So they lost MacFarland. What's the big deal? THe Colts were 32nd in the league in run defense last year. They aren't going to get any worse!
I think the real question is if the replacements at DT and OT can hold their own and gel with the players around them. Essentially just avoid being a glaring weak link that requires adjustment from the rest of the unit to avoid disaster.
With this in mind, I think the Colts should be able to juggle their tackles reasonably well without impacting the overall offense (no long passes, keeping extra TE/RB in to protect, running to the opposite side, etc.). Not that I think Glenn's performance can be replaced this year...just that the Colt offense can absorb the relative drop in productivity from the LT without collapsing.
The situation at DT is a little more dicey. How many players will the Colts have to put in the box to compensate for DT? Will the DE's have to hesitate a half-second to avoid huge draw plays? Will the safeties have to make a living 5 yards from the line of scrimmage? Will this leave the new starters at corner on an island more they would like?
Remember the Pats were a "2002 Steve Martin" from potentially winning 4 in a row. Not that he was a bad player (ok, he was), but his inability to do what was expected of him forced the entire defensive unit to adjust.
The Colts face a litany of teams with solid running games + defenses good enough to prevent a shoot-out:
DEN, @JAX, @CAR, NE, @SD, JAX, @BAL
There is also a reasonable chance that the Colts will need to get through 2 or 3 of those AFC teams in the playoffs to get back to the SB. I'm not predicting the Colts will suck, but I'm also questioning the prevailing sentiment in the media that the Colts can withstand almost any loss (outside of Manning, Freeney and Sanders). They are paper-thin right now and will need some good fortune to have the type of season expected of them.
The JAX/CAR/NE/SD stretch is in consecutive weeks just after their bye. That gives them a reasonable amount of time to get everything sorted out. If they don't (and don't at least split those 4 games), that may be enough to cost them home field, first round bye or even their division. So look for how the overall Colt defense is performing in the 1st five games. Deep passes allowed, sacks, completion percentage, etc. If those opposing offenses seem comfortable, watch out.