To keep the feel of it being actually something from DnD intact, I do agree it'd have to have an "Earth people in a different world" set-up. It may be harder to do right, but that doesn't mean it's impossible. (For instance, if it's set up like people actually playing the game and switching between worlds and showing real-world stuff as well, that'd give you a whole extra dimension. One player could be in it to cope with his depression, another to make friends and not actually be interested in the game at first, there could be the divide between the roleplayer and the powergamer, who later come to see they're not so different after all, for you Stormwind Fallacy lovers out there.)
Furthermore, that might actually make it more interesting to people who don't play DnD, as you have to take into account the people who aren't the direct target demographic. It's also much more likely to be watched by kids, so throwing in certain things like language barriers is a bad idea (at least right from the start, I do think that the main characters running into it later would be a nifty idea and embroil them into the setting further). Making the characters come from locations in the world that the people most likely to be watching them is also the most logical, but this doesn't mean they couldn't have connections to other parts of the world. For instance, if you have an Asian in the group, perhaps he only moved recently from Malaysia and got into the group to make friends, not knowing anything about the game. Such a thing would be easiest if the characters either work at an international company or all go to some university with a high level of foreign students.