First-phase insulin secretion
In response to i.v. glucose, insulin is secreted in a biphasic pattern with an early burst of insulin release within the first 10 min followed by a progressively increasing phase of insulin secretion that persists as long as the hyperglycemic stimulus is present . This biphasic insulin response is not observed after oral glucose, because of the more gradual rise in plasma glucose concentration. Loss of first-phase insulin secretion is a characteristic and early abnormality in patients destined to develop T2DM [1–3]. In most type 2 diabetic subjects a reduction in the early phase of insulin secretion during the OGTT (0–30min) and during the IVGTT (0–10min) becomes evident when fasting plasma glucose concentration exceeds >110–120mg dL−1 (6.1–6.7mmol L−1) [1–3,48,85,86]. During the OGTT, the defect in early insulin secretion is most obvious if the incremental plasma insulin response at 30 min is expressed relative to the incremental plasma glucose response at 30 min (ΔI30/ΔG30). Although the first-phase insulin secretory response to i.v. glucose characteristically is diminished or lost in T2DM, this defect is not consistently observed until the fasting plasma glucose concentration rises to ∼115–120mg dL−1 (6.4–6.7mmol L−1). The defect in first-phase insulin response can be partially restored with tight metabolic control [87–91], indicating that at least part of the defect is acquired (see subsequent discussion). Loss of the first phase of insulin secretion has important pathogenic consequences, since this early burst of insulin primes insulin target tissues, especially the liver, that are responsible for the maintenance of normal glucose homeostasis [60,61].
Pathogenesis of ?-cell failure (Figure 25.4)
Age. Numerous studies [92,93] have demonstrated a progressive age-related decline in β-cell function. This is consistent with the well-established observation that the incidence of diabetes increases progressively with advancing age. However, it is clear that factors in addition to age must be involved to account for the major impairment in β-cell function in T2DM.
Genes. β-Cell failure also clusters in families, and studies in first-degree relatives of T2DM parents and in twins have provided strong evidence for the genetic basis of the β-cell dysfunction [94–96]. A number of genes have been associated with T2DM in multiple ethnic populations. Of these, the most common are transcription factors associated with β-cell function [34,97–102]. In Finnish families with T2DM impaired insulin secretion is an inherited trait with evidence for a susceptibility locus on chromosome 12 . Of these genes, the transcription factor TCF7L2 is best established [97,98]. Studies by Groop and colleagues  have shown that the T-allele of single nucleotide polymorphism rs7903146 of the TCF7L2 gene is associated with impaired insulin secretion in vivo and reduced responsiveness to glucagon-like peptide 1 (GLP-1).
Both the CT and TT genotypes predict T2DM in multiple ethnic groups . In both the Malmö and Botnia studies, presence of either the CT or TT genotype was associated with a significant reduction in the diabetes-free survival time . TCF7L2 encodes for a transcription factor involved in Wnt signaling, which plays a central role in the regulation of β-cell proliferation and insulin secretion . A number of other transcription factors have also been associated with impaired insulin secretion in T2DM including: GCK, a gene responsible for MODY-2; SLC30A8, a zinc transporter involved in maintaining the appropriate amount of zinc in β-cell secretion granules; KCNJ11 and ABCC8 which encode the subunits of\ the ATP-sensitive potassium channel; and others .
At present there are no known therapeutic interventions that can reverse either the age-related decline or genetic-related factors responsible for impaired insulin secretion. However, there are\ a number of causes of β-cell failure that can be reversed or Ameliorated.
Insulin resistance. Insulin resistance places an increased demand on the β cells to hypersecrete insulin  and thus contributes to the progressive β-cell failure in T2DM . Therefore, interventions aimed at enhancing insulin sensitivity are of paramount importance. The precise mechanism(s) via which insulin resistance leads to β-cell failure remain(s) unknown. It is commonly stated that the β cell, by being forced to continuously hypersecrete insulin, eventually wears out. Although simplistic in nature, this explanation lacks a mechanistic cause. Nonetheless, β cell “unloading” with thiazolidinediones in IGT subjects has been shown to markedly enhance β-cell function and reduce the conversion to T2DM [107,108]. An alternate hypothesis, for which considerable evidence exists, is that the etiology of the insulin resistance also is responsible for the β-cell failure. Thus, excess deposition of fat (long chain-fatty acyl CoAs, diacylglycerol, and ceramide) in liver and muscle impairs insulin signaling, causing insulin resistance in these organs, that is, lipotoxicity. Similarly, deposition of fat in the β cell and chronically elevated plasma FFA lead to impaired insulin secretion and β-cell failure [109–112]. Hypersecretion of islet amyloid polypeptide (IAPP) has also been implicated as a cause of the β-cell failure [54,113,114]. IAPP is especially toxic to the β cell in the presence of elevated intracellular fat content . Further, as the IAPP ammulates it coalesces and encroaches upon the β cell, leading to β cell destruction [54,67,114,115]. Lastly, studies in the β-cell insulin receptor knock out (BIRKO) mouse  and in humans with gly → arg substitution of codon 972 of IRS-1 [117–119] have demonstrated that defects in insulin signaling in the β cell are\ associated with impaired insulin secretion.
