Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors.

Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an ∼40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P < 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P < 0.01). Pancreata in DM treated with incretin therapy were notable for α-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. β-Cell mass was reduced by ∼60% in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumors

β-Cell failure in type 2 diabetes: a case of asking too much of too few?

The islet in type 2 diabetes (T2DM) is characterized by a deficit in β-cells, increased β-cell apoptosis, and extracellular amyloid deposits derived from islet amyloid polypeptide (IAPP). In the absence of longitudinal studies, it is unknown if the low β-cell mass in T2DM precedes diabetes onset (is a risk factor for diabetes) or develops as a consequence of the disease process. Although insulin resistance is a risk factor for T2DM, most individuals who are insulin resistant do not develop diabetes. By inference, an increased β-cell workload results in T2DM in some but not all individuals. We propose that the extent of the β-cell mass that develops during childhood may underlie subsequent successful or failed adaptation to insulin resistance in later life. We propose that a low innate β-cell mass in the face of subsequent insulin resistance may expose β-cells to a burden of insulin and IAPP biosynthetic demand that exceeds the cellular capacity for protein folding and trafficking. If this threshold is crossed, intracellular toxic IAPP membrane permeant oligomers (cylindrins) may form, compromising β-cell function and inducing β-cell apoptosis

β-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency.

ObjectiveThe islet in type 2 diabetes is characterized by β-cell apoptosis, β-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in β-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum-associated degradation/ubiquitin/proteasome system.Research design and methodsWe used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832/13 cells and apoptosis was evaluated.ResultsWe report accumulation of polyubiquinated proteins and UCH-L1 deficiency in β-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in β-cells induced endoplasmic reticulum stress leading to apoptosis.ConclusionsOur results indicate that defective protein degradation in β-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises β-cell viability

Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model.

Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP-protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis

The Routine Use of Antibiotics to Promote Animal Growth Does Little to Benefit Protein Undernutrition in the Developing World

Some persons argue that the routine addition of antibiotics to animal feed will help alleviate protein undernutrition in developing countries by increasing meat production. In contrast, we estimate that, if all routine antibiotic use in animal feed were ceased, there would be negligible effects in these countries. Poultry and pork production are unlikely to decrease by more than 2%. Average daily protein supply would decrease by no more than 0.1 g per person (or 0.2% of total protein intake). Eliminating the routine use of in-feed antibiotics will improve human and animal health, by reducing the development and spread of antibiotic-resistant bacteri

Archaeological Investigations at the Ikirahak Site Raise Questions Concerning Taltheilei Land Use in Southern Nunavut

