Plasma glucose, insulin, and FFA concentrations were determined in 15 normal subjects and 15 patients with noninsulin-dependent diabetes mellitus (NIDDM) from 0800 to 1600 h. Breakfast and lunch were consumed at 0800 and 1200 h, respectively, and plasma concentrations were measured at hourly intervals from 0800-1600 h. Plasma glucose concentrations between 0800 and 1600 h were significantly elevated in patients with NIDDM, and the higher the fasting glucose level, the greater the postprandial hyperglycemia. Hyperglycemia in patients with NIDDM was associated with plasma insulin levels that were significantly higher (P less than 0.001) than those in normal subjects, and substantial hyperinsulinemia occurred between 0800 and 1600 h in patients with mild NIDDM (fasting plasma glucose concentrations, less than 140 mg/dl). Both fasting and postprandial FFA levels were also increased in patients with NIDDM (P less than 0.001), and the greater the plasma glucose response, the higher the FFA response (r = 0.70; P less than 0.001). However, there was no significant correlation between plasma insulin and FFA concentrations. More specifically, hyperinsulinemic patients with mild diabetes (fasting plasma glucose, less than 140 mg/dl) maintained normal ambient FFA levels, while FFA concentrations were significantly elevated in patients with severe NIDDM (fasting plasma glucose, greater than 250 mg/dl), with insulin concentrations comparable to those in normal subjects. These results demonstrate that patients with NIDDM are not capable of maintaining normal plasma FFA concentrations. This defect in FFA metabolism is proportionate to the magnitude of hyperglycemia and occurs despite the presence of elevated levels of plasma insulin. These results are consistent with the view that insulin resistance in NIDDM also involves the ability of insulin to regulate FFA metabolism.

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This study was initiated to compare the abilities of two alternative approaches to the measurement of insulin-dependent glucose disposal in normal humans. The ability of insulin to stimulate glucose disposal was measured in 12 normal subjects by determining glucose disposal rates during insulin clamp studies carried out at both basal insulin concentrations (approximately 6 microU/ml) and during a period of sustained hyperinsulinemia (approximately 60 microU/ml). The increment in glucose disposal was defined as insulin-dependent disposal and compared to estimates of insulin action generated by both the conventional insulin clamp approach and the minimal model technique. The results documented an extremely close correlation (r = 0.99; P less than 0.001) between the direct determination of insulin-dependent glucose disposal and insulin-stimulated glucose disposal as estimated by the insulin clamp technique. In contrast, there was a poor correlation (r = 0.44; P = NS) between insulin sensitivity as estimated by the minimal model technique and insulin-dependent glucose disposal. These results indicate that the value of glucose disposal determined by the insulin clamp approach, which includes both insulin-independent and insulin-dependent glucose disposal, provides an excellent estimate of insulin-dependent glucose disposal in subjects with normal glucose tolerance. Unfortunately, this does not appear to be true of the minimal model technique. However, it must be emphasized that these conclusions are only applicable to normal humans, and may not apply to normal subjects of other species or to humans under different physiological or pathological situations.

The study was carried out to quantify the ability of physiological increases in the plasma insulin concentration to stimulate glucose disposal above basal levels in 25 normal subjects and 25 patients with noninsulin-dependent diabetes mellitus (NIDDM). Patients were sex, age, and weight matched, and glucose disposal was determined under basal conditions (plasma insulin, approximately 10 microU/ml) and after plasma insulin levels had been increased to approximately 90 microU/ml. The mean (+/- SEM) glucose disposal rate was significantly greater (P less than 0.001) under basal conditions in patients with NIDDM (110 +/- 5 mg/m2 X min) than in individuals with normal glucose tolerance (77 +/- 4 mg/m2 X min). Glucose disposal rates increased in both normal subjects and NIDDM patients when plasma insulin concentrations were increased to about 90 microU/ml; however, the increment was much greater in normal subjects. Thus, glucose disposal only rose to a mean (+/- SEM) value of 145 +/- 7 mg/m2 X min in patients with NIDDM, representing an approximate 30% increase due to insulin. In contrast, a similar elevation of plasma insulin in normal subjects resulted in an increase in glucose disposal of approximately 300%, reaching a mean (+/- SEM) value of 310 +/- 24 mg/m2 X min. These results indicate that the defect in insulin-stimulated glucose uptake is significantly greater in patients with NIDDM than has previously been found.

