Values represent mean ± SEM.

*'§ Like symbols compared, prepubertal versus pubertal (P < 0.05). Adapted from Bloch CA, Clemons P, Sperling MA. Puberty decreases insulin sensitivity. J Pediatr 1987;110(3):481-7.

Values represent mean ± SEM.

*'§ Like symbols compared, prepubertal versus pubertal (P < 0.05). Adapted from Bloch CA, Clemons P, Sperling MA. Puberty decreases insulin sensitivity. J Pediatr 1987;110(3):481-7.

glucagon, and delayed gastric emptying [14,15]. The drug is approved for use in patients with type 2 diabetes. Studies in type 1 DM suggest that when given with insulin before meals, the drug can decrease exaggerated glycemic excursions by up to 90%, emphasizing its therapeutic potential for both children and adults with either type 1 or type 2 DM [14].

The effects of glucagon-like peptide-1 in suppressing glucagon secretion and delaying gastric emptying are also mimicked by amylin, a peptide hormone cosecreted with insulin from pancreatic (-ells [16]. In experimental studies in children with type 1 DM, synthetic amylin, given together with the recommended bolus dose in patients treated by an insulin pump, significantly reduced the immediate postprandial hyperglycemia and glucagon secretion [17]. This drug, due for release in 2005, may prove of benefit to reduce postprandial glucose excursions in children with type 1 DM.

The result of this physiologic interaction is that insulin secretion is tightly linked to the cycle of feeding and fasting. The early insulin response to ingested meals is the physiologic counterpart of the biphasic response to intravenous glucose, so important for signaling immediate and ongoing disposition of ingested nutrients [18].

Biochemical and molecular aspects of insulin secretion

Insulin is synthesized as a prohormone, proinsulin, with the amino terminus of the A chain linked to the carboxy terminus of the B chain by a connecting peptide called C peptide (Fig. 4). Enzymatic cleavage by carboxypeptidase at the

Fig. 4. Human proinsulin. Insulin is derived from the cleavage of the connecting peptide (C peptide) from the proinsulin molecule. C peptide is secreted in equimolar amounts with insulin and has a longer half-life.

appropriate sites results in the two chains of insulin linked by disulfide bonds and C peptide; both are cosecreted along with amylin. Inappropriate cleavage at the NH2 or COOH terminus results in an abnormal insulin with less biologic potency, thereby predisposing to DM [19]. Because C peptide is so different than insulin or proinsulin, measurement of C peptide is useful to distinguish endogenous insulin secretion (C peptide at least as high as insulin) from ex-ogenously administered insulin, wherein insulin is high but C peptide is low because of suppression of endogenous insulin secretion. The two major uses of C peptide measurements are assessment of residual insulin secretion in new-onset DM treated with insulin, and distinction of factitious insulin administration from endogenous secretion in hypoglycemia [20].

The combination of insulin measurements in isolated islets, electrophysiologic studies by patch clamp techniques, and molecular approaches have revolutionized the understanding of insulin secretion in health and disease [21]. The (-cell transforms chemical signals from glucose metabolism to electrical signals that allow K+ and Ca++ channels to open or close and result in release of insulin. These concepts are summarized in Fig. 5. In the resting state, the (-cell synthesizes and stores insulin as granules distributed close to the cell membrane or more centrally in the cytoplasm. The ATP-sensitive K+ channel, KATP, is composed of four separate KIR 6.2 subunits that form a pore, which is surrounded by four sulfonylurea receptor (SUR1) subunits. Each KATP channel is an octamer; synthesis and assembly of these subunits is critical for insulin secretion. In the resting state, the ratio of ATP/ADP is such that the KATP remains open, permitting

Fig. 5. Pancreatic (-cell stimulus-secretion coupling for glucose (see text for details).

efflux of the K+ so that the cell membrane is hyperpolarized and a family of Ca++ channels remains closed. With glucose ingestion or infusion, glucose enters the (-cell by the non-insulin sensitive glucose transporter, GLUT 2, and is rapidly phosphorylated by glucokinase with subsequent metabolism to generate energy as ATP. The change in ATP/ADP closes the KATP as does sulfonylurea acting on its receptor SUR1. This causes a buildup of potassium within each cell ultimately resulting in depolarization of the cell membrane. In turn, depolarization opens the voltage-gated calcium channel Cav1.2/1.3, resulting in a rapid release of the immediate pool of available insulin and accounting for the first phase of insulin release that occurs within the first 3 to 5 minutes (see inset of Fig. 5). Ongoing metabolism of glucose mobilizes preformed or newly synthesized insulin from the interior of the cell by calcium entering a second distinct group of calcium channels, known as Cav 2.3 and located distal to the KATP. This results in the sustained second phase of insulin secretion. In this model, defects of insulin secretion can occur because of faulty formation of (-cells, faulty genetic control of factors that regulate insulin synthesis, defects in metabolic steps of glycolysis, or defects in the KATP channel secondary to mutations in the Kir 6.2 or SUR1 components and in the calcium channel family described previously. Examples of each of these mutations have been reported and although relatively rare, they may collectively contribute to impaired insulin secretion, which when coupled to increasing IR as occurs in obesity, results in type 2 DM, because (-cells cannot compensate for the increased IR [22]. Likewise, these defects may contribute to type 1 DM because less damage to (-cells is required by autoimmune destruction before failure is unmasked.

Glucotoxicity or lipotoxicity are concepts that imply exhaustion or functional interference, but not death, of (-cells and may also contribute to apparent (-cell failure. Remarkably, in most circumstances, early failure of insulin secretion is manifest by impairment of the first-phase response to intravenous glucose. The mechanisms for this are not fully understood. Failure of first-phase insulin response, however, can be used to predict those who may go on to develop clinical DM [23]. Measures of (-cell function in terms of insulin secretion are

Table 2

Measures of (-cell function

Measure Reference

Fasting insulin or C peptide [24,25]

Homeostatic model assessment: (-cell function [24,25]

Insulin profile during oral glucose tolerance test (see Table 1)

Hyperglycemic clamp [24,25]

The insulinogenic index* [24]

Mixed meal tolerance test [78]

Insulin profile during intravenous glucagon tolerance test [26]

Arginine stimulation [27]

* The insulinogenic index is calculated as the ratio of increment in the plasma insulin level to that of plasma glucose level during the first 30 minutes after the ingestion of glucose (1.75 g/kg, maximum 75 g).

summarized in Table 2 [24-27]. For each of the listed tests, one must rely on the age-specific values considered normal for the specific laboratory.

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