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The early steps of insulin biosynthesis occur in the endoplasmic reticulum (ER), and the beta-cell has a highly developed and active ER. All cells regulate the capacity of their ER to fold and process client proteins and they adapt to an imbalance between client protein load and folding capacity (so-called ER stress). Mutations affecting the ER stress-activated pancreatic ER kinase (PERK) and its downstream effector, the translation initiation complex eukaryotic initiation factor 2 (eIF2), have a profound impact on islet cell development, function, and survival. PERK mutations are associated with the Wolcott-Rallison syndrome of infantile diabetes and mutations that prevent the alpha-subunit of eIF2 from being phosphorylated by PERK, block beta-cell development, and impair gluconeogenesis. We will review this and other rare forms of clinical and experimental diabetes and consider the role of ER stress in the development of more common forms of the disease. [ABSTRACT FROM AUTHOR]

BACKGROUND. The islet in humans with type 2 diabetes is characterized by an ∼65% beta-cell deficit, increased beta-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed and secreted with insulin. Beta-cell specific over expression of human IAPP (h-IAPP) in mice leads to endoplasmic reticulum (ER) stress induced beta-cell apoptosis. This effect of the h-IAPP transgenic expression is dose-dependant, and depends on the propensity of the protein to form toxic oligomers (a property of h-IAPP but not rodent IAPP). In health ER stress is avoided by the unfolded protein response (UPR), mediated in part by the ER membrane protein PERK. PERK -/- mice develop beta-cell ER stress induced apoptosis and diabetes. We posed the following question, does decreased PERK expression in the setting of modest expression rates of h-IAPP lead to ER stress, beta cell apoptosis and diabetes? METHODS. We cross bred homozygous transgenic mice for h-IAPP (and for controls homozygous transgenic mice rodent IAPP) with PERK+/- mice. Four groups of mice were studied; (1) h-IAPP+/-, PERK+/+, (2) h-IAPP+/-, PERK+/-, (3) r-IAPP+/-, PERK+/+, (4) r-IAPP+/-, PERK+/-. Mice were exposed to a high fat diet. Islet PERK expression was quantified by RT-PCR and western blot. Fasting blood glucose was measured throughout the experiment and glucose tolerance tests were performed at 40 weeks of age. RESULTS. In PERK +/+ mice modest transgenic expression of h-IAPP versus comparable r-IAPP led to both fasting (116.4±5.2 vs 95.4±4.6 mg/dl, p<0.01) and post glucose challenge hyperglycemia (p<0.01), but not diabetes. However, neither fasting nor post glucose challenge blood glucose concentrations were higher in h-IAPP+/-, PERK+/- mice compared to h-IAPP+/,PERK+/+ mice. The UPR in beta-cells of h-IAPP+/-, PERK+/- mice remained intact as revealed by increased ER chaperone protein GRP78 expression compared to that of h-IAPP+/-, PERK+/+ mice (p<0.05). CONCLUSIONS. While complete ablation of PERK expression in beta cells leads to ER stress induced beta cell apoptosis and diabetes, we report here that a ∼50% decrement in PERK expression is sufficient to permit an effective protective unfolded protein response in h-IAPP transgenic mice, even on a high fat diet. [ABSTRACT FROM AUTHOR]