We report a new Taltheilei site-type found off the west coast of Hudson Bay in southern Nunavut. The Taltheilei is an archaeological culture that existed in the Barrenlands of the central Canadian Subarctic between 2600 and 300 years ago. Their land use strategies were tethered to the seasonal migrations of the Beverly and Qamanirjuaq caribou herds throughout tundra and forest landscapes. Tundra-based sites are typically interpreted as short-lived summer camps, but our discovery of three unique pit-house sites on the shores of Maguse Lake raises new questions concerning diversity in Taltheilei tundra land use. Architectural, faunal, lithic, and geoarchaeological data recovered from the Ikirahak site (JjKs-7) support the hypothesis that Taltheilei groups were extending their tundra stays into the fall. We report the evidence from four excavated pit-house features. Terraced platforms along the internal perimeters of these houses suggest they were designed for cold season use. The faunal assemblage is dominated by caribou remains. Higher relative frequencies of appendicular elements suggest a focus on secondary butchering. A large fraction of the faunal assemblage is highly fragmented and calcined, which is consistent with heavy processing and the use of bone as an alternative fuel source. Higher frequencies of lithic debris around dwelling floor perimeters are suggestive of maintenance activities. Multi-element concentrations in dwelling and site-wide sediments also show that hearth refuse was dumped outside. These findings seem to reflect longer tundra occupations during fall, a land use strategy that was likely guided by Qamanirjuaq herd behaviour specific to the Maguse Lake area, fall hunting and processing goals, and ecologically couched mobility logistics. As just four pit-houses from one Taltheilei camp have been investigated to date, our understanding of these places within Taltheilei worlds and northern socio-ecologies is currently limited. Further research at Ikirahak, the other Maguse Lake pit-house sites, and at other caribou water crossings on the tundra of the Qamanirjuaq caribou range is needed to support or refute our hypotheses.Nous signalons un nouveau site de type taltheilei trouvé sur la côte ouest de la baie d’Hudson, dans le sud du Nunavut. La culture taltheilei est une culture archéologique qui a existé dans les landes de la zone subarctique centrale canadienne il y a de cela 2600 à 300 ans. Les stratégies d’utilisation des terres de cette culture étaient rattachées aux migrations saisonnières des hardes de caribous de Beverly et de Qamanirjuaq dans la toundra et la forêt. De manière générale, les sites trouvés dans la toundra sont interprétés comme des campements d’été de courte durée. Cependant, notre découverte de trois sites uniques de maisons semi-souterraines sur les rives du lac Maguse soulève de nouvelles questions au sujet de la diversité de l’utilisation de la toundra par les Taltheilei. Les données architecturales, fauniques, lithiques et géoarchéologiques recueillies au site d’Ikirahak soutiennent l’hypothèse selon laquelle les groupements de Taltheilei occupaient la toundra jusqu’à l’automne. Nous signalons des preuves en provenance de quatre aménagements de maisons semi-souterraines. Le long du périmètre interne de ces maisons, les plateformes en terrasses suggèrent qu’elles étaient conçues pour servir pendant la saison froide. Des restes de caribous dominent l’assemblage faunique. Des fréquences relatives plus élevées d’éléments appendiculaires laissent entrevoir que le dépeçage secondaire y occupait une grande place. Une grande fraction de l’assemblage faunique est fortement fragmentée et calcinée, ce qui correspond à une transformation importante et à l’utilisation des os comme source de combustible. Les grandes fréquences de débris lithiques entourant le périmètre des planchers d’habitations suggèrent des activités de maintenance. Les concentrations d’éléments multiples dans les sédiments des habitations et de l’ensemble du site indiquent également que les déchets des âtres étaient jetés à l’extérieur. Ces constatations laissent entrevoir de plus longues occupations de la toundra à l’automne, une stratégie d’utilisation des terres vraisemblablement guidée par le comportement propre à la harde de Qamanirjuaq dans la région du lac Maguse, par la chasse automnale et par les objectifs de transformation, de même que par la logistique de la mobilité en termes écologiques. Puisque seulement quatre maisons semi-souterraines d’un seul campement taltheilei ont été étudiées jusqu’à maintenant, nous comprenons toujours peu de choses au sujet de ces endroits dans le monde des Taltheilei et des socioécologies nordiques. Il y a lieu de pousser les recherches plus loin à Ikirahak, là où se trouvent les autres sites de maisons semi-souterraines du lac Maguse, ainsi qu’à d’autres passages de franchissement de l’eau sur la toundra du parcours des caribous de Qamanirjuaq afin de confirmer ou de réfuter nos hypothèses

Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas

Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of beta cell mass in vivo. We questioned, (1) What proportion of beta cells express VMAT2? (2) Is VMAT2 expressed by other pancreatic endocrine or non-endocrine cells? (3) Is the relationship between VMAT2 and insulin expression disturbed in type 1 (T1DM) or type 2 diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained for insulin, VMAT2 and other pancreatic hormones. Most beta cells expressed VMAT2. VMAT2 expression was not changed by the presence of diabetes. In tail of pancreas VMAT2 immunostaining closely correlated with insulin staining. However, VMAT2 was also expressed in some pancreatic polypeptide (PP) cells. Although VMAT2 was not excluded as a target for beta cell mass measurement, expression of VMAT2 in PP cells predicts residual VMAT2 expression in human pancreas even in the absence of beta cells

Mapping Large-Scale CO Depletion in a Filamentary Infrared Dark Cloud

Infrared Dark Clouds (IRDCs) are cold, high mass surface density and high density structures, likely to be representative of the initial conditions for massive star and star cluster formation. CO emission from IRDCs has the potential to be useful for tracing their dynamics, but may be affected by depleted gas phase abundances due to freeze-out onto dust grains. Here we analyze C18O J=1-0 and J=2-1 emission line data, taken with the IRAM 30m telescope, of the highly filamentary IRDC G035.39.-0033. We derive the excitation temperature as a function of position and velocity, with typical values of ~7K, and thus derive total mass surface densities, Sigma_C18O, assuming standard gas phase abundances and accounting for optical depth in the line, which can reach values of ~1. The mass surface densities reach values of ~0.07 g/cm^2. We compare these results to the mass surface densities derived from mid-infrared (MIR) extinction mapping, Sigma_SMF, by Butler & Tan, which are expected to be insensitive to the dust temperatures in the cloud. With a significance of >10sigma, we find Sigma_C18O/Sigma_SMF decreases by about a factor of 5 as Sigma increases from ~0.02 to ~0.2 g/cm^2, which we interpret as evidence for CO depletion. Several hundred solar masses are being affected, making this one of the most massive clouds in which CO depletion has been observed directly. We present a map of the depletion factor in the filament and discuss implications for the formation of the IRDC.Comment: 9 pages, accepted to ApJ, Mac users: Figure 1 is best viewed with Adobe acroread rather than previe