Insulin Resistance Alters Islet Morphology in Nondiabetic Humans

Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell–to–α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes.     

Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet

Acetylcholine regulates hormone secretion from the pancreatic islet and is thus crucial for glucose homeostasis. Little is known, however, about acetylcholine (cholinergic) signaling in the human islet. We recently reported that in the human islet, acetylcholine is primarily a paracrine signal released from α-cells rather than primarily a neural signal as in rodent islets. In this study, we demonstrate that the effects acetylcholine produces in the human islet are different and more complex than expected from studies conducted on cell lines and rodent islets. We found that endogenous acetylcholine not only stimulates the insulin-secreting β-cell via the muscarinic acetylcholine receptors M3 and M5, but also the somatostatin-secreting δ-cell via M1 receptors. Because somatostatin is a strong inhibitor of insulin secretion, we hypothesized that cholinergic input to the δ-cell indirectly regulates β-cell function. Indeed, when all muscarinic signaling was blocked, somatostatin secretion decreased and insulin secretion unexpectedly increased, suggesting a reduced inhibitory input to β-cells. Endogenous cholinergic signaling therefore provides direct stimulatory and indirect inhibitory input to β-cells to regulate insulin secretion from the human islet.     

Suramin Inhibits Not Only Tumor Growth and Metastasis but Also Angiogenesis in Experimental Pancreatic Cancer

Suramin inhibits the proliferation of several human tumors in vivo and in vitro. In this study, the effects of Suramin on proliferation and angiogenesis were investigated in human pancreatic cancer cell lines and in an orthotopic nude mouse model of human pancreatic cancer. The effects of Suramin on proliferation, viability, cell cycle, and apoptosis were studied in five human pancreatic cancer cell lines. Suramin inhibited the proliferation of pancreatic cancer cells in a dose-dependent manner and reduced viability at high concentrations. Cell cycle analysis revealed a decreased S-phase fraction in most cell lines, whereas the apoptotic fraction was not notably different. In vivo treatment with Suramin significantly reduced pancreatic tumor size (MiaPaCa-2, −74%; AsPC-1, −41%; and Capan-1, −49%) and metastatic spread (MiaPaCa-2, −79%; AsPC-1, −34%; and Capan, −38%). As a parameter for angiogenic activity, vascular endothelial growth factor (VEGF) secretion was measured, revealing reduced VEGF concentrations under Suramin treatment in both cell culture medium and ascites. Also, microvessel density quantified in primary tumors was reduced in animals treated with Suramin. Therefore, Suramin inhibits the proliferation of human pancreatic cancer in vitro and in vivo. The therapeutic effects seem to involve cell cycle kinetics and may be in part related to the antiangiogenic action of the drug. Supported by the R.S. Hirshberg Foundation and the Deutsche Forschungsgemeinschaft (Grant HO 1843/2-1 & 1843/3-1).     

Central Resistin Overexposure Induces Insulin Resistance Through Toll-Like Receptor 4

Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. However, the resistin receptor and the molecular mechanisms mediating its effects in the hypothalamus, crucial for energy homeostasis control, and key insulin-sensitive tissues are still unknown. In the current study, we report that chronic resistin infusion in the lateral cerebral ventricle of normal rats markedly affects both hypothalamic and peripheral insulin responsiveness. Central resistin treatment inhibited insulin-dependent phosphorylation of insulin receptor (IR), AKT, and extracellular signal–related kinase 1/2 associated with reduced IR expression and with upregulation of suppressor of cytokine signaling-3 and phosphotyrosine phosphatase 1B, two negative regulators of insulin signaling. Additionally, central resistin promotes the activation of the serine kinases Jun NH₂-terminal kinase and p38 mitogen-activated protein kinase, enhances the serine phosphorylation of insulin receptor substrate-1, and increases the expression of the proinflammatory cytokine interleukin-6 in the hypothalamus and key peripheral insulin-sensitive tissues. Interestingly, we also report for the first time, to our knowledge, the direct binding of resistin to Toll-like receptor (TLR) 4 receptors in the hypothalamus, leading to the activation of the associated proinflammatory pathways. Taken together, our findings clearly identify TLR4 as the binding site for resistin in the hypothalamus and bring new insight into the molecular mechanisms involved in resistin-induced inflammation and insulin resistance in the whole animal.The hypothalamus integrates hormonal and metabolic signals to respond to energy body requirements through the regulation of energy homeostasis (1,2). The disruption of this regulatory loop promotes the onset of obesity, currently considered a worldwide epidemic. Obesity is linked to common metabolic diseases including insulin resistance, which constitutes a principal risk factor for type 2 diabetes (3–5). Accumulating evidence indicates that changes in adipose-secreted factors in obesity, including release of inflammatory cytokines, dramatically affect insulin sensitivity (3–7). Among these adipokines, resistin is described as a potential factor in obesity-mediated insulin resistance and type 2 diabetes. Resistin is a cysteine-rich 12.5-kDa polypeptide secreted by adipose tissue in rodents and by macrophages in humans (7,8), promoting inflammation and insulin resistance (9–12). Circulating resistin is increased in obese insulin-resistant rodents (6) and humans (7), and fasting decreases resistin mRNA expression (6,13). Peripheral administration or transgenic overexpression of resistin impairs insulin action in insulin-sensitive tissues (14–16). Conversely, deletion of the resistin gene or infusing of resistin antibodies or antisense oligonucleotides restores insulin responsiveness (6,17–19). In humans, recent studies have linked resistin to insulin resistance, atherosclerosis, and inflammation (12,20,21). More recently, it has been shown that resistin is expressed in the hypothalamus (22) and activates specific hypothalamic neurons (23). Central resistin also modulates glucose homeostasis, lipid metabolism, and food intake and impairs liver insulin sensitivity (24–27).Resistin also regulates the synthesis and secretion of key proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-6, and IL-12 in macrophages via a nuclear factor-κB–dependent pathway promoting insulin resistance (4,6,28,29). Moreover, recent studies have provided evidence for the contribution of Toll-like receptor-4 (TLR4) in the pathogenesis of obesity and insulin resistance. Saturated fatty acids activate both hypothalamic and peripheral TLR4 signaling, leading to proinflammatory cytokine production and endoplasmic reticulum stress (30–32). Conversely, TLR4 loss-of-function prevents saturated fatty acid-induced inflammation and insulin resistance (30,31,33). Resistin and TLR4 have been linked to a proinflammatory process in a human epithelial cell line in which resistin competes with lipopolysaccharide (LPS) for binding to TLR4 (34). Recently, an isoform of decorin was identified as a resistin receptor involved in white adipose tissue expansion (35). Another report has described that mouse resistin modulates glucose uptake and promotes adipogenesis in 3T3-L1 cells through the receptor tyrosine kinase-like orphan receptor-1 (36). In addition, in rheumatoid arthritis disease, resistin has been shown to use the IGF-1R signaling pathway (37). These data reveal a puzzling situation in which resistin could potentially interact with different receptors depending upon cellular model. However, in vivo at the neuronal level, the resistin receptor and its signaling have not yet been identified.Thus, we aimed to characterize hypothalamic resistin receptor and its signaling pathways involved in the impairment of insulin responsiveness. We show that resistin signals through TLR4 in the hypothalamus lead to the activation of Jun NH₂-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways by the recruitment of the adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP), promoting overall inflammation. These findings reveal strong evidence for the direct role of hypothalamic TLR4 signal transduction in resistin-induced whole-body inflammation and insulin resistance.     

Lipid-Induced Insulin Resistance Is Not Mediated by Impaired Transcapillary Transport of Insulin and Glucose in Humans

