Insulin secretion has a diurnal rhythm, with an increased rate of secretion during the day and decreased secretion at night (12). Also, insulin is secreted in both an ultradian (13) and a high-frequency pulsatile pattern (14). The ultradian pulses occur with a frequency of one pulse each 40 minutes, a rate that is decreased in patients with type 2 diabetes. The high-frequency pulses occur at one pulse per 6 minutes. Almost all insulin is secreted in these high-frequency discrete insulin secretory pulses. The amplitude of the resulting insulin concentration oscillations in the portal vein (1000-4000 pmol/L) is very large, but hepatic insulin clearance results in a marked attenuation of these oscillations by the time they reach the systemic circulation (amplitude —10 pmol/L) (15). The pacemaker responsible for generating this high-frequency pulsatile rhythm is unknown, but each islet independently secretes insulin in a comparable pulsatile manner so the property must be present within islets. Also, die mechanism that allows the 1 million islets to be coordinated to secrete pulses in a synchronous manner is not known although the intrapancreatic neural network is believed to be important. Transplanted islets in the liver secrete insulin in a coordinate fashion once the islets have been reinnervated (16).
The significance of these high-frequency insulin oscillations for insulin action is not fully understood, although there is some evidence that they are impor s
tant. Clearly, reproducing the insulin-concentration profile present in the portal vein in humans—either in the fasting state or, particularly, after a meal—would be impossible with insulin exogenously injected into the subcutaneous tissue or even the systemic circulation. Consistent with the observations of Leahy and colleagues that |3-cell rest can overcome diabetes in animal models with a partial pancreatectomy, overnight (3-cell rest can at least temporarily restore pulsatile insulin secretion in patients with type 2 diabetes (17). It is therefore rational to increase insulin sensitivity in patients with a partial decrease in (3-cell mass (such as those with type 2 diabetes). This strategy is likely to at least partially restore the pattern of insulin secretion toward normal, and the available evidence suggests that the pattern of insulin secretion is important for effective insulin action.
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