Oscillations in Insulin Secretion During Constant Glucose Infusion in Normal Man: Relationship to Changes in Plasma Glucose

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 < 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 Cpeptide 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. (J Clin Endocrinol Metab 67: 307, 1988). © 1988 by The Endocrine Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Differential effects of glucose stimulation upon rapid pulses and ultradian oscillations of insulin secretion

To determine the effect of glucose stimulation on the rapid 8- to 15-min pulses and the ultradian 80- to 170-min oscillations of insulin secretion, peripheral concentrations of glucose, insulin, and C-peptide were measured at 2-min intervals over 2 h (i.e. rapid experiments), at 15-min intervals over 8-20 h (i.e. ultradian experiments) in 17 normal subjects during saline infusion, or during constant glucose infusion at a rate of 3 mg/(kg.min) (i.e. low dose) or 6 mg/(kg.min) (i.e. high dose). In the ultradian experiments, insulin secretory rates (ISR) were calculated by deconvolution of the plasma C-peptide concentrations. Significant oscillations with 125- to 166-min periods were detected in all glucose and ISR profiles. The numbers of ISR oscillations per 24 h were similar during saline infusion and low and high dose glucose infusion. In contrast, the amplitude of the ISR peaks increased progressively from 14 ± 1 pmol/min during saline infusion to 50 ± 7 pmol/min and further to 97 ± 9 pmol/min during low and high dose glucose infusions, respectively. When expressed as percent increment, the amplitude of the ISR oscillations increased significantly from 31 ± 5% during saline infusion to 41 ± 4% during low dose glucose infusion and 44 ± 3% during high dose glucose infusion (P < 0.05). In all profiles obtained from the 2-min sampling experiments, rapid pulses of glucose, insulin, and C-peptide were apparent. The number of insulin pulses during saline and glucose infusions corresponded to a mean periodicity of 10 min. The amplitude of these rapid insulin pulses increased from 17.3 ± 2.9 to 39.8 ± 11.8 pmol/L (P < 0.01) in response to glucose. In contrast to the ultradian oscillations, the relative amplitude of the rapid insulin pulses decreased significantly from 28.8 ± 3.4% during saline infusion to 13.6 ± 1.6% during high dose glucose infusion (P < 0.01). Our findings demonstrate that the pancreatic response to glucose stimulation is different for the rapid pulses and the ultradian oscillations. When the rate of glucose stimulation is increased, the absolute amplitude of both the rapid pulses and the ultradian oscillations increases. However, when expressed as percent increment, the amplitude of the rapid pulses decreases during glucose stimulation, whereas the amplitude of the ultradian oscillations increases. These findings suggest that the two oscillatory modes have a different origin and physiological significance. © 1993 by The Endocrine Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Nocturnal elevation of glucose levels during fasting in noninsulin-dependent diabetes

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 < 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 < 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 < 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 setpoint of glucose regulation amplified by counterregulatory mechanisms activated by the fasting condition. © 1991 by The Endocrine Society.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Abnormal Patterns of Insulin Secretion in Non-Insulin-Dependent Diabetes Mellitus

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<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 break-fast, 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<0.03) and were less frequently concomitant with a glucose pulse (54.7±4.9 vs. 82.2±5.0, P<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<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. (N Engl J Med 1988; 318:1231–9.) © 1988, Massachusetts Medical Society. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Digitally assisted planning and monitoring of supportive recommendations in cancer patients

This publication presents a solution approach for digitally assisted planning and monitoring of supportive recommendations in cancer patients. This solution approach shall support patients in overcoming the after-effects of therapy effectively without extensive involvement of health professionals. Health professionals and patients are provided with a web application and a mobile application respectively, which use methods from mathematical decision support and artificial intelligence. This technological basis facilitates a closed-loop workflow for the cooperation of health professional and patient in oncological aftercare. The solution approach is illustrated for an exemplary case scenario of colorectal cancer

A hybrid artificial intelligence solution approach to aftercare for cancer patients

This publication presents a solution approach to oncological aftercare for cancer patients by means of artificial intelligence (AI) methods. This approach shall support patients in overcoming the after-effects of therapy effectively with suitable supportive actions and health-care professionals in goal-oriented planning of these actions. Different AI methods are used for analyzing patients’ needs for supportive actions depending on the available health data and for a monitoring of these actions. Decision support methods are used for effective planning of actions based on the AI results of analysis. The solution approach is realized in the form of a web application for health-care professionals, which allows for data analysis and planning of actions, and a mobile application for patients, which facilitates documentation and monitoring of supportive actions. In combination, they facilitate a closed-loop workflow for the effective cooperation of health-care professionals and cancer patients. The solution approach is illustrated for an exemplary case scenario of colorectal cancer