Increased lipid availability reduces insulin-stimulated glucose disposal in skeletal muscle, which is generally explained by fatty acid–mediated inhibition of insulin signaling. It remains unclear whether lipids also impair transcapillary transport of insulin and glucose, which could become rate controlling for glucose disposal. We hypothesized that lipid-induced insulin resistance is induced by inhibiting myocellular glucose uptake and not by interfering with the delivery of insulin or glucose. We measured changes in interstitial glucose and insulin in skeletal muscle of healthy volunteers during intravenous administration of triglycerides plus heparin or glycerol during physiologic and supraphysiologic hyperinsulinemia, by combining microdialysis with oral glucose tolerance tests and euglycemic-hyperinsulinemic clamps. Lipid infusion reduced insulin-stimulated glucose disposal by ∼70% (P < 0.05) during clamps and dynamic insulin sensitivity by ∼12% (P < 0.05) during oral glucose loading. Dialysate insulin and glucose levels were unchanged or even transiently higher (P < 0.05) during lipid than during glycerol infusion, whereas regional blood flow remained unchanged. These results demonstrate that short-term elevation of free fatty acids (FFAs) induces insulin resistance, which in skeletal muscle occurs primarily at the cellular level, without impairment of local perfusion or transcapillary transport of insulin and glucose. Thus, vascular effects of FFAs are not rate controlling for muscle insulin-stimulated glucose disposal.Skeletal muscle accounts for the majority of glucose uptake after a meal and almost all glucose disposal during hyperinsulinemic-euglycemic clamps (1). In type 2 diabetes (T2DM), muscle insulin resistance predicts postprandial hyperglycemia, but the underlying mechanisms are unclear. Insulin-resistant humans frequently present with increased plasma free fatty acids (FFAs) (2), which can give rise to myocellular diacylglycerols or ceramides and impair insulin signaling (3–5). Insulin increases muscle microvascular perfusion and facilitates delivery of nutrients and hormones to the interstitium (6). Animal models of lipid-induced insulin resistance suggest that insulin-mediated microvascular perfusion is already reduced in prediabetic states and relates to impaired insulin action (7,8). Preventing the access of glucose and insulin to myocytes could contribute to lower glucose disposal and place abnormal microvascular insulin action as an early event in the development of T2DM.We hypothesized that lipid-induced insulin resistance results from myocellular glucose uptake, but not from impaired delivery of insulin or glucose to the interstitium. We monitored changes of interstitial insulin and glucose in muscle of humans during intravenous triglycerides or glycerol administration under physiologic dynamic (oral glucose tolerance test [OGTT]) and supraphysiologic constant hyperinsulinemic (clamp) conditions.     

Vascular Endothelial Growth Factor-A and Islet Vascularization Are Necessary in Developing,but Not Adult,Pancreatic Islets

Pancreatic islets are highly vascularized mini-organs, and vascular endothelial growth factor (VEGF)-A is a critical factor in the development of islet vascularization. To investigate the role of VEGF-A and endothelial cells (ECs) in adult islets, we used complementary genetic approaches to temporally inactivate VEGF-A in developing mouse pancreatic and islet progenitor cells or in adult β-cells. Inactivation of VEGF-A early in development dramatically reduced pancreatic and islet vascularization, leading to reduced β-cell proliferation in both developing and adult islets and, ultimately, reduced β-cell mass and impaired glucose clearance. When VEGF-A was inactivated in adult β-cells, islet vascularization was reduced twofold. Surprisingly, even after 3 months of reduced islet vascularization, islet architecture and β-cell gene expression, mass, and function were preserved with only a minimal abnormality in glucose clearance. These data show that normal pancreatic VEGF-A expression is critical for the recruitment of ECs and the subsequent stimulation of endocrine cell proliferation during islet development. In contrast, although VEGF-A is required for maintaining the specialized vasculature observed in normal adult islets, adult β-cells can adapt and survive long-term reductions in islet vascularity. These results indicate that VEGF-A and islet vascularization have a lesser role in adult islet function and β-cell mass.The pancreatic islets are endocrine mini-organs with a specialized vasculature. Islets are highly vascularized, with a dense network of capillaries that are thicker and more tortuous than vessels of the exocrine tissue (1). While islets occupy only a small volume of the pancreas, they receive a disproportionally greater fraction of pancreatic blood flow (2,3). Ultrastructurally, islets have a fenestrated endothelium, which allows for the rapid exchange of nutrients and hormones between endocrine cells and the bloodstream (1,4,5). This highly vascularized state leads to a greater partial oxygen pressure in islets than in exocrine tissue (6). The polyhedral β-cells appear to have multiple faces contacting blood vessels, and hypoxia impairs glucose-stimulated insulin secretion (7,8). Furthermore, the islet vasculature and the ECs near or in the developing pancreas and islet provide critically important instructive signals necessary for islet formation and β-cell differentiation (9,10).Much work to understand the mechanisms directing normal islet vascularization has focused on the role of islet-derived angiogenic factors. Islet endocrine cells produce multiple factors from the VEGF, angiopoietin, and ephrin families, with VEGF-A being the predominant regulator of islet angiogenesis and vascularization. When VEGF-A is inactivated either in the early pancreas (5) or in newly formed β-cells (1), the intraislet capillary plexus fails to fully mature, resulting in substantial defects in insulin secretion and glucose intolerance. In contrast, overexpression of VEGF-A in developing pancreata (11) or β-cells (12) is detrimental to endocrine cell differentiation and islet formation. Therefore, VEGF-A expression must be precisely controlled in the developing pancreas for proper islet development and long-term glucose homeostasis.While existing genetic mouse models demonstrated a role for VEGF-A and ECs in islet formation, the precise role of VEGF-A in adult islets is unclear. Prior studies inactivated VEGF-A during embryogenesis, thus making it difficult to identify which phenotypes resulted from developmental defects and which reflected the role of VEGF-A and ECs in adult islets. In an alternate approach, VEGF signaling inhibitors administered to adult mice demonstrated the importance of VEGF-A in maintaining the islet vascular density and permeability (13). However, the effects of VEGF inhibitors on the vasculature of multiple tissues prevented a full understanding of the role of ECs in established islets.To investigate the role of VEGF-A and ECs in adult islet function, we used complementary genetic approaches to temporally inactivate VEGF-A in developing pancreatic and islet progenitors or in adult β-cells using a tamoxifen (Tm)-inducible Cre-loxP system. We found that adult pancreatic β-cells tolerated a significant and prolonged reduction in intraislet capillary density and still maintained relatively normal function. By comparison, inactivation of VEGF-A in early pancreas development resulted in hypovascularized islets with a sustained reduction in β-cell proliferation and mass. These data indicate that VEGF-A plays distinctive roles in developing and adult pancreatic islets.     

