Role of muscle in CO2 production after oral glucose administration in man.

A significant increase in CO2 production, reflecting carbohydrate oxidation and/or fat synthesis, is observed in normal subjects after the ingestion of glucose. The anatomic site(s) of this CO2 production has not yet been localized, although liver and muscle are logical considerations. To assess the contribution of skeletal muscle to this process, we measured whole-body and forearm CO2 flux in normal, postabsorptive subjects after the ingestion of 100 g of glucose and calculated their total muscle CO2 production. In the basal state, muscle accounted for 19% of total CO2 production, and, after glucose administration, muscle CO2 production did not change significantly. Thus, muscle is not the principal site of the observed increase in CO2 production.

Hyperinsulinemia of obesity is due to decreased clearance of insulin.

The hyperinsulinemia of obesity could result from a decrease in the metabolic clearance rate of insulin (MCR-I), an increase in the secretory rate of insulin (SR-I), or a combination of both these processes. Because C-peptide and insulin are secreted in an equimolar ratio, the plasma concentrations of C-peptide (C) and insulin (I) are inversely proportional to their rates of metabolic clearance (C/I = MCR-I/MCR-C). We obtained 24-h integrated concentrations (IC) of insulin (IC-I) and C-peptide (IC-C) in 23 obese and 45 nonobese subjects over a period of normal activity and food intake. The IC-I was 69% higher in the obese subjects (P less than 0.0001). A 13% increase in the IC-C (P = 0.04), with a constant rate of C-peptide clearance, indicates a proportionate increase in SR-I. A 33% decrease in the IC-C/IC-I in the obese group (P less than 0.005) reflects a decrease in MCR-I; hence, 75% of the hyperinsulinemia is due to a decrease in the clearance of insulin. Because peripheral MCR-I (pMCR-I) is similar in obese and nonobese subjects, the decrease in MCR-I may be due to a decrease in the hepatic clearance of insulin. This conclusion was supported by our comparison of 24-h IC-C/IC-I ratios in the obese and nonobese subjects. Whereas the 24-h IC-C/IC-I of the nonobese resembled the fasting state, the 24-h IC-C/IC-I of the obese resembled the postprandial state, when insulin removal by the liver is known to be suppressed. These data are consistent with a decreased 24-h hepatic MCR-I (hMCR-I) as the cause of the hyperinsulinemia of obesity.

Evidence for restoration of hepatic glucose processing in type I diabetes mellitus.

The role of muscle in the processing of dietary carbohydrate in nine type I diabetic patients was assessed using combined forearm-indirect calorimetry-glucose meal (100 g) studies performed before and after 72 h of artificial beta-cell directed insulin therapy. On conventional insulin therapy, initially elevated arterial glucose concentrations rose markedly, free insulin increased slightly, and the respiratory quotient (R.Q.) did not change during the study. The forearm glucose extraction rate increased significantly over basal at 60 min. After 72 h of artificial beta-cell therapy and while still on the instrument, arterial glucose increased moderately, and free insulin levels increased markedly. The R.Q. increased significantly at 60 and 120 min. The forearm glucose extraction rate increased significantly over basal at 30 and 60 min. Importantly, forearm glucose extraction rates did not differ during the two studies at each of the measured time points. These observations demonstrate that conventional insulin therapy is effective in facilitating glucose entry into muscle. In addition, they suggest that the marked improvement in glucose processing exhibited by type I diabetic patients after 72 h of artificial beta-cell therapy is primarily attributable to the liver. Finally, the data strongly imply that the primary clinical objective of insulin therapy in type I diabetes mellitus should be reactivation of the hepatic component of the glucose disposal system.

Integrated concentrations of growth hormone, insulin, C-peptide and prolactin in human obesity.

