Both PPARα and PPARγ have been detected in pancreatic β-cells [76, 77]. One caveat that complicates interpretation of some of the work described below is that PPARα and PPARγ agonists have effects on β-cell function independent of their interaction with the transcription factors. Thus, both fibrates and TZD can alter ATP-dependent K channel activity and rapidly (within 10 minutes) increase insulin secretion . In addition, the generalized metabolic effects of these compounds may mean that effects observed in vitro on isolated islets may not apply to the in vivo situation. Therefore, the mode of delivery of the agents (directly onto islets versus in diets) and the time frame of study are important considerations.
In pancreatic islets, exposure to long chain fatty acids (mixed unsaturated and saturated) induces PPARα expression  whereas high glucose in vitro or hyperglycemia in vivo suppresses expression [79, 80]. Artificial ligands of PPARα such as WY14643 and clofibrate also induce PPARα expression in rat islets [76, 81, 82]. Similar to hepatocytes, this leads to up-regulation of enzymes favouring lipolysis, including acyl-CoA oxidase [76, 81], pyruvate dehydrogenase-4  and CPT-I [76, 81].
The question arises as to the role of PPARα in the physiological regulation of insulin secretion. Its induction by long chain fatty acids and its ability to augment the insulin response to low glucose  suggests that it may play a role in sustaining β-cell secretory capacity during normal, cyclical periods of fasting. Thus, when glucose is low, PPARα will be induced, favouring β-oxidation of lipids to maintain β-cell ATP at a maintenance level. Moreover, the ability of β-cells to oxidize lipids is a critical for resumption of glucose-stimulated insulin secretion at the end of the fasting period . However, when glucose is elevated above basal, PPARα will be reduced, allowing efficient glucose metabolism-dependent insulin secretion while inhibiting fatty acid oxidation. Overall, the effect of oscillating PPARα activity inversely with glucose concentration may help to maintain glucose responsiveness of the β-cell . Four-to-six-hour fasted PPARα KO mice had normal circulating insulin [84, 85] and their islets had normal glucose sensitivity  whereas 24 hour fasted mice had a 3-fold increase in circulating insulin . The longer-term fast would allow for greater adaptation to occur; higher fasting insulin may reflect hepatic insulin resistance rather than altered β-cell function.
In addition to these postulated mechanisms of PPARα control over β-cell glucose and lipid metabolism, it has also been proposed that amino acid metabolism might be affected. In the liver, an increase in PPARα is associated with a decrease in amino acid catabolism . Because glutamine metabolites are potential signaling molecules in the β-cell , PPARα induction under conditions of low glucose could impair glucose-stimulated insulin secretion via its effects on glutamine catabolism . This hypothesis has yet to be proven.
In pathophysiological conditions involving deranged glucose and lipid metabolism, altered expression of PPARα may be important in the β-cell's lack of glucose responsiveness. In Zucker diabetic fatty rat islets, despite chronic hyperlipidemia, expression of PPARα, acyl-CoA oxidase and CPT-I mRNA is reduced . It has thus been proposed that glucose is the dominant regulator of PPARα in the β-cell and that its suppression is a component of glucolipoxicity .
Glucolipotoxicity is a state in which β-cells are exposed to elevated plasma concentrations of both glucose and FFA, as is the case in insulin resistance. Several signalling pathways of the β-cell may be affected by altered PPARα expression and the overall outcome is predicted to depend upon whether fat or glucose has the dominant effect. In cases where glucose is elevated relative to lipid, a chronic reduction in PPARα would be expected to decrease the lipid oxidizing capacity of the β-cell [88, 89], eliminating a detoxification route for fat metabolites . Accumulation of lipids, for example as triglyceride within the β-cell, is associated with impaired glucose-stimulated insulin secretion, increased ceramide formation and apoptosis . When lipid is chronically elevated relative to carbohydrate, induction of PPARα presumably would cause strong up-regulation of fat oxidizing genes but also UCP2 (see below), which would suppress glucose-stimulated insulin secretion. The implication of these hypotheses is that either too much or too little PPARα would impair β-cell function. Evidence in the literature supports this contention when in vitro models are employed. Notably, culture of islets or INS-1 cells with high glucose (6–20 mM) for 48 hours strongly suppresses PPARα protein expression by 80%. As predicted, fatty acid oxidation and glucose-stimulated insulin secretion are attenuated, while islet triglyceride and lipid esterification are increased . Conversely, induction of endogenous β-cell PPARα (with clofibrate) leads to an increase in CPT-I expression and fatty acid oxidation, resulting in blunted basal and glucose-stimulated insulin secretion . However, the situation is less clear when experiments are performed in vivo, leading to the conclusion that activation of PPARα in tissues other than β-cells causes indirect effects on insulin secretion secondary to changes in peripheral insulin sensitivity . Thus, type 2 diabetic mice given dietary WY14,643, a PPARα agonist, have normalized serum lipids, glucose and insulin. PPARα activation also improves glucose-stimulated insulin secretion, reduces β-cell proliferation and β-cell mass compared with untreated controls . Similarly, fenofibrate-treated obese diabetes-prone OLETF rats retain β-cell mass and have lower islet triglyceride content and fatty oxidation than untreated animals . In both cases, the effects on β-cells are likely secondary to the observed weight loss and increase in insulin sensitivity of peripheral tissues.
