This study was undertaken to determine if glucose toxicity in normal rats caused decreased whole body insulin-stimulated glucose disposal and in vivo impaired muscle glucose transport and, if so, whether it was mediated by changes in GLUT-4 content or tissue distribution. Rats were infused with 50% dextrose for 48 h after which they were clamped and injected with 2-deoxy-D-[3H]glucose. Hindlimb muscles were removed for measurement of uptake of radioactivity (glucose transport) and GLUT-4 levels in total, plasma and internal membrane fractions. Dextrose infusions caused significant hyperglycemia [15.5 +/- 1.4 vs. 6.7 +/- 0.3 (SE) mM], hyperinsulinemia [678 +/- 108 vs. 168 +/- 42 (SE) pM], and depressed insulin-mediated whole body glucose disposal [12.8 +/- 2.0 vs. 47.0 +/- 10.6 (SE) mg glucose.kg-1.min-1.pmol insulin-1.1(-1) x 10(3)]. Muscle glucose transport (ng.min-1.mg tissue-1) was significantly decreased in biceps (4.0 +/- 0.6 vs. 13.4 +/- 2.5), gastrocnemius (4.6 +/- 1.1 vs. 12.9 +/- 2.2), and plantaris (5.5 +/- 0.7 vs. 17.5 +/- 3.6) muscles compared with saline-infused rats. The difference in the soleus muscle (13.2 +/- 1.6 vs. 19.4 +/- 2.7) did not quite reach statistical significance. There were no differences in total, plasma, or internal membrane GLUT-4 content between the two groups. It is concluded that glucose toxicity causes impaired insulin-stimulated glucose transport, probably due to decreased activity of GLUT-4.
Subcutaneous abdominal adipose tissue was removed from six normal weight patients (118–184 lb.) at laparotomy and six obese subjects (280–533 lb.) under local anesthesia and incubated in vitro. Glucose-C-14 incorporation into CO2, total lipids and glycogen were measured. Although insulin (10 mU./ml.) stimulated CO2 production from glucose in all twelve subjects (p < .001), the average increase was only 26.6 per cent (5.3 to 50.8). Radioactive glucose incorporation into total lipids was increased by insulin in eight of twelve subjects (average rise = 21.9 per cent; range, −45.5 to 107.1 per cent), but this failed to achieve significance. This small insulin effect on human adipose tissue reflects the experience of others. On the other hand, insulin-stimulated glycogen synthesis proved to be the most sensitive indicator of hormonal activity (mean rise = 231.9 per cent; range, 66.2 to 562.2 per cent). There was no significant difference in basal or insulin-stimulated glucose incorporation into CO2, total lipids or glycogen between the obese and normal weight subjects. The insulin effect on glycogen synthesis could not be correlated with either weight index or body fat in these twelve subjects. Basal conversion of glucose to CO2 was significantly correlated with these two measures of obesity (r = 0.6, p < .05). These data corroborate two other reports that obesity is associated with increased basal glucose metabolism by human adipose tissue in vitro. However, they fail to substantiate the postulate that adipose tissue of the obese is insensitive in insulin. These results and the fact that only approximately 5 per cent of basal or. insulin-stimulated glucose turnover in vivo involves adipose tissue suggest that insensitivity of the muscle mass and/or a circulating insulin antagonist should be more important in the insulin antagonism of obesity.
This study was undertaken to ascertain whether enhanced oxidation of intracellular lipids could explain the impaired carbohydrate metabolism of diabetes. Pieces of diaphragms removed from diabetic (60--75 mg/kg streptozotocin i.v.) and control rats were incubated for 1 h with palmitate-1-14C. Tissue lipids from one piece were separated on silicic acid columns and the amount and specific activity of free fatty acids (FFA), triglycerides (TG) and phospholipids (PL) were measured. 14CO2 production was also assessed in some experiments. The other pieces of tissue were incubated for a subsequent hour (without radioactivity) at which time measurements of tissue lipid content and specific activity and 14CO2 production were again performed. FFA incorporation into CO2, tissue TG and PL was normal. TG content was moderately and PL content was slightly reduced in diabetic tissue. Changes in diaphragm TG and PL content and specific activity during the 2nd h of incubation strongly suggested that most of the 14CO2 produced during this period was derived from TG. Approximately 25% of tissue TG in both control and diabetic muscle was oxidized to CO2 during the 2nd h of incubation. In diaphragms from diabetic rats, (+)-octanoylcarnitine (an inhibitor of FFA oxidation) decreased TG oxidation considerably but had no effect on the impaired glucose uptake. Thus, these data do not support the hypothesis that the glucose-fatty acid cycle (utilizing either extra- or intracellular lipids) may account for the altered carbohydrate metabolism of diabetic muscle.
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