Loss of RAGE defense: a cause of Charcot neuroarthropathy?

OBJECTIVE: This study investigated the relationship between circulating soluble receptor for advanced glycation end products (sRAGE) and parameters of bone health in patients with Charcot neuroarthropathy (CNA). RESEARCH DESIGN AND METHODS: Eighty men (aged 55.3±9.0 years), including 30 healthy control subjects, 30 type 2 diabetic patients without Charcot, and 20 type 2 diabetic patients with stage 2 (nonacute) CNA, underwent evaluations of peripheral and autonomic neuropathy, nerve conduction, markers of bone turnover, bone mineral density, and bone stiffness of the calcaneus. RESULTS: CNA patients had worse peripheral and autonomic neuropathy and a lower bone stiffness index than diabetic or control individuals (77.1, 103.3, and 105.1, respectively; P<0.05), but no difference in bone mineral density (P>0.05). CNA subjects also had lower sRAGE levels than control (162 vs. 1,140 pg/mL; P<0.01) and diabetic (162 vs. 522 pg/mL; P<0.05) subjects, and higher circulating osteocalcin levels. CONCLUSIONS: CNA patients had significantly lower circulating sRAGE, with an accompanying increase in serum markers of bone turnover, and reduced bone stiffness in the calcaneus not accompanied by reductions in bone mineral density. These data suggest a failure of RAGE defense mechanisms against oxidative stress in diabetes. Future studies should determine if medications that increase sRAGE activity could be useful in mitigating progression to CNA.

Targeted expression of islet neogenesis associated protein to beta cells enhances glucose tolerance and confers resistance to streptozotocin-induced hyperglycemia.

Islet neogenesis associated protein (INGAP) stimulates experimental pancreatic islet growth, as evidenced by elevated markers of beta cell mass, in rodents, dogs and primates. Previous analyses of mice that have a transgenic expression of INGAP targeted to the exocrine pancreas have indicated additional biological activity attributed to INGAP. In this study we report on mice with a targeted expression of INGAP to the islet beta cell. The beta cell transgenic mice (IP-INGAP) showed enhanced normalization of blood glucose during IPGTT. Further, IP-INGAP mice had a significant delay in development of hyperglycemia following a diabetogenic dose of streptozotocin. INGAP conferred beta cell protection and enhanced islet function. Analysis of oxidative stress genes in IP-INGAP mice revealed a decrease in islet expression of the NADPH oxidase, NOX1, in both basal state and in response to pro-inflammatory cytokine stimulation. These data are consistent with a pleiotropic role for INGAP and reveal new pathways to target in the discovery of improved diabetic therapies.

Harnessing the pancreatic stem cell.

Building on the elaborate research studies that have helped map out key decision points in the process of pancreas development, reprogramming of pluripotent embryonic stem cells or induced pluripotent stem cells offers the possibility of overcoming restrictions on tissue supply associated with transplantation of donor islets. In a healthy pancreas, the beta-cell mass can exhibit significant plasticity, as reflected in the normal adaptive response in beta-cell mass to offset the metabolic challenge associated with pregnancy and obesity. In this article, alternative strategies and potential sources of pancreatic stem cells are considered.

Topiramate improves neurovascular function, epidermal nerve fiber morphology, and metabolism in patients with type 2 diabetes mellitus.

PURPOSE: To assess the effects of topiramate on C-fiber function, nerve fiber morphology, and metabolism (including insulin sensitivity, obesity, and dyslipidemia) in type 2 diabetes. PATIENTS AND METHODS: We conducted an 18-week, open-label trial treating patients with topiramate. Twenty subjects with type 2 diabetes and neuropathy (61.5 ± 1.29 years; 15 male, 5 female) were enrolled and completed the trial. Neuropathy was evaluated by total neuropathy scores, nerve conduction studies, quantitative sensory tests, laser Doppler skin blood flow, and intraepidermal nerve fibers in skin biopsies. RESULTS: Topiramate treatment improved symptoms compatible with C-fiber dysfunction. Weight, blood pressure, and hemoglobin A(1c) also improved. Laser Doppler skin blood flow improved significantly after 12 weeks of treatment, but returned to baseline at 18 weeks. After 18 weeks of treatment there was a significant increase in intraepidermal nerve fiber length at the forearm, thigh, and proximal leg. Intraepidermal nerve fiber density was significantly increased by topiramate in the proximal leg. CONCLUSION: This study is the first to demonstrate that it is possible to induce skin intraepidermal nerve fiber regeneration accompanied by enhancement of neurovascular function, translating into improved symptoms as well as sensory nerve function. The simultaneous improvement of selective metabolic indices may play a role in this effect, but this remains to be determined.