Inflammatory Blockade Improves Human Pancreatic Islet Function and Viability

The pathogenesis of pancreatic beta-cell death in diabetes mellitus is still under investigation. Inflammation is likely to be one of the factors responsible for beta-cell death during disease development. In this study, we have used a novel antiinflammatory compound, Lisofylline (LSF), to investigate the role of inflammatory blockade in protecting human pancreatic islets. LSF is a small synthetic molecule that reduces inflammatory cytokine production and action, improves beta-cell mitochondrial metabolism, and regulates immune activities. The present study has demonstrated that the treatment of human islets with LSF not only allows the retention of glucose responsiveness and insulin secretion in the presence of multiple proinflammatory cytokines, but also enhances basal insulin secretion of beta cells in vitro. LSF also significantly reduces islet apoptosis, protects beta cells from proinflammatory cytokine damage, and maintains cellular viability. In a mouse transplantation model, insulin independence could be reached in diabetic recipient mice by implantation of 30% fewer islets when LSF was used in islet culture compared to the control group. These results demonstrate that LSF profoundly enhances beta-cell function, and suggest the potential of using inflammatory blockade, such as LSF, to improve beta-cell function for islet transplantation.     

Metabolic Profile of Pancreatic Acinar and Islet Tissue in Culture

Background

The amount and condition of exocrine impurities may affect the quality of islet preparations, especially during culture. In this study, the objective was to determine the oxygen demand and viability of islet and acinar tissue post-isolation and whether they change disproportionately while in culture.

Method

We compared the oxygen consumption rate (OCR) normalized to DNA (OCR/DNA, a measure of fractional viability in units of nmol/min/mg DNA), and the percent change in OCR and DNA recoveries between adult porcine islet and acinar tissue from the same preparation (paired) over 6–9 days of standard culture. Paired comparisons were done to quantify differences in OCR/DNA between islet and acinar tissue from the same preparation, at specified time points during culture.

