They did DIAB with IM2, just replaced the alcoholism with palladium poisoning. All the stuff with War Machine's creation, distancing himself from his friends and hitting an all-time low was lifted from that story according to Favs, just modified for the movie and it worked pretty great if you ask me. Doing it in the third would be rehashing. He's had blood toxicity problems in one way or another, so as Rhodey says, "Deal with it. Let's move on."
I think the central them should definitely be Iron Man vs. Mandarin. The big questions are where to go with the character. Iron Man is unique in that his alter ego is arguably more interesting and fun to watch than his superhero identity. He's already hit his lowest as a person, now what? What about his relationship with Pepper? Rhodey and Stark are pretty much solid at this point, despite their differences in the first two. That's the biggest thing if you ask me. With any of these movies for that matter. Is his arc done? Or does he still have one more thing to learn? One thing's for sure, he'd better stay an egomaniac. That's been a huge part of his character since his inception and is, in my opinion, his best quality in terms of being entertaining to watch.
As for tone, it should stay fairly consistent with the first two, lighthearted with humor but some good serious character beats throughout. However, since this will likely be the last Iron Man solo film in the MCU (unless they recast - and holy **** DON'T recast, just wait 25 years when you reboot the MCU for v.2 or whatever), they should up the ante and make it a little more epic. We've seen Stark defend other countries, defend himself, now let's see him bust this underground terrorist organization that's haunted him for the first two and defend the world. Not an Avengers-type epic, smaller scale but still a worldwide threat.
And one more thing- I really really don't like the "mini-arc reactors" idea everyone keeps throwing around. We saw it in the second and to a lesser extent, the first. So let's try being a little more creative than that. If Thor/Dr. Strange/Avengers are successful, they can very well pull off alien rings even if their alien origin is modified. Who knows where they'll go. Justin Hammer's coming back, right?