The role of islet neogeneis-associated protein (INGAP) in pancreatic islet neogenesis.

Efforts to cure diabetes are now focused on restoring a physiologically-regulated population of insulin-producing cells to the patient. A number of animal models of beta cell regeneration have been employed to study the mechanisms of the process. Islet neogenesis, the regeneration of pancreatic islets from pancreatic stem cells, is arguably the least fraught with barriers to widespread use as a therapy for diabetes. These animal models have led to the description of the reg family of proteins that appear to be related to islet regeneration. Islet neogenesis-associated protein (INGAP) is an initiator of islet neogenesis in animal models and a peptide sequence from INGAP carries the biological activity. INGAP peptide has been shown to stimulate an increase in beta cell mass in mice, rats, hamsters and dogs. INGAP is also found in the pancreas in human pathological states involving islet neogenesis. The peptide has been tested in human clinical trials, with success being reported. The evidence points to INGAP as a major factor in stimulating islet neogenesis, and, therefore, may play a significant therapeutic role in diabetes.

A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy.

OBJECTIVE: Diabetes leads to protein kinase C (PKC)-beta overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-beta inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN. RESEARCH DESIGN AND METHODS: Endothelium-dependent and C fiber-mediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo- and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged > or =18 years; with type 1 or type 2 diabetes and A1C < or =11%) during a randomized, double-masked, single-site, 6-month study. RESULTS: Endothelium-dependent (+78.2%, P < 0.03) and C fiber-mediated (+56.4%, P < 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months -48.3%, P = 0.01; end point -66.0%, P < 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point -41.2%, P = 0.01, and -41.0, P = 0.04, respectively). Between-group differences in baseline-to-end point change were observed for NTSS-6 total score (placebo -13.1%; ruboxistaurin -66.0%, P < 0.03) and the Norfolk QOL-DN symptom subscore (placebo -4.0%; ruboxistaurin -41.2%, P = 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies. CONCLUSIONS: In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated.

Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes.

Diabetic neuropathy (DN) is a common severe complication of type 2 diabetes. The symptoms of chronic pain, tingling, and numbness are generally attributed to small fiber dysfunction. However, little is known about the pathology among innervation to distal extremities, where symptoms start earliest and are most severe, and where the innervation density is the highest and includes a wide variety of large fiber sensory endings. Our study assessed the immunochemistry, morphology, and density of the nonvascular innervation in glabrous skin from the hands of aged nondiabetic rhesus monkeys and from age-matched monkeys that had different durations of spontaneously occurring type 2 diabetes. Age-related reductions occurred among all types of innervation, with epidermal C-fiber endings preferentially diminishing earlier than presumptive Adelta-fiber endings. In diabetic monkeys epidermal innervation density diminished faster, became more unevenly distributed, and lost immunodetectable expression of calcitonin gene-related peptide and capsaicin receptors, TrpV1. Pacinian corpuscles also deteriorated. However, during the first few years of hyperglycemia, a surprising hypertrophy occurred among terminal arbors of remaining epidermal endings. Hypertrophy also occurred among Meissner corpuscles and Merkel endings supplied by Abeta fibers. After longer-term hyperglycemia, Meissner corpuscle hypertrophy declined but the number of corpuscles remained higher than in age-matched nondiabetics. However, the diabetic Meissner corpuscles had an abnormal structure and immunochemistry. In contrast, the expanded Merkel innervation was reduced to age-matched nondiabetic levels. These results indicate that transient phases of substantial innervation remodeling occur during the progression of diabetes, with differential increases and decreases occurring among the varieties of innervation.