Lipotoxicity. Lipid deposition in the β cell [109,111,112] and chronic elevation of the plasma FFA concentration impair insulin secretion, and this has been referred to as lipotoxicity. A physiologic elevation of the plasma FFA concentration for as little as 48 hours markedly impairs insulin secretion in genetically predisposed individuals  (Figure 25.5). In vivo studies in rodents [120,121] and in vitro studies [122,123] also support an important role for lipotoxicity. Incubation of human pancreatic islets for 48 h with FFA (oleate-to-palmitate ratio 2:1) impairs both the acute and late insulin response, inhibits insulin mRNA expression, and reduces islet insulin content . The peroxisome proliferator–activated receptor (PPAR)γ agonist, rosiglitazone, has been shown to prevent all of these deleterious effects of FFA [123,124]. Consistent with these in vitro observations, both rosiglitazone and pioglitazone markedly improve the insulin secretion/insulin resistance index in vivo in type 2 diabetic humans . Weight loss, which mobilizes fat out of the β cell, also reverses lipotoxicity and preserves β-cell function .
Glucotoxicity. Chronically elevated plasma glucose levels impair β-cell function, and this has been referred to as glucotoxicity . Studies by Rossetti et al.  have provided definitive proof of this concept. Partially pancreatectomized diabetic rats are characterized by severe defects in both first and second-phase insulin secretion compared with control rats. Phlorizin, an inhibitor of renal glucose transport, normalizes the plasma glucose profile without change in any other circulating metabolites and restores both the first and second phases of insulin secretion. In vitro studies with isolated human islets have also demonstrated that chronic exposure to elevated plasma glucose levels impairs insulin secretion [128,129]. In rats, elevation of the mean day-long plasma glucose concentration in vivo by as little as 16mg dL−1 leads to a marked inhibition of glucose-stimulated insulin secretion in the isolated perfused pancreas . In humans correction of hyperglycemia with insulin [87,89–91,131,132] or inhibitors of renal glucose tranpsort (DeFronzo, unpublished results) reverses the glucotoxic effect of chronic hyperglycemia on the β cells [80–84], leading to improved first- and second-phase insulin secretion, as well as reversal of hepatic and muscle insulin resistance.
IAPP. Excessive secretion of IAPP with subsequent amyloid deposition within the pancreas has also been shown to contribute to progressive β-cell failure in T2DM [54,113,114,133]. Convincing evidence for a pathogenic role of IAPP exists in rodents [134,135] and baboons [54,67,115] and the natural history of pancreatic amylin deposition in humans parallels that in rodents and primates .
The baboon genome shares more than 98% homology with the human genome [137,138]. Therefore, results in baboons are likely to be pertinent to those in humans. As the relative amyloid area of the pancreatic islets increase from <5.5% to >51%, there is a progressive decline in the log of HOMA-β, which was strongly correlated with the increase in fasting plasma glucose concentration . Studies by the investigators [139,140] have provided additional evidence for a β-cell toxic effect for soluble IAPP fibrils.
It follows that interventions that improve insulin sensitivity, that is, TZDs/metformin/weight loss,\ by leading to a reduction in insulin secretion, and therefore IAPP secretion (insulin and IAPP are co-secreted in a one-to-one molar ratio), would be expected to preserve β-cell function, and rosiglitazone has been shown to protect human islets against IAPP toxicity by a PI-3 kinase-dependent pathway .
Incretins. In T2DM some investigators have demonstrated a small decline in GLP-1 secretion or a delayed GLP-1 response (reviewed in ), while GIP secretion has been reported to be normal or slightly increased . More importantly, there is severe resistance to the stimulatory effect of both GLP-1 and GIP [143–145]. The resistance to GLP-1 can be observed in individuals with IGT and worsens progressively with progression to T2DM . Of note the resistance to GLP-1 can be overcome by infusing GLP-1  or administration of GLP-1 analogues [148–150] to generate pharmacologic levels (70–90 pM) of the incretin. Tight glycemic control for as little as 4 weeks can improve the β cells’ insulin secretory response to both GLP-1 and GIP . Studies in patients with chronic pancreatitis and T2DM also indicate that the reduced incretin defect in T2DM is not a primary effect for the development of impaired insulin secretion . Thus, β-cell resistance to GLP-1 and GIP is another manifestation of glucotoxicity.