Abstract
The effects of insulin therapy in streptozotocin diabetic rats on the glucose transport response to insulin in adipose cells have been examined. At sequential intervals during subcutaneous insulin infusion, isolated cells were prepared and incubated with or without insulin, and 3-O-methylglucose transport was measured. Insulin treatment not only reversed the insulin-resistant glucose transport associated with diabetes, but resulted in a progressive hyperresponsiveness, peaking with a 3-fold overshoot at 7-8 days (12.1 +/- 0.3 versus 3.4 +/- 0.1 fmol/cell/min, mean +/- S.E.) and remaining elevated for more than 3 weeks. During the peak overshoot, glucose transporters in subcellular membrane fractions were assessed by cytochalasin B binding. Insulin therapy restored glucose transporter concentration in the plasma membranes of insulin-stimulated cells from a 40% depleted level previously reported in the diabetic state to approximately 35% greater than control (38 +/- 4 versus 28 +/- 2 pmol/mg of membrane protein). Glucose transporter concentration in the low-density microsomes from basal cells was also restored from an approximately 45% depleted level back to normal (50 +/- 4 versus 50 +/- 6 pmol/mg of membrane protein), whereas total intracellular glucose transporters were further increased due to an approximately 2-fold increase in low-density microsomal membrane protein. However, these increases remained markedly less than the enhancement of insulin-stimulated glucose transport activity in the intact cell. Thus, insulin treatment of diabetic rats produces a marked and sustained hyperresponsive insulin-stimulated glucose transport activity in the adipose cell with little more than a restoration to the non-diabetic control level of glucose transporter translocation. Because this enhanced glucose transport activity occurs through an increase in Vmax, insulin therapy appears to be associated with a marked increase in glucose transporter intrinsic activity.
Highlights
Glucosetransporter concentration in thelow- streptozotocin diabetic rats, resistant oceinsulin’s stimulatory density microsomes from basal cells was restored effect on glucose transport has been demonstrated to be a from an -45% depleted level back to normal (50 f 4 consequence of a depletion of intracellular glucose transportversas 50 f6 pmolfmgof membrane protein), whereas ers, resulting ina decrease in the number translocated to the total intracellular glucose transporters were further plasma membrane inresponse to insulin [3]
As previously reported [3], basal glucose transport activity is nostignificantly changed in cells from diabetic rats compared t o cells from control rats, but insulin-stimulated glucose transport activity is decreased by rats in each group wereincubated for 1 h at 37 "C in the presence of 7 nM insulin and 0.5-40 mM unIabeled 3-0-methy~glucoseR. esults are meansof triplicate samplesfrom two separate experiments
Intracellular protein arseflected in77,53, and109% increases in intracellular water and high- and low-density microsomal protein, respectively, with no change in plasma membrane protein
Summary
Vol 262, No 11, Issue of April 15,pp. 5118-5124, 1987 Prinked in U S A. Glucosetransporter concentration in thelow- streptozotocin diabetic rats, resistant oceinsulin’s stimulatory density microsomes from basal cells was restored effect on glucose transport has been demonstrated to be a from an -45% depleted level back to normal (50 f 4 consequence of a depletion of intracellular glucose transportversas 50 f6 pmolfmgof membrane protein), whereas ers, resulting ina decrease in the number translocated to the total intracellular glucose transporters were further plasma membrane inresponse to insulin [3]. A corollary mechanism has pose cell with littlemore than a restoration tothe non- been reported in states of insulin hyperresponsiveness assodiabetic control level of glucose transporter translo- ciated with chronic hyperinsulinemieaxperimentally induced cation Because this enhanced glucose transport activ- in normal rats [18] or naturally occurring in young, obese ity occurs through an increase inV,.,, insulin therapy Zucker rats [19] or with physical training [20]. For experimentsin which subcellular membrane fractions were to be prepared, samples of cells were taken for the determination of 3-0methylglucosetransport from larger volume incubations (see below)
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