Intramuscular injection of islet neogenesis-associated protein peptide stimulates pancreatic islet neogenesis in healthy dogs.

OBJECTIVES: Diabetes is a serious health problem. It has been proposed that islet neogenesis from pancreatic progenitor cells may restore insulin secretion in diabetic mammals. Islet neogenesis- associated protein (INGAP) stimulates islet neogenesis; therefore, we hypothesized that it would stimulate islet neogenesis in dogs. METHODS: Forty nondiabetic beagle dogs were randomly divided into 4 groups. Group 1 received daily intramuscular injections of vehicle, whereas the other 3 groups received daily INGAP injections of 0.5, 1.5, or 10 mg/kg. After 30 days, pancreatic tissues were collected, and RNA and histological sections were analyzed. RESULTS: In dogs treated with 1.5 mg/kg INGAP, there was a significant (P < 0.001) increase in the percentage of insulin-positive cells (P < 0.001) and insulin gene expression. There was a trend to increased insulin-positive cells and gene expression with treatments of 0.5 and 10 mg/kg peptide. Protein gene product 9.5-positive cells were increased with treatment. CONCLUSIONS: These results indicate that INGAP stimulates cells in the pancreatic duct epithelium of healthy dogs (putative islet progenitor cells) to develop along a neuroendocrine pathway and form new islets in response to INGAP peptide. The INGAP might be an effective therapy for diabetes.

Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS).

OBJECTIVE: Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease. PATIENTS: Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests. RESULTS: All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation. CONCLUSIONS: Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.

PDX-1 can repress stimulus-induced activation of the INGAP promoter.

Islet neogenesis associated protein (INGAP) promotes the generation of new islet mass in adult animal models. It is not understood what factors control the expression of INGAP. In this study, factors that regulate the expression of INGAP promoter activity are reported. To determine factors that regulate INGAP expression, we previously cloned the promoter region for INGAP. Analysis of the INGAP promoter suggested that candidate regulators of INGAP expression include the transcription factors PDX-1, NeuroD, PAN-1, STAT and AP-1. Using gene addition experiments in the 293 cell line the activity of these transcription factors on an INGAP-promoter construct linked to the beta-galactosidase reporter has been determined. Induction of AP-1 activity or STAT activity using PMA or LIF stimulation respectively, or direct expression of PAN-1 specifically up-regulates INGAP promoter activity. In contrast, co-expression of PDX-1 but not NeuroD inhibits activation of the INGAP-promoter driven by PAN-1, PMA or LIF stimulation. PDX-1 binds directly to the INGAP promoter as determined in electromobility shift and antibody supershift assays. Expression of the INGAP-promoter-reporter construct in the HIT-T15 beta-cell line, a cell line that expresses endogenous PDX-1, did not reveal PMA-mediated stimulation of INGAP promoter activity. HIT-T15 cells however did efficiently transfect (> 68%) and respond (2-fold) to PMA-induced signal transduction to a transfected AP-1-CAT reporter. Partial reduction of PDX-1 expression in HIT-T15 cells was associated with recovery of PMA induced INGAP promoter activity. These data suggest that expression of PDX-1 is associated with a repression of stimulus-induced INGAP promoter activity that appears to be mediated by a direct DNA interaction. These findings implicate PDX-1 in a possible feedback loop to block unbridled islet expansion.

Small fiber neuropathy is associated with the metabolic syndrome.