Results

The mean (±SE) OCR/DNA was 74.0 ± 11.7 units higher for acinar (vs islet) tissue on the day of isolation (n = 16, P < .0001), but 25.7 ± 9.4 units lower after 1 day (n = 8, P = .03), 56.6 ± 11.5 units lower after 2 days (n = 12, P = .0004), and 65.9 ± 28.7 units lower after 8 days (n = 4, P = .2) in culture. DNA and OCR recoveries decreased at different rates for acinar versus islet tissue over 6–9 days in culture (n = 6). DNA recovery decreased to 24 ± 7% for acinar and 75 ± 8% for islets (P = .002). Similarly, OCR recovery decreased to 16 ± 3% for acinar and remained virtually constant for islets (P = .005).

Conclusion

Differences in the metabolic profile of acinar and islet tissue should be considered when culturing impure islet preparations. OCR-based measurements may help optimize pre–islet transplantation culture protocols.     

Disseminated Intravascular Coagulation and Portal Hypertension Following Pancreatic Islet Autotransplantation

A patient undergoing subtotal pancreatectomy and intraportal islet tissue autotransplantation for chronic pancreatitis developed severe portal hypertension (49 cm of H₂O) and acute disseminated intravascular coagulation (DIC). In an attempt to identify the cause of these problems, portal pressure and the activities of the coagulation and fibrinolytic systems were studied in dogs undergoing intraportal autotransplantation of islet tissue. Following intraportal injection of the pancreatic tissue in five control dogs, the portal pressure rose to a maximum of 43.2 cm of H₂O ± 2.4 and major coagulation abnormalities occurred. The mean hematocrit value fell to 18% ± 8.6, the mean platelet count to 218,000 ± 31,000, the mean plasma fibrinogen to 40 mg/dl ± 18, and the mean euglobulin clot lysis time (ECLT) to 25 min ± 4. Partial thromboplastin time (PTT) became prolonged (233 secs ± 30) and significant quantities of fibrinogen-fibrin degradation products (FDP-fdp) (1:128 ± 32) appeared. These changes indicate the development of DIC probably secondary to significant amounts of tissue thromboplastin detected in the tissue homogenate infused at time of autotransplantation. In a group of seven dogs in whom heparin and Trasylol (aprotinin) were added to the pancreatic tissue at the time of transplantation, portal pressure rose only to a peak of 28.3 cm of H₂O ± 3.6 and no significant abnormalities occurred in mean hematocrit value, plasma fibrinogen, platelet count or ECLT. Minor prolongation of PTT occurred secondary to the activity of heparin. FDP-fdp (1:16) were present transiently during tissue injection. Four patients in whom heparin and Trasylol were added to the pancreatic tissue at the time of autotransplantation developed only minor elevations of portal pressure (mean 15.5 cm of H₂O) without intravascular coagulopathy.     

Mitochondrial Efflux of Citrate and Isocitrate Is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function

The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. The mitochondrial export of citrate and isocitrate through the citrate-isocitrate carrier (CIC) has been suggested to initiate a key pathway that amplifies glucose-stimulated insulin secretion, though the physiological significance of β-cell CIC-to-glucose homeostasis has not been established. Here, we generated constitutive and adult CIC β-cell knockout (KO) mice and demonstrate that these animals have normal glucose tolerance, similar responses to diet-induced obesity, and identical insulin secretion responses to various fuel secretagogues. Glucose-stimulated NADPH production was impaired in β-cell CIC KO islets, whereas glutathione reduction was retained. Furthermore, suppression of the downstream enzyme cytosolic isocitrate dehydrogenase (Idh1) inhibited insulin secretion in wild-type islets but failed to impact β-cell function in β-cell CIC KO islets. Our data demonstrate that the mitochondrial CIC is not required for glucose-stimulated insulin secretion and that additional complexities exist for the role of Idh1 and NADPH in the regulation of β-cell function.     