In this study we have attempted to quantify the plasma insulin response to glucose and insulin action in 22 nonobese subjects: 11 with normal glucose tolerance and 11 with mild [mean fasting plasma glucose concentration, 128 +/- (+/- SEM) 5 mg/dL] noninsulin-dependent diabetes mellitus (NIDDM). Estimates of the plasma insulin response were made by determining the plasma insulin concentration at hourly intervals from 0800-1600 h, before and after mixed meals consumed at 0800 h (breakfast) and 1200 h (lunch). Insulin action was assessed by measuring glucose uptake during insulin clamp studies performed at steady state plasma insulin levels of approximately 10 and 60 microU/mL, with the difference between the 2 values defined as insulin-stimulated glucose uptake. Plasma glucose (P less than 0.001) and insulin (P less than 0.001) concentrations were significantly higher in patients with NIDDM throughout the 8-h period (by two-way analysis of variance). However, mean (+/- SEM) insulin-stimulated glucose uptake was markedly reduced (P less than 0.001) in patients with type 2 diabetes mellitus (112 +/- 72 vs. 336 +/- 44 mg/m2 min-1). Thus, patients with NIDDM and mild fasting hyperglycemia were both insulin resistant and hyperinsulinemic compared to normal individuals. These data indicate that a defect in insulin-stimulated glucose uptake can occur in NIDDM in the absence of significant hyperglycemia and/or hypoinsulinemia.

Glucose disposal rates (Rd) during an insulin clamp study reflect both basal and insulin-stimulated Rd. To quantify the amount of glucose taken up in response to a known increase in insulin concentration, two consecutive studies were performed on 10 patients with mild to moderate NIDDM (mean fasting glucose = 146 mg/dl) and 10 normal subjects. Endogenous insulin secretion was inhibited by somatostatin and plasma glucose level maintained at 180 mg/dl for 5. Rd (mg/m2/min) was determined isotopically for 2.5 h at insulin concentrations approximately 6 microU/ml and during 2.5 h of physiologic hyperinsulinemia at approximately 60 microU/ml (total glucose disposal), with the increase in Rd resulting from the approximate 10-fold elevation of plasma insulin concentration defined as insulin-stimulated glucose disposal. Results showed that the increment in Rd resulting from the elevation of plasma insulin concentration was relatively minor in NIDDM (38 +/- 6), increasing from a mean (+/- SEM) value of 83 +/- 8 to 121 +/- 12. Similar values in normal subjects were 90 +/- 7 and 274 +/- 26 with an increment of 183 +/- 21. Thus, insulin-stimulated glucose uptake in patients with NIDDM was only one-fifth of that in normals, and accounted for only 31% (38 divided by 121) of total glucose disposal during the clamp study. These data indicate that the majority of previous insulin clamp studies of in vivo insulin action in patients with NIDDM, in which total glucose disposal and insulin-stimulated glucose disposal have been equated, have underestimated the magnitude of insulin resistance present in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

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To test the hypothesis that hepatic lipase plays a key role in lipoprotein removal in vivo, a novel system was used. Hepatoma cells (HTC 7288c) were transfected with a cDNA encoding hepatic lipase in culture and grown as solid tumors in vivo. In culture, transfected cells degraded chylomicron remnants and low density lipoprotein (LDL) somewhat more efficiently than untransfected cells. Tumors from the transplanted cells produced hepatic lipase localized to the surface of tumors from transfected cells but not tumors from non-transfected cells, grown in the same rat. The tumors from transfected cells removed, per gm of tissue, 34% ( P Ͻ 0.001) more 125 I-labeled LDL than tumors from non-transfected cells in the same animal. The uptake of chylomicron remnants (by tumors from transfected cells) was also modestly enhanced (15 ؎ 6%, P Ͻ 0.005). There were no differences in the uptake of 125 I-labeled albumin or 125 I-labeled asialoglycoprotein. Compared to the liver, the untransfected tumors took up 12%, and the transfected tumors took up about 18% as much LDL per gram of tissue. The uptake of chylomicron remnants compared to liver was far lower. Both types of tumors had about twice as much LDL receptor related protein as the liver. Wild-type tumors had the highest level of LDL receptor, twice hepatic lipasesecreting tumors, and six times that of the liver. Using the novel approach of transfecting transplantable tumor cells with hepatic lipase, the ability of hepatic lipase to facilitate the removal of apoB-containing lipoproteins was demonstrated. The liver still removes low density lipoprotein and especially chylomicron remnants more rapidly than the tumors, suggesting factors in addition to hepatic lipase and LDL receptor level play a major role in hepatic lipoprotein removal.-Donner, C., S. Choi, M. Komaromy, and A. D. Cooper. Accelerated lipoprotein uptake by transplantable hepatomas that express hepatic lipase.