Citations

OBJECTIVE The 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 METHODS We 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. RESULTS We 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. CONCLUSIONS Our 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.

OBJECTIVE— Little is known about the capacity, mechanisms, or timing of growth in β-cell mass in humans. We sought to establish if the predominant expansion of β-cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively abundant β-cell replication. We also sought to establish if there is a secondary growth in β-cell mass coincident with the accelerated somatic growth in adolescence. RESEARCH DESIGN AND METHODS— To address these questions, pancreas volume was determined from abdominal computer tomographies in 135 children aged 4 weeks to 20 years, and morphometric analyses were performed in human pancreatic tissue obtained at autopsy from 46 children aged 2 weeks to 21 years. RESULTS— We report that 1) β-cell mass expands by severalfold from birth to adulthood, 2) islets grow in size rather than in number during this transition, 3) the relative rate of β-cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary accelerated growth phase during adolescence, 4) β-cell mass (and presumably growth) is highly variable between individuals, and 5) a high rate of β-cell replication is coincident with the major postnatal expansion of β-cell mass. CONCLUSIONS— These data imply that regulation of β-cell replication during infancy plays a major role in β-cell mass in adult humans.

Object The pathogenesis of intraneural ganglia has been a controversial issue for longer than a century. Recently the authors identified a stereotypical pattern of occurrence of peroneal and tibial intraneural ganglia, and based on an understanding of their pathogenesis provided a unifying articular explanation. Atypical features, which occasionally are observed, have offered an opportunity to verify further and expand on the authors' proposed theory. Methods Three unusual cases are presented to exemplify the dynamic features of peroneal and tibial intraneural ganglia formation. Results Two patients with a predominant deep peroneal nerve deficit shared essential anatomical findings common to peroneal intraneural ganglia: namely, 1) joint connections to the anterior portion of the superior tibiofibular joint, and 2) dissection of the cyst along the articular branch of the peroneal nerve and proximally. Magnetic resonance (MR) images obtained in these patients demonstrated some unusual findings, including the presence of a cyst within the tibial and sural nerves in the popliteal fossa region, and spontaneous regression of the cysts, which was observed on serial images obtained weeks apart. The authors identified a clinical outlier, a case that could not be understood within the context of their previously reported theory of intraneural ganglion cyst formation. Described 32 years ago, this patient had a tibial neuropathy and was found at surgery to have tibial, peroneal, and sciatic intraneural cysts without a joint connection. The authors' hypothesis about this case, based on their unified theory, was twofold: 1) the lesion was a primary tibial intraneural ganglion with proximal extension followed by sciatic cross-over and distal descent; and 2) a joint connection to the posterior aspect of the superior tibiofibular joint with a remnant cyst within the articular branch would be present, a finding that would help explain the formation of different cysts by a single mechanism. The authors proved their hypothesis by careful inspection of a recently obtained postoperative MR image. Conclusions These three cases together with data obtained from a retrospective review of the authors' clinical material and findings reported in the literature provide firm evidence for mechanisms underlying intraneural ganglia formation. Thus, expansion of the authors' unified articular theory permits understanding and elucidation of unusual presentations of intraneural cysts. Whereas an articular connection and fluid following the path of least resistance was pivotal, the authors now incorporate dynamic aspects of cyst formation due to pressure fluxes. These basic principles explain patterns of ascent, cross-over, and descent down terminal nerve branches based on articular connections, paths of diminished resistance to fluid flow within recognized anatomical compartments, and the effects of fluctuating pressure gradients.

Object The pathogenesis of intraneural ganglia has been a controversial issue for longer than a century. Recently the authors identified a stereotypical pattern of occurrence of peroneal and tibial intraneural ganglia, and based on an understanding of their pathogenesis provided a unifying articular explanation. Atypical features, which occasionally are observed, have offered an opportunity to verify further and expand on the authors' proposed theory. Methods Three unusual cases are presented to exemplify the dynamic features of peroneal and tibial intraneural ganglia formation. Results Two patients with a predominant deep peroneal nerve deficit shared essential anatomical findings common to peroneal intraneural ganglia: namely, 1) joint connections to the anterior portion of the superior tibiofibular joint, and 2) dissection of the cyst along the articular branch of the peroneal nerve and proximally. Magnetic resonance (MR) images obtained in these patients demonstrated some unusual findings, including the presence of a cyst within the tibial and sural nerves in the popliteal fossa region, and spontaneous regression of the cysts, which was observed on serial images obtained weeks apart. The authors identified a clinical outlier, a case that could not be understood within the context of their previously reported theory of intraneural ganglion cyst formation. Described 32 years ago, this patient had a tibial neuropathy and was found at surgery to have tibial, peroneal, and sciatic intraneural cysts without a joint connection. The authors' hypothesis about this case, based on their unified theory, was twofold: 1) the lesion was a primary tibial intraneural ganglion with proximal extension followed by sciatic cross-over and distal descent; and 2) a joint connection to the posterior aspect of the superior tibiofibular joint with a remnant cyst within the articular branch would be present, a finding that would help explain the formation of different cysts by a single mechanism. The authors proved their hypothesis by careful inspection of a recently obtained postoperative MR image. Conclusions These three cases together with data obtained from a retrospective review of the authors' clinical material and findings reported in the literature provide firm evidence for mechanisms underlying intraneural ganglia formation. Thus, expansion of the authors' unified articular theory permits understanding and elucidation of unusual presentations of intraneural cysts. Whereas an articular connection and fluid following the path of least resistance was pivotal, the authors now incorporate dynamic aspects of cyst formation due to pressure fluxes. These basic principles explain patterns of ascent, cross-over, and descent down terminal nerve branches based on articular connections, paths of diminished resistance to fluid flow within recognized anatomical compartments, and the effects of fluctuating pressure gradients.

OBJECTIVE—Type 1 and type 2 diabetes are characterized by an ∼98 and ∼65% loss of pancreatic β-cells, respectively. Efforts to reverse either form of diabetes increasingly focus on the possibility of promoting β-cell replacement and/or regeneration. Islet transplantation has been explored, but it does not provide long-term insulin independence. One possible source of β-cell regeneration is hematopoietic stem cells. In mice, there are conflicting data as to whether hematopoietic stem cells contribute to pancreatic β-cells. We sought to establish whether hematopoietic stem cells (derived from adult donors) transdifferentiate into pancreatic β-cells in adult humans. RESEARCH DESIGN AND METHODS—We addressed this in 31 human pancreata obtained at autopsy from hematopoietic stem cell transplant recipients who had received their transplant from a donor of the opposite sex. RESULTS—Whereas some donor-derived cells were observed in the nonendocrine pancreata, no pancreatic β-cells were identified that were derived from donor hematopoietic stem cells, including two cases with type 2 diabetes. CONCLUSIONS—We conclude that hematopoietic stem cells derived from adult donors contribute minimally to pancreatic β-cells in nondiabetic adult humans. These data do not rule out the possibility that hematopoietic stem cells contribute to pancreatic β-cells in childhood or in individuals with type 1 diabetes.

Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in β-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m2; 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m2; 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative β-cell volume, frequency of β-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative β-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative β-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of β-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of β-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that β-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased β-cell apoptosis. Since the major defect leading to a decrease in β-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and β-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.