I've owned at three 250 straight sixes in various GM trucks--a 81 G-10 van with a TH350 & lock up converter and 3:08 gears,a '79 C-10 with a TH350,and a '75 2wd Blazer that had a 3 speed manual originally,I swapped in a 4 speed Saginaw from a '75 Vega,it had 4:10's ..
None of the above got over 16 mpg,the '81 van did a few times on a long trip to TN back when gas had no ethanol ,but it dropped to 12-15 mpg on todays fuel...and it was so under powered on long grades on the interstate it was hazardous,you'd bog down to 50 mph and even have it downshift into second gear sometimes and gain no speed..merging onto a highway was also a dangerous thing..
The two pickups did no better on fuel mileage,the '79 C-10 was probably the one that did the best on fuel having highway gears,but it too could bog down on hills unless you got it going 70+ mph before you hit the hill..that truck got a 305 after the 250 decided to lose the #6 piston's top ring lands,years of pinging ate the head off the piston,those integeral head straight sixes were noted for spark knock and loose wrist pins..I'd avoid any built after 1975 with that head design..the old style with the removeable intake & exhaust manifolds were much better..
That truck went much better with the 305 in it,and if anything it delivered the same mpg or close to it as the 250 six..
The 292 is a strong engine with good low end torque but its long stroke makes it a gas hog,and it wont like winding out in a truck with low gearing..friends that had one in square body trucks said 12-14 mpg was tops as far as mpg,and though that engine does pull well,you might not be maintaining 65 mph up hill if your towing something heavier than a tent trailer..
These engines can be made to scream though,if built right...a local dirt track champ used several 292's and beat many cars with big block chevy's ,one was in a Volvo PV544..
I do not think it is worth swapping in a straight six in hopes of getting better mpg,you wont--these trucks weigh 3+ tons and a small engine will be struggling to propel it all the time,and straight sixes were never mpg champs to begin with,maybe the dinky ones like a 194 or 230 cubic inch were better,but only in light vehicles like an old Nova..
I'd like to have a straight six just for reliability and ease of repair,but daily driving one does get irritating when you wish it had more guts to pass or maintain 65 mpg on interstates..
The 4.3 V6's do not have a stellar reputation,but they would probably do better than a straight six for power and mpg..the early ones with a 4 bbl were junk though,and a later one would require the wiring harness and computer to run..thats a ton of work,for what might be little to no improvement in mpg..
The 6.2--well,they may give a few more mpg than a gas engine,but you'll have to deal with glow plugs that might refuse to come out,diesel fuel is at least .50 more here than gasoline,so any "savings" are lost at the pump..and if it needs any injectors,the injector pump,etc,get ready to spend $500 ..they are about as powerful as a 250 straight six,and if I had a choice I'd prefer the straight six over a 6.2 that might break the crank or end up having the main bearing webs crack..
The straight sixes aren't bullet proof either--all 3 of mine had the masonite cam gear strip the teeth off and left me stranded on the interstate..they sell aluminum ones ,that is what I put back on--but to replace the timing gears you'll either have to pull the engine out--or take a lot of things off it like the fuel pump,distributor,lifters,valve cover,and take off the radiator & grill,and hope you can get the camshaft out...pulling the engine is faster and easier..
Keep in mind all of these engines are now practically extinct,and you'll have to do some searching to find one,and parts for it..up here they are getting very scarce,in "drop in and run it" condition..
I think the best way to get better mpg in a chevy pickup is to buy an S-10 with a 2.5 4 banger and a 5 speed...no work,it'll get you around OK,and you can still haul some stuff with it..