Twenty-four hour integrated concentrations of growth hormone (IC-GH) were significantly lower in young, obese subjects than in young subjects who were lean. Significant inverse correlations were found between IC-GH and body mass index (BMI) as well as the IC-GH and the 24 hr integrated concentrations of insulin (IC-I) and C-peptide (IC-C) in obese subjects below 30 yr of age. Since IC-GH decreases with age, the effect of obesity on IC-GH could not be demonstrated in the older subjects; a weak inverse correlation (p less than 0.05) between IC-GH and IC-C was found. Prolactin was significantly lower in the older subjects but did not correlate with IC-GH and was similar in lean and obese. Lipid deposition in adipose cells is promoted by high concentrations of insulin as well as low concentrations of growth hormone. We found a significant correlation between the IC-I/IC-GH ratio and BMI of both the young and older subjects. Correlations between these two factors do not necessarily imply a cause and effect relationship. It is plausible, however, that the elevated IC-I/IC-GH of the obese may facilitate their lipid storage and counter their efforts at weight reduction.

Estimation of the secretion rate of insulin from the urinary excretion rate of C-peptide. Study in obese and diabetic subjects.

Direct methods for measuring the secretion rate of insulin are too cumbersome for clinical application. Since C-peptide is secreted in an equimolar ratio with insulin and is excreted into the urine, measuring the urinary excretion rate of C-peptide (U-C) could serve as an indicator of its secretion rate (SR-C) if its urinary clearance (UCI-C) is constant and unaffected by plasma C-peptide concentration, body mass, or diabetes. We measured clearance ratios of C-peptide/creatinine (CR) in the fasting state and integrated 0-1, 1-3, and 3-5 h after 100 g of glucose p.o. as well as over a full 24-h in eight obese, eight lean, and six maturity-onset diabetic subjects. CR did not differ significantly when values in the fasting state were compared with those in the postprandial periods and was therefore unaffected by plasma C-peptide concentration. Furthermore, CR was similar in the lean, obese, and diabetic subjects. SR-C, determined as the product of the metabolic clearance rate of C-peptide and its fasting or integrated plasma concentrations, correlated significantly with U-C in all the subjects (r = 0.87, P less than 0.0001). The correlation of U-C with SR-C in the diabetic subjects alone was also significant (r = 0.88, P less than 0.0001). In conclusion, our data support the use of U-C as an indirect measure of SR-C and therefore of SR-I.

Correlation of urinary excretion of C-peptide with the integrated concentration and secretion rate of insulin.

The secretion rate of insulin (SR-I) of 50 normal subjects was calculated from the 24-h integrated concentration of insulin (IC-I), the peripheral metabolic clearance of insulin (pMCR-I), and the mean fractional hepatic insulin extraction (fhMCR-I) that was derived from our data. fhMCR-I was determined as the difference in the molar secretory rate of C-peptide (SR-C) and the molar peripheral clearance of insulin (pMCR-I x IC-I) divided by SR-C. The IC-I in our 50 subjects was 1.19 +/- 0.38 ng/ml and the IC-C was 2.93 +/- 0.58 ng/ml. Based on these data, the fhMCR-I was 0.40 and the Sr-I was estimated to be 54.8 +/- 18.0 U/24 h. The 24-h urinary C-peptide excretion (U-C), 44.9 +/- 20.4 micrograms/24 h, had a statistically significant correlation with SR-I (r = 0.838, P less than 0.0001), while the IC-I correlated significantly with the 24-h urinary C-peptide/g of creatinine (r = 0.838, P less than 0.0001). The U-C may thus serve as a practical method for estimating the SR-I.

Diagnosis of self-induced hyperinsulinism in an insulin-dependent diabetic patient by radioimmunoassay of free C-peptide.

On the basis of results of simultaneous determinations of plasma free insulin and free c-peptide, episodes of hypoglycemia in an insulin-dependent diabetic were attributed to surreptitious self-administration of insulin. Immunoreactive c-peptide values were falsely increased and diagnostically misleading when measured in unextracted plasma. After preliminary removal of antigen/antibody complexes from the plasma by extraction with polyethylene glycol, the c-peptide values, referred to as "free c-peptide," were suppressed. We suggest that insulin antibodies formed complexes with proinsulin-like material in the plasma of this patient, which accounted for most of the c-peptide immunoreactivity in her unextracted plasma. These complexes must be removed if c-peptide measurements are to be accurate.