Chronic induction of PPARα may influence also insulin secretion indirectly because PPRE have been found in the promoter region of uncoupling protein-2 (UCP2) . In general, uncoupling proteins (numbered 1–3 in order of their discovery) decrease metabolic efficiency by dissociating ATP synthesis from substrate oxidation in the mitochondrion by promoting translocation of protons from the inter-membrane space, across the inner mitochondrial membrane to the matrix . Therefore, circumstances that limit mitochondrial proton gradient formation, such as up-regulation of UCP2 expression and activity, are predicted to limit insulin secretion. A study specifically examining the role of PPARα by use of the ligand clofibrate demonstrated induction UCP2 in islets . In liver, stimulation of PPARα (or PPARδ when PPARα was absent) caused induction of UCP2 . UCP2 expression inversely correlates with β-cell ATP and glucose-stimulated insulin secretion [96–99]. The significance of these findings is that up-regulation of UCP2 expression suppresses glucose-stimulated insulin secretion and is implicated as a potential contributor to lipotoxic effects mediated by PPARα in β-cells.
PPARγ may also be an important transcriptional regulator of both normal and abnormal metabolism in pancreatic β-cells. In hyperglycemic, pancreatectomized rats the expression of PPARγ mRNA is increased  but others found that high fat but not high glucose up-regulates PPARγ protein expression in vitro . In adipocytes, PPARγ alters the expression of fat metabolizing enzymes to increase FFA uptake into storage while simultaneously preventing the release of FFA [66, 67]. However, in the β-cell some actions of PPARγ seem to mimic those of PPARα. Thus, one of the earliest demonstrations in islets of direct activation of PPARγ showed that TZD caused mobilization of triglyceride and increased FFA oxidation in Zucker diabetic fatty rats , resulting in improved insulin secretion [101, 102]. This observation has been reinforced in more recent work. Induction of PPARγ by three different methods enhances expression of genes that participate in fatty acid oxidation . Glucose-stimulated insulin secretion is enhanced by both PPARα and -γ agonists in db/db mice . Consistent with this, mice with a partial global knockdown of PPARγ (PPARγ+/-) on a high fat diet had blunted glucose-stimulated insulin secretion in isolated islets that was associated with an islet-specific accumulation of triglyceride  even though insulin resistance was partially prevented .
The TZD increase glucokinase and GLUT2 expression and activity via interaction with PPRE in the respective gene promoters [107, 108]. A PPARα-agonist also induced GLUT2 expression in islets but the effect on glucokinase was not documented . Improved glucose metabolism, however, has not been a consistent outcome of PPARγ induction . Nonetheless, overexpression of PPARγ in a β-cell line is detrimental to glucose-stimulated insulin secretion and proinsulin synthesis, with PPARγ agonists causing a further negative effect . Since PPARγ was not detected in control cells, it is unclear whether these results are physiologically relevant to primary β-cell function. Interestingly, in rodent islets PPARα is expressed at higher levels than PPARγ , while in human islets the situation is reversed ; the functions regulated by PPARα in rodents may be more pertinent to PPARγ in human β-cells.
PPARγ activation also regulates some β-cell functions that have not been ascribed to PPARα. PPARγ activation by TZD may relieve oxidative stress in β-cells of diabetic animals , leading to preservation of β-cell mass [104, 112–114] and partial improvement in glucose-stimulated insulin secretion from isolated islets . The potential anti-oxidative or anti-inflammatory effects of TZD in islets of type 2 diabetes models are interesting in light of reports that TZD reduce diabetes incidence in non-obese diabetic (NOD) mice  and more generalized inflammatory/immune responses in a variety of tissues . Moreover, PPARγ appears to be a critical determinant of β-cell expansion in response to a high fat diet . However, despite these studies showing that PPARγ exists in β-cells and that its activation can regulate gene expression and cell function, Rosen et al.  recently showed that the TZD's antidiabetic effects are still fully present in mice in which PPARγ has been specifically eliminated only in β-cells. Thus, the dominant effects of dietary TZD on insulin secretion are likely indirect, a consequence of improved lipemia and glycemia.