To determine whether non-insulin-dependent diabetes is associated with specific alterations in the pattern of insulin secretion, we studied 16 patients with untreated diabetes and 14 matched controls. The rates of insulin secretion were calculated from measurements of peripheral C-peptide in blood samples taken at 15- to 20-minute intervals during a 24-hour period in which the subjects ate three mixed meals. Incremental responses of insulin secretion to meals were significantly lower in the diabetic patients (P less than 0.005), and the increases and decreases in insulin secretion after meals were more sluggish. These disruptions in secretory response were more marked after dinner than after breakfast, and a clear secretory response to dinner often could not be identified. Both the control and diabetic subjects secreted insulin in a series of discrete pulses. In the controls, a total of seven to eight pulses were identified in the period from 9 a.m. to 11 p.m., including the three post-meal periods (an average frequency of one pulse per 105 to 120 minutes), and two to four pulses were identified in the remaining 10 hours. The number of pulses in the patients and controls did not differ significantly. However, in the patients, the pulses after meals had a smaller amplitude (P less than 0.03) and were less frequently concomitant with a glucose pulse (54.7 +/- 4.9 vs. 82.2 +/- 5.0, P less than 0.001). Pulses also appeared less regularly in the patients. During glucose clamping to produce hyperglycemia (glucose level, 16.7 mmol per liter [300 mg per deciliter]), the diabetic subjects secreted, on the average, 70 percent less insulin than matched controls (P less than 0.001). These data suggest that profound alterations in the amount and temporal organization of stimulated insulin secretion may be important in the pathophysiology of beta-cell dysfunction in diabetes.

IntroductionThe secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight 57.2±2.8 nmol/m2 per 180 min, P < 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly Jifferent in the normal and obese subjects (53.1±3.8 vs. 51.6±4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P < 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61±3 vs. 45±6%, P < 0.05).During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant.Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concen-trations that are characteristic of the obese state.

To determine whether glucose and insulin responses to a mixed meal are influenced by time of day irrespective of duration of prior fast, eight normal subjects (4 males, 4 females) were studied on two separate occasions, involving ingestion of identical meals at either 6- or 12-h intervals. The 24-h profiles of plasma glucose, serum insulin, and plasma C-peptide were obtained at 20-min intervals. Plasma cortisol levels were measured on each sample to evaluate possible relationship between diurnal variations in metabolic responses and circadian rhythm of cortisol. Rates of secretion of insulin and cortisol were mathematically derived from peripheral concentrations by deconvolution using two-compartment models for clearance kinetics. Postmeal responses of glucose, insulin, and insulin secretion rate were evaluated by calculating maximum postmeal increment, total area under curve, area under curve for 2 h after meal ingestion, and total duration of response. Postmeal cortisol responses were quantified by increment in plasma level and amount secreted in postmeal pulse. For glucose responses, irrespective of duration of prior fast, all four parameters characterizing the response were significantly greater in the evening than in the morning, with total area under curve and 2-h area under curve being approximately twofold larger in the evening than in the morning. Time of day did not significantly influence maximum postmeal increment in insulin secretion rate or duration of insulin secretory response, but total and 2-h areas under curve were 25-50% greater in the evening than in the morning. Meal ingestion was followed by a significant pulse of cortisol secretion in 37 of 40 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral plasma or serum concentrations of glucose, insulin, C-peptide, glucagon, and cortisol and insulin secretory rates (ISR) were determined at 15-min intervals in eight normal subjects during a constant iv infusion of 4.5 mg glucose/kg.min for a 24-h period. During each sampling interval, the secretory rate of insulin was calculated by deconvolution of the peripheral plasma C-peptide concentration using C-peptide kinetic parameters derived after bolus injections of C-peptide in individual subjects. Periodogram analysis of the individual glucose curves demonstrated a circadian rhythm in all subjects, with a major nocturnal acrophase occurring at an average clock time of 0228 h (range, 0045-0350 h). In five of the eight subjects, a minor acrophase occurred at an average time of 1774 h (range, 1530-2045 h). This diurnal variation in plasma glucose levels was not paralleled by a similar pattern in insulin secretion. Although glucose was infused at a constant rate, significant pulses were found in glucose, insulin, and C-peptide levels and ISR; the pulse durations of these parameters were 182 +/- 30 (+/- SE), 89 +/- 5, 100 +/- 8, and 85 +/- 5 min, respectively, and their periodicities were 208 +/- 33, 106 +/- 7, 114 +/- 10, and 106 +/- 7 min. The durations and frequencies for pulses of insulin, C-peptide, and ISR were not significantly different, whereas glucose pulses had a longer duration and were less frequent (P less than 0.05, by analysis of variance). On the average, 54 +/- 9% of the C-peptide pulses and 47 +/- 8% of the ISR pulses were concomitant with a pulse in glucose levels. Moreover, approximately half of the C-peptide and ISR pulses that were not concomitant with a glucose pulse occurred in synchrony with a shoulder on the up-stroke or down-stroke of glucose pulses. Analysis of glucagon and cortisol profiles revealed no significant associations with the insulin and glucose oscillations. In conclusion, during a constant glucose infusion in normal subjects, regular oscillations of insulin secretion occur at 80- to 120-min intervals. Their tight coupling with glucose oscillations and the lack of association with fluctuations of glucagon and cortisol suggest that these oscillations represent a dynamic property of the insulin-glucose feedback loop.