BACKGROUND: The etiology of sensory neuropathies is often not found. We tested the hypothesis that the metabolic syndrome (MS) may be associated with painful neuropathy, in the absence of frank diabetes. METHODS: Clinical and quantitative neuropathy assessments were performed on 10 neuropathy patients with MS, 20 with MS with type 2 diabetes (10 recent onset and 10 of >5 years in duration), and 10 healthy, age-matched subjects. Intraepidermal nerve fiber density (IENF) and mean dendrite length (MDL) were determined by quantitative immunofluorescence on skin biopsies using antibody to PGP 9.5. RESULTS: In metabolic syndrome, MDL was reduced and correlated negatively with sensory symptoms, signs, HDL-C, and sural nerve amplitude. The strongest inverse metabolic correlate of the metabolic syndrome neuropathy was HDL-C, which also correlated negatively with sensory symptoms, signs, and sural nerve amplitudes. The strongest metabolic correlate of diabetic sensorimotor neuropathy was HbA1c, which was associated with reduced IENF in patients with >5 years in duration of disease as well as reduced peroneal nerve amplitudes. CONCLUSIONS: These data indicate that metabolic features, including HDL-C in metabolic syndrome, are associated with small fiber neuropathy and that MDL is an early marker of sensory neuropathy in patients with MS. Reductions in IENF reflect a longer duration of diabetes, with hyperglycemia leading to a sensorimotor neuropathy. These findings support the possibility that there is a sensory neuropathy with reduced intraepidermal nerve fiber length, which cosegregates with features of metabolic syndrome.

A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice.

OBJECTIVE: The objective of this study was to demonstrate that islet neogenesis-associated protein (INGAP) peptide, a pentadecapeptide containing the biologically active portion of native INGAP, increases functional beta-cell mass in normal animals and can be used therapeutically to reverse hyperglycemia in streptozotocin-induced diabetes. SUMMARY BACKGROUND DATA: INGAP, a 175 amino acid pancreatic acinar cell protein, has been suggested to be implicated in beta-cell mass expansion. METHODS: In the first part of this study, normoglycemic hamsters were administered either 500 microg INGAP peptide (n = 30) or saline (n = 20) intraperitoneally daily and sacrificed after 10 or 30 days of treatment. Blood glucose and insulin levels were measured, and a histologic and morphometric analysis of the pancreas was performed to determine the effect of INGAP peptide on the endocrine pancreas. In the second part of the study, 6- to 8-week-old C57BL/6J mice (n = 8) were administered multiple low doses of the beta-cell toxin streptozotocin (STZ) inducing insulitis and hyperglycemia. The mice were then injected with INGAP peptide (n = 4) or saline (n = 4) for 39 days and sacrificed at 48 days. Two additional groups of diabetic mice were administered either a peptide composed of a scrambled sequence of amino acids from INGAP peptide (n = 5) or exendin-4 (n = 5), an incretin that has been associated with amelioration of hyperglycemia. RESULTS: Islet cell neogenesis was stimulated in INGAP-treated hamsters by 10 days. At 30 days, the foci of new endocrine cells had the appearance of mature islets. There was a 75% increase in islet number, with normal circulating levels of blood glucose and insulin. Administration of INGAP peptide to diabetic mice reversed the diabetic state in all animals, and this was associated with increased expression of PDX-1 in duct cells and islet cell neogenesis with a reduction of insulitis in the new islets. Diabetic mice treated with exendin-4 or a scrambled INGAP peptide did not revert from hyperglycemia. CONCLUSION: Because there is a deficiency of beta-cell mass in both type-1 and type-2 diabetes, INGAP peptide stimulation of fully functional neoislet differentiation may provide a novel approach for diabetes therapy.

Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients.

