What does "The Middle" refer to in the TV show "The Middle"?

The show is set in Indiana, and the title is trying to evoke the idea that this is a fun, "meat and potatoes" family sitcom that represents "middle" America (i.e. it's not New York, it's not California, it's not the South ... just the "Heartland").

Here's a "TV Tropes" link that can really do a better job answering your question than me: Flyover Country

I think there's also a secondary nod to the economic, "middle class" suburban community depicted on the show.

I think it refers to the middle class lifestyle of Frankie and the rest of the family. The show is mostly about the day-to-day problems of them in (again) a middle-class town somewhere in the middle of America, to get the audience to relate to the characters.

Indiana is in the Midwest of the US (the Middle). The East Coast and West Coast intellectuals look down on middle America and refer to it as "flyover".

In Czech, the series' name is translated as Pr?m?r?ákovi (The Averages). I think it correctly describes the fact that the Hecks are not very successful in their lives (especially Sue I would say). Of course, a lot of their problems are caused by the Hecks themselves, for example when they are not paying their bills.