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.
In the first trimester of pregnancy, inactive renin in plasma rapidly increases (to 5 times the average concentration in plasma of nonpregnant controls), then declines slowly until midpregnancy, and falls quickly to the normal range after delivery. Inactive renin has the same large apparent molecular weight in pregnancy as in control plasma. Amniotic fluid contains very high levels of inactive renin; its mobility on Sephadex G-100 is the same as that of inactive plasma renin, but a lower molecular weight is indicated by the delayed elution of inactive renin of amniotic fluid from Sephacryl S-200. This anomalous behavior is probably responsible for the different estimates of molecular is probably responsible for the different estimates of molecular weight previously reported. The plasma concentration of active renin in pregnancy is modestly increased in the first trimester, declining gradually until term, and falling quickly after delivery. Although the increased PRA in early pregnancy involves an increase in active renin, increased angiotensinogen appears to play a more important part in sustaining the increased PRA of late pregnancy. The apparent molecular weight of te active renin in pregnancy plasma is larger than that in normal plasma. Gross changes in sodium intake during pregnancy result in changes in active and inactive renin concentrations parallel to those observed in nonpregnant controls. These responses suggest that the kidneys are an important source of the altered plasma renin in pregnancy, but do not exclude a contribution from other sources.
Plasma glucose, insulin, and free fatty acid (FFA) concentrations were measured from 0800 to 1600 hours in 40 nondiabetic individuals, separated into younger (38 +/- 1.4 years) and older (64 +/- 1.5 years) age groups. Meals were served at 0800 (20% total daily calories) and 1200 h (40% of total daily calories), and blood drawn just before the 0800 hours meal and at hourly intervals thereafter until 1600 hours. Statistical evaluation of the results of these measurements indicated that day-long plasma glucose and insulin levels were higher in the older individuals. In contrast, the day-long FFA response was reduced in this age group. These data suggest that the ability of insulin to maintain normal plasma glucose levels deteriorates with age, whereas regulation of FFA levels does not.
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.
PRA, active renin, and prorenin were measured in 32 normotensive diabetic patients and 14 normal subjects of similar ages before and after iv injection of 40 mg furosemide. The majority of the diabetic patients had normal PRA and active renin levels before and after furosemide, but in 4 normal subjects and 5 diabetic patients PRA did not rise after furosemide treatment to at least 0.25 ng angiotensin I/(L.s) as previously found in 90% of normal subjects. Two thirds of the diabetic patients had higher plasma prorenin levels than the normal subjects. Four of the 5 diabetic patients whose PRA failed to rise to the usual level after furosemide treatment attained a plasma prorenin level higher than any normal subject, suggesting that furosemide stimulated synthesis and secretion of prorenin, but that conversion of prorenin to active renin was impaired. These 5 diabetic patients also had higher plasma creatinine and potassium levels as well as an increased frequency of albuminuria compared with the other diabetic patients. In contrast, the 4 normal subjects whose PRA failed to reach the usual level after furosemide treatment had low unresponsive prorenin levels, indicating that furosemide did not evoke the expected increase in prorenin or renin synthesis. We conclude that the inability of some diabetic patients to increase PRA after furosemide treatment is not dependent on failure of renin synthesis, but reflects an impairment of the normal processing of prorenin, leading to high levels of prorenin in plasma.
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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