Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.

Abstract

The pattern of endogenous insulin secretion over a 24-h period, which included three mixed meals, was evaluated in 14 normal volunteers and 15 obese subjects. Insulin secretory rates were calculated from plasma C-peptide levels using individually derived C-peptide kinetic parameters and a validated open twocompartment model of peripheral C-peptide kinetics. Insulin secretion rates were consistently elevated in the obese subjects under basal conditions (11.6±1.2 vs. 5.4±0.5 nmol/h) and in the 4 h after breakfast (139±15 vs. 63±5 nmol/4 h, P < 0.001), lunch (152±16 vs. 67±5 nmol/4 h, P < 0.001), and dinner (145±18 vs. 65±6 nmol/4 h, P < 0.001).In the normal subjects, basal insulin secretion represented 50±2.1% of total 24-h insulin production, insulin secretion returned to baseline between meals, and equal quantities of insulin were secreted in the 4 h after breakfast, lunch, and dinner, despite the fact that subjects consumed half the number of calories at breakfast compared to lunch and dinner. Overall glucose responses were also similar after the three meals.In contrast, the pattern of insulin secretion in obese subjects was largely normal, albeit set at a higher level. However, the insulin secretion rate after meals did not return to baseline, and the secretion rate immediately before lunch (350.5±81.9 pmol/min) and dinner (373.6±64.8 pmol/min) was considerably higher than the secretion rate immediately before breakfast (175.5±18.5 pmol/min). In these overweight subjects, the glucose response after lunch was lower than after dinner.Analysis of individual 24-h insulin secretory profiles in the normal subjects revealed that insulin secretion was pulsatile. On average 11.1±0.5 pulses were produced in each 24-h period. The most prevalent temporal distribution of postmeal secretory pulses was two pulses after breakfast and three pulses after both lunch and dinner. Insulin secretion was also pulsatile during the period without meal stimuli: 3.9±0.3 pulses occurred during the period of overnight sampling and in the 3-h period before ingestion of the breakfast meal. In the obese subjects, the number and timing of secretory pulses was similar to those of normal volunteers, although the amplitude of the pulses was significantly greater. In both groups of subjects, > 80% of insulin pulses were concomitant with a pulse in glucose concentration in the postmeal period. The concomi-

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“…Both rodent and human studies confirm that daily rhythms of blood glucose and insulin secretion are regulated by the timing system [53][54][55], whilst lesions of the SCN or environmental circadian disruption can lead to insulin resistance and obesity [56,57]. The molecular clock is essential for glucose metabolism, as evidenced by the impairment of glucose tolerance and insulin sensitivity upon disruption of core clock gene expression [51,[58][59][60][61][62][63].…”

“…1) [77]. The insulin secretion rate (ISR) from beta cells displays a circadian rhythm and serum insulin levels vary across the 24 h day in both rodents and humans, reaching a peak during the latter half of the feeding period [53,55,78]. Mice with targeted disruption of the clock in beta cells present with glucose intolerance and impaired glucose-stimulated insulin secretion [59,76].…”

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

“…Normal fasting plasma insulin levels in humans are < 1 ng/mL and they are elevated many times over the basal levels after ingesting a meal; however, obese humans display insulin levels often 3 to 5 times higher at fasting and postprandial states (Polonsky et al, 1988 Figure 7 A schematic of the mechanisms underlying cerebrovascular insulin resistance (IR) in Zucker obese (ZO) rats. Insulin binding to insulin receptor leads to activation of kinase signaling by phosphorylation that in turn activates downstream signaling pathways.…”

Dynamics of insulin secretion in obesity and diabetes

“…The pattern of endogenous insulin secretion of a 24 h period, which included three mixed meals, was evaluated in 14 normal volunteers and 15 obese subjects. 4 Insulin secretory rates were calculated from plasma C-peptide levels using individually derived C-peptide kinetic parameters and a validated open two-compartment model of peripheral C-peptide kinetics. Insulin secretion rates were consistently elevated in the obese subjects under basal conditions (11.6AE 1.2 vs 5.4 AE 0.5 nmolah) and in the 4 h after breakfast (139AE 15 vs 63AE 5 nmola4 h, P`0.001), lunch (152AE 16 vs 67AE 5 nmola4 h, P`0.001), and dinner (145AE 18 vs 65 AE 6 nmola4 h, P`0.001).…”