Insulin secretion and clearance were studied in 2 groups of 7 normal subjects who each received 25, 50, and 100 g of glucose either orally or intravenously (iv) on separate occasions. Insulin secretion rates were calculated during a 1-h base line and for 5 h after glucose administration from a two-compartmental analysis of peripheral C-peptide concentrations using individual kinetic parameters derived after iv bolus injections of biosynthetic human C-peptide. Incremental glucose areas after oral or iv glucose increased as a function of the glucose dose (P = 0.0001). Incremental insulin secretion increased with increasing doses of both oral and iv glucose (P = 0.0001). The metabolic clearance rate (MCR) of endogenous insulin was calculated as the ratio of the total area under the insulin secretion rate curve and the simultaneous peripheral insulin concentration curve. The basal MCR was 1,879.5 +/- 110.5 ml/min (mean +/- SE). The poststimulatory MCR decreased with increasing doses of both oral and iv glucose concomitant with the greater insulin secretory response (P = 0.0014). This decrease in insulin clearance was not significantly different between oral and iv administration of glucose (P = 0.495). In conclusion diminished insulin clearance may be seen after marked stimulation of insulin secretion with larger doses of oral and iv glucose.

The mechanism of tumor-associated hypoglycemia was examined in 11 patients with hepatocellular carcinoma, 6 of whom presented with severe hypoglycemia and 5 in whom plasma glucose was persistently normal. Serum insulin levels in the hypoglycemic patients were low. Although total serum insulinlike growth factor II (IGF-II) levels in both groups of tumor patients were lower than normal, tumor tissue from hypoglycemic patients contained levels of IGF-II mRNA that were 10-20-fold higher than those present in normal liver.IGF-II immunoreactivity consisted in all cases of a mixture of both higher molecular weight forms and material having the character of IGF-II itself. The former comprised a greater proportion of total IGF-II, in patients with hypoglycemia. Studies to characterize the interactions of IGF-II with serum proteins showed that (a) the radiolabeled peptide bound to an -40,000-D protein in sera from both hypoglycemic patients and normal subjects, (b) sera from hypoglycemic patients and normal subjects had similar capacity to bind the radiolabeled peptide, and (c) the apparent affinities of serum binding proteins for IGF-II were the same for both hypoglycemic patients and normal subjects. Whereas, acid extracted, tumor-derived IGF-II immunoreactive peptides with low or intermediate molecular weights bound to serum proteins in a manner indistinguishable from that of IGF-II itself, the highest molecular weight IGF-II immunoreactive peptide exhibited negligible ability to compete for radiolabeled ligand binding to serum proteins. The low affinity of serum binding proteins for this component suggests that high molecular weight IGF-II immunoreactivity might circulate free and be available for interaction with cell-surface receptors. (J. Clin. Invest. 1990.

To define the spontaneous diurnal variations in glucose regulation during fasting in noninsulin-dependent diabetes (NIDDM), we measured circulating levels of glucose, insulin, C-peptide, GH, cortisol, and glucagon at 15-min intervals in 11 patients with untreated diabetes and 7 matched control subjects studied during a 24-h period. The rates of insulin secretion were derived from the concentrations of C-peptide by deconvolution using a two-compartment mathematical model for C-peptide distribution and metabolism. In both groups of subjects, despite continued fasting, glucose levels stopped declining in the evening and subsequently rose throughout the night to reach a morning maximum. Elevated levels persisted until noon. The morning glucose maximum corresponded to a relative increase of 23.8 +/- 5.5% above the evening nadir in NIDDM patients and 13.2 +/- 4.6% in nondiabetic subjects (P less than 0.05). In NIDDM patients, insulin levels and insulin secretion rates did not parallel the nocturnal glucose changes. In contrast, in control subjects, this nocturnal glucose rise coincided with a similar increase in insulin secretion rates. Cortisol concentrations in patients with NIDDM were higher than those in control subjects throughout the study period (P less than 0.001) and rose earlier in the evening than in control subjects, thus failing to demonstrate the normal nocturnal suppression. In both groups of subjects, the nighttime glucose elevation was temporally and quantitatively correlated with the circadian cortisol rise. GH secretion was increased in the evening and nighttime periods compared to the daytime values, and in NIDDM patients, but not in control subjects, the size of the morning glucose elevation was directly related to the magnitude of this increase in GH secretion (r = 0.88; P less than 0.01). Glucagon concentrations were similar in both groups of subjects and remained essentially constant throughout the study period. We hypothesize that the nocturnal glucose rise that occurs during fasting represents a normal diurnal variation in the set-point of glucose regulation amplified by counterregulatory mechanisms activated by the fasting condition.

To investigate the temporal organization of insulin secretion and glucose concentration during fasting in Type 2 (non-insulin-dependent) diabetes mellitus, we studied seven patients with Type 2 diabetes, eight obese non-diabetic control subjects and eight normal weight non-diabetic subjects. Blood sampling for glucose, insulin and C-peptide was performed at 15-min intervals during a 24-h period of fasting for the diabetic and the obese control subjects and during an 8-h fasting period for the normal subjects. Insulin secretion rates were calculated from the peripheral C-peptide concentration profiles. Ultradian oscillations of glucose levels and insulin secretion rates were evident during fasting in all subjects. An additional study with blood sampling at 2-min intervals for 8 h further indicated that this ultradian periodicity is expressed independently of rapid 10-15 min insulin oscillations. There were no differences between diabetic and non-diabetic subjects in the frequency of the ultradian oscillations of insulin secretion (which averaged 12-15 oscillations per 24 h) and in the rate of concomitancy of oscillations of insulin secretion with oscillations in glucose levels, which averaged 63-65%. The relative amplitudes of both the insulin and glucose oscillations were also similar in diabetic and nondiabetic subjects. The major abnormality in patients with Type 2 diabetes was evidenced by spectral analysis, and confirmed by calculations of the distributions of inter-pulse intervals. It consisted of a slowing of the glucose oscillations, without a similar slowing of the oscillations in insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)