Heavily modifying an existing frame doesn't change the fact that it'll still be registered as that original motorcycle, but yes, insurance is going to be an issue as it's not stock, and if you declare it as such and ever *need* that insurance there's a good chance the underwriter will cancel the policy when they find out you misrepresented what they insured. In order to get it insured you'll probably have to have it structurally inspected at minimum, but the insurance company will probably want more including an appraisal if you're insuring it for more than just liability, etc.
Starting with a complete custom frame changes things and is even more complicated:
I had a really good info link I had found in the past that detailed all the hoops for the latter, but I can't find it ATM. Suffice to say it was very complicated.