital signs, and body mass.

1. The investigators will obtain measurements of fasting glucose, insulin, vital signs, and body mass at baseline, 2-months, 4-months, and 6-months follow-up and keep weekly logs monitoring glucose and adverse events.
2. Safety substudy: In the first 20 DM patients treated with subcutaneous insulin, the investigators will conduct continuous glucose monitoring (CGM) OR 5 finger sticks/day (effective after 9/25/2017) for 1 week during baseline and during the first week of INI or placebo treatment to evaluate the INI effects on glycemic control, hypoglycemic episodes, and body weight.

This study may pave the way to potential treatment and/or cure of DM- and age-related cognitive decline.

Inclusion Criteria:

• Men and women aged 50-85 years old
• Able to walk for 6 minutes
• Diabetes type 2 (DM) group: diagnosis and treatment for type 2 DM with non-insulin oral or injectable agents
• Non-DM group with similar age range as the DM group, non-diabetic fasting plasma glucose (<126 mg/dL) and hemoglobin A1c (HbA1c) (<6.5%)
• Participants capable of providing informed consent

Exclusion Criteria:

• Type 2 DM treated with insulin (since 9/25/2017)
• Type 1 DM
• Intolerance to insulin
• History of severe hypoglycemia
• Participants who have >1 asymptomatic and/or symptomatic episode of hypoglycemia (glucose < 54 mg/dL) during finger stick or plasma glucose (cut off value since 6/11/2018)
• Acute medical condition that required either hospitalization or surgery within the past 6 months (e.g., severe hypoglycemia, malignancies, myocardial infarction,stroke)
• Liver or renal failure or transplant
• Dementia (Mini Mental State Examination [MMSE] scores ≤20)
• Current recreational drug or alcohol abuse
• Serious systemic disease that would interfere with conduction of clinical trial (mild forms of neurological conditions e.g. Parkinson's Disease, autonomic neuropathy etc. would be allowed)
• Magnetic Resonance Imaging (MRI) substudy in 40 DM patients only: claustrophobia and implants incompatible with 3-Tesla MRI
• Safety substudy in 20 IDDM patients only: Insulin-treated type 2 diabetics with a C-peptide of <0.8 ng/mLd and fasting blood glucose >150 mg/dL will be excluded even without history of hypoglycemia during finger stick measurements.

Of 244 randomized participants, 223 participants completed baseline assessment.

48 weeks.