OBJECTIVE: Small-fiber neuropathies may be symptomatic yet escape detection by standard tests. We hypothesized that morphologic changes in intraepidermal nerves would correlate with clinical measures of small-fiber neuropathy. RESEARCH DESIGN AND METHODS: We studied 25 diabetic and 23 nondiabetic patients with neuropathy defined by signs, symptoms, and quantitative testing and 20 control subjects. Skin biopsies were obtained from forearm, thigh, proximal leg, and distal leg, and nerves identified using immunofluorescence with antibody to protein gene product (PGP) 9.5. RESULTS: Mean dendritic length (MDL) (P < 0.01) and intraepidermal nerve fiber density (IENF) (P < 0.001) progressively decreased from proximal to distal sites only in patients with neuropathy. There was a significant reduction in IENF when comparing control subjects and patient groups in the distal leg (P < 0.001). MDL was significantly decreased in the thigh (P < 0.005) and in the proximal (P < 0.01) and distal (P < 0.002) leg in patients compared with control subjects. IENF was not significantly altered in diabetic patients of <5 years' duration, but significantly decreased in patients with >5 years' duration. MDL showed a linear decrease with increasing duration of diabetes. Distal leg IENF showed significant negative correlations with warm (P < 0.02) and cold (P < 0.05) thermal threshold, heat pain (P < 0.05), pressure sense (P < 0.05), and neurological disability score total sensory (P < 0.03) and total neuropathy (P < 0.03) values. CONCLUSIONS: IENF was not significantly altered in these patients at <5 years' duration of diabetes, but fell significantly after 5 years of diabetes. MDL exhibited a linear loss with time, suggesting a different mechanism of change. MDL and IENF together may prove a useful end point in therapeutic trials for neuropathy.

Advances in diabetes for the millennium: toward a cure for diabetes.

What does the future hold for the person with diabetes, since current therapies, including insulin, are all symptomatic and do not address the underlying biology? This article reviews the current state-of-the-art strategies aimed at curing diabetes. The central rationale to curing diabetes revolves around replacing the function of pancreatic islets, either directly through pancreatic/islet transplantation, indirectly through artificial pancreas/beta cells, or via a rebirth of islet function by reprogramming the body to create a new and expanded islet cell mass protected from further assault by autoimmune and other processes. All of these approaches are considered in context of their current status, progress, future challenges or limitations, and long-term prospects for a cure. Although the horizon is in the distance, the advances reviewed in this study predict the future to be bright, and whereas the prospect of islet neogenesis was once considered to be heretical, it is now quite fashionable amongst the scientific community.

Nerve growth factor and diabetic neuropathy.

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50-90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium.

Cloning genomic INGAP: a Reg-related family member with distinct transcriptional regulation sites.

The protein product of hamster islet neogenesis-associated protein (INGAP) cDNA induces new pancreatic islet development. Manipulation of this process provides a new therapeutic strategy for the treatment of diabetes. As regulators of INGAP gene expression are unknown over 6 kb of hamster genomic INGAP has been cloned. Sequence analysis has identified a 3 kb 5-prime region with core promoter elements that is rich in transcription factor binding sites and six exons for the coding region. Analysis of promoter activity reveals stimulus-responsive DNA elements which have been identified though deletion analysis. Comparison of transcription factor binding sites in INGAP to the related gene RegIIIdelta exposes potential sites for differential gene regulation.

Clinical case seminar: hypoglycemia after pancreas transplantation: association with allograft nesidiodysplasia and expression of islet neogenesis-associated peptide.

We report a case of severe hypoglycemia occurring in a 35-yr-old woman, 6 yr after pancreas transplantation for type 1 diabetes mellitus. Extensive preoperative and intraoperative exploration failed to disclose the presence of a focal adenomatous lesion. Partial allograft pancreatectomy was performed initially, but it failed to control the hypoglycemic symptoms, leading to complete removal of the pancreas allograft. Histopathological examination of the resected pancreas allograft showed the presence of nesidioblastosis, characterized by foci of islet cells budding off ducts, accompanied by an increase in the number of islets, numerous small intralobular islet cell aggregates, and nesidiodysplasia (large, hyperchromatic islet cell nuclei). Islet neogenesis-associated protein-positive islets and ducts were seen by immunofluorescence. Insulin-positive islets ranged from very small to large, with isolated insulin-positive cells diffusely scattered, consistent with islet neogenesis. Very little glucagon staining was identified. Reported cases of adult nesidioblastosis are reviewed. The significance of nesidioblastosis in the context of pancreas transplantation and possible mechanisms of posttransplant hypoglycemia are discussed.