Hyperinsulinemia; a mediator of decreased food intake and weight loss in anorexia nervosa and major depression.

Decreased food intake and weight loss are seen in eating and depressive disorders. No satisfactory pathophysiological mechanisms have been proposed to explain those findings. While it should be kept in mind that the etiology of those diseases is still unclear, it seems reasonable to propose that the maintenance of anorectic behavior in the eating disorders as well as the decreased food intake of major depression, leading to continued weight loss seen in both conditions, are either caused or mediated by insulin in levels which are elevated but insufficient to cause hypoglycemia. A brief review is made of the role of insulin in satiety and in the control of body weight, and of the newly available techniques to accurately quantify secretion, hepatic extraction, and post-hepatic delivery rates of insulin. Neural, metabolic, and endocrine stimuli affect insulin secretion. The hypothesis is therefore compatible with several etiologic factors leading to hyperinsulinemia in anorexia nervosa and major depression, and resulting in decreased food intake and weight loss.

Proinsulin radioimmunoassay in the evaluation of insulinomas and familial hyperproinsulinemia.

Two new radioimmunoassays for human proinsulin (hPI) have been developed and used to study patients with islet cell tumors and familial hyperproinsulinemia. Both antisera were adsorbed against human C-peptide conjugated to Sepharose, following which cross-reactivity to insulin and C-peptide was less than 0.001%. Antiserum 18D recognized the junction between the insulin B-chain and C-peptide and provided fivefold greater sensitivity than our previously reported hPI assay. Antiserum 11E recognized a determinant which includes or is adjacent to the A-chain-C-peptide junction or which is specified by the tertiary structure. In all 20 patients studied with surgically confirmed islet cell tumors, fasting plasma proinsulinlike material (PLM) was abnormal (greater than 3 SD from the mean measured in either lean or obese subjects) in both assays. This provided better discrimination than has been reported for PLM measured by gel filtration (abnormal in 13 of 14 of the present samples) with a considerably less laborious procedure. Samples from two families in which a mutant proinsulin is present in the circulation have immunoreactivity in the two assays consistent with previous identification of the molecule as an A-chain-C-peptide-linked intermediate of proinsulin conversion. The immunoreactivity of a sample from another family in which large amounts of proinsulin circulate are consistent with an intact molecule being the predominant form. This assay will be useful for confirming the diagnosis of insulin-secreting tumor in patients suspected of recurrent fasting hypoglycemia and in physiologic studies of proinsulin secretion.

Ingestion of a mixed meal does not affect the metabolic clearance rate of biosynthetic human C-peptide.

The validity of C-peptide as a peripheral marker of insulin secretion during different physiological conditions depends on the demonstration that C-peptide clearance is constant under these circumstances. Recently biosynthetic human C-peptide, identical in structure to pancreatic human C-peptide, became available for use in human subjects. The present study was undertaken to determine if the metabolic clearance of C-peptide was altered by ingestion of a mixed meal. Eight insulin-dependent diabetic patients received constant iv infusions of biosynthetic human C-peptide which raised the plasma C-peptide concentration to a level of 3.8 +/- 0.2 (+/- SEM) pmol/ml. The MCR of C-peptide was 4.5 +/- 0.3 ml/kg X min. After steady state levels of C-peptide had been reached, each patient consumed a 530 calorie mixed meal. The plasma glucose concentration increased from a baseline value of 104.5 +/- 4.8 mg/dl to a 336 +/- 10 mg/dl 150 min later. This change in plasma glucose was not associated with a significant alteration in the plasma C-peptide concentration and the MCR of the infused C-peptide was not affected by meal ingestion (4.5 +/- 0.3 vs. 4.3 +/- 0.3 ml/kg X min). These results therefore support the validity of using C-peptide as a marker for changes in insulin secretion after mixed meals.

Calculation of the systemic delivery rate of insulin in normal man.

The accuracy with which the systemic delivery rate of insulin can be estimated from peripheral insulin concentrations was investigated in eight normal men. Endogenous insulin secretion was suppressed by somatostatin, and insulin was infused exogenously via a peripheral vein. The infusion rate was progressively increased and then decreased to stimulate the changes in insulin secretion that occur after a secretory stimulus. The infusion rate of insulin was then estimated by analyzing peripheral insulin concentrations using both single and two-compartment mathematical models and was compared with the actual infusion rates. Model parameters were measured in each subject by analysis of the insulin decay curve after a bolus injection. Estimated infusion rates based on the single compartment model were 84.3 +/- 3.0% (mean +/- SE) of the actual infusion rate as it was increasing and 110.3 +/- 3.7% of the infusion rate as it was decreasing. The mean overall absolute percent error associated with this approach was 14.1 +/- 1.0% (range, 10.2-18.8%), and model estimates of the total amount of insulin infused over the duration of the experiment were 97.1 +/- 3.2% of the quantity actually infused (range, 85.4-110.7%). Estimates of the infusion rate based on a two-compartment model represented 90.3 +/- 3.1% of the actual infusion rate as it was increasing and 98.2 +/- 3.2% of the actual rate as it was falling. The area under the derived infusion rate curve was 94.8 +/- 2.8% of the area under the actual curve. The overall error associated with the use of the two-compartment model was 12.9 +/- 1.1% (range, 8.8-18.6%). Differences between the single and two-compartment models were minor and not statistically significant. These data demonstrate that under euglycemic conditions, changes in the plasma insulin concentration within the physiological range are not associated with changes in the clearance kinetic rate constants of the hormone. Furthermore, the systemic delivery rate of insulin can be accurately derived from peripheral insulin concentrations using either a single or two-compartmental model if model parameters are accurately measured in individual subjects by analysis of insulin decay curves.

Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.

We undertook this study to examine the accuracy of plasma C-peptide as a marker of insulin secretion. The peripheral kinetics of biosynthetic human C-peptide (BHCP) were studied in 10 normal volunteers and 7 insulin-dependent diabetic patients. Each subject received intravenous bolus injections of BHCP as well as constant and variable rate infusions. After intravenous bolus injections the metabolic clearance rate of BHCP (3.8 +/- 0.1 ml/kg per min, mean +/- SEM) was not significantly different from the value obtained during its constant intravenous infusion (3.9 +/- 0.1 ml/kg per min). The metabolic clearance rate of C-peptide measured during steady state intravenous infusions was constant over a wide concentration range. During experiments in which BHCP was infused at a variable rate, the peripheral concentration of C-peptide did not change in proportion to the infusion rate. Thus, the infusion rate of BHCP could not be calculated accurately as the product of the C-peptide concentration and metabolic clearance rate. However, the non-steady infusion rate of BHCP could be accurately calculated from peripheral C-peptide concentrations using a two-compartment mathematical model when model parameters were derived from the C-peptide decay curve in each subject. Application of this model to predict constant infusions of C-peptide from peripheral C-peptide concentrations resulted in model generated estimates of the C-peptide infusion rate that were 101.5 +/- 3.4% and 100.4 +/- 2.8% of low and high dose rates, respectively. Estimates of the total quantity of C-peptide infused at a variable rate over 240 min based on the two-compartment model represented 104.6 +/- 2.4% of the amount actually infused. Application of this approach to clinical studies will allow the secretion rate of insulin to be estimated with considerable accuracy. The insulin secretion rate in normal subjects after an overnight fast was 89.1 pmol/min, which corresponds with a basal 24-h secretion of 18.6 U.