Failure of Homeostatic Model Assessment of Insulin Resistance to Detect Marked Diet-Induced Insulin Resistance in Dogs

Accurate quantification of insulin resistance is essential for determining efficacy of treatments to reduce diabetes risk. Gold-standard methods to assess resistance are available (e.g., hyperinsulinemic clamp or minimal model), but surrogate indices based solely on fasting values have attractive simplicity. One such surrogate, the homeostatic model assessment of insulin resistance (HOMA-IR), is widely applied despite known inaccuracies in characterizing resistance across groups. Of greater significance is whether HOMA-IR can detect changes in insulin sensitivity induced by an intervention. We tested the ability of HOMA-IR to detect high-fat diet–induced insulin resistance in 36 healthy canines using clamp and minimal model analysis of the intravenous glucose tolerance test (IVGTT) to document progression of resistance. The influence of pancreatic function on HOMA-IR accuracy was assessed using the acute insulin response during the IVGTT (AIR_G). Diet-induced resistance was confirmed by both clamp and minimal model (P < 0.0001), and measures were correlated with each other (P = 0.001). In striking contrast, HOMA-IR ([fasting insulin (μU/mL) × fasting glucose (mmol)]/22.5) did not detect reduced sensitivity induced by fat feeding (P = 0.22). In fact, 13 of 36 animals showed an artifactual decrease in HOMA-IR (i.e., increased sensitivity). The ability of HOMA-IR to detect diet-induced resistance was particularly limited under conditions when insulin secretory function (AIR_G) is less than robust. In conclusion, HOMA-IR is of limited utility for detecting diet-induced deterioration of insulin sensitivity quantified by glucose clamp or minimal model. Caution should be exercised when using HOMA-IR to detect insulin resistance when pancreatic function is compromised. It is necessary to use other accurate indices to detect longitudinal changes in insulin resistance with any confidence.     

胰岛素抵抗综合征与麻醉

1胰岛素抵抗和胰岛素抵抗综合征 胰岛素抵抗（insulin resistance，IR）是胰岛素协助机体靶细胞（包括肝细胞、肌细胞、脂肪细胞和血管内皮细胞）摄取和利用葡萄糖的能力低下，即生理剂量的胰岛素产生低于正常生物学效应的一种状态。在早中期，机体为克服高血糖，往往代偿性分泌过多胰岛素，     

Donor Height in Combination With Islet Donor Score Improves Pancreas Donor Selection for Pancreatic Islet Isolation and Transplantation

To maximize the islet isolation yield for successful islet transplantation, the key task has been to identify an ideal pancreas donor. Since implementation of the islet donor score in donor selection, we have consistently obtained higher islet yields and transplantation rates. In this study, we tested whether assessing donor height as an independent variable in combination with the donor score could improve the pancreas donor selection. Donor and islet isolation information (n = 22) were collected and studied between 2011 and 2012. Pearson correlation analysis was used in statistical analysis. Donor height as an independent variable was significantly correlated to the weight of the pancreas, pre-Islet Equivalents (pre-IEQ), post-IEQ, and IDS (P < .05). When donor with height of 179 cm ± 3 was selected in combination with IDS > 80, the clinical islet transplantation rate reached 80%.     

Islet Heparan Sulfate but Not Heparan Sulfate Proteoglycan Core Protein Is Lost During Islet Isolation and Undergoes Recovery Post‐Islet Transplantation

Islet beta cells in situ express intracellular heparan sulfate (HS), a property previously shown in vitro to be important for their survival. We report that HS levels inside islet beta cells correlate with the novel intracellular localization of the HSPG core proteins for collagen type XVIII (Col18), a conventional extracellular matrix component. Syndecan‐1 (Sdc1) and CD44 core proteins were similarly localized inside beta cells. During isolation, mouse islets selectively lose HS to 11–27% of normal levels but retain their HSPG core proteins. Intra‐islet HS failed to recover substantially during culture for 4 days and was not reconstituted in vitro using HS mimetics. In contrast, significant recovery of intra‐islet HS to ～40–50% of normal levels occurred by 5–10 days after isotransplantation. Loss of islet HS during the isolation procedure is independent of heparanase (a HS‐degrading endoglycosidase) and due, in part, to oxidative damage. Treatment with antioxidants reduced islet cell death by ～60% and increased the HS content of isolated islets by ～twofold compared to untreated islets, preserving intra‐islet HS to ～60% of the normal HS content of islets in situ. These findings suggest that the preservation of islet HS during the islet isolation process may optimize islet survival posttransplant.     

Gastric Bypass for Insulin Resistance due to Lipodystrophy

We report a 41-year-old woman with severe insulin resistance due to partial lipodystrophy, who was successfully treated with gastric bypass surgery.