Insulin, glucagon and somatostatin stores in the pancreas of subjects with type-2 diabetes and their lean and obese non-diabetic controls.

In type-2 diabetes, both insufficient insulin and excessive glucagon secretion contribute to hyperglycemia. We compared insulin, glucagon and somatostatin stores in pancreas obtained at autopsy of 20 lean and 19 obese non-diabetic (ND), and 18 type-2 diabetic (T2D) subjects. From concentrations and pancreas weight, total content of hormones was calculated. Insulin content was 35% lower in T2D than ND subjects (7.4 versus 11.3 mg), whereas glucagon content was similar (0.76 versus 0.81 mg). The higher ratio of glucagon/insulin contents in T2D was thus explained by the decrease in insulin. With increasing BMI of ND subjects, insulin and glucagon contents respectively tended to increase and decrease, resulting in a lower glucagon/insulin ratio in obesity. With aging, insulin and glucagon contents did not significantly change in ND subjects but declined in T2D subjects, without association with the duration of diabetes or type of treatment. The somatostatin content was lower in T2D than ND subjects (0.027 versus 0.038 mg), but ratios somatostatin/insulin and somatostatin/glucagon were not different. In conclusion, insulin stores are about 1/3 lower in T2D than ND subjects, whereas glucagon stores are unchanged. Abnormal secretion of each hormone in type-2 diabetes cannot be attributed to major alterations in their pancreatic reserves.

Relevance of activated hepatic stellate cells in predicting the development of pediatric liver allograft fibrosis.

Activated hepatic stellate cells (HSCs) are the main collagen-producing cells in liver fibrogenesis. With the purpose of analyzing their presence and relevance in predicting liver allograft fibrosis development, 162 liver biopsies of 54 pediatric liver transplantation (LT) recipients were assessed at 6 months, 3 years, and 7 years after LT. The proportion of activated HSCs, identified by α-smooth muscle actin (ASMA) immunostaining, and the amount of fibrosis, identified by picrosirius red (PSR%) staining, were determined by computer-based morphometric analysis. Fibrosis was also staged by using the semiquantitative liver allograft fibrosis score (LAFSc), specifically designed to score fibrosis in the pediatric LT population. Liver allograft fibrosis displayed progression over time by PSR% (P < 0.001) and by LAFSc (P < 0.001). The ASMA expression decreased in the long term, with inverse evolution with respect to fibrosis (P < 0.01). Patients with ASMA-positive HSCs area ≥ 8% at 6 months (n = 20) developed a higher fibrosis proportion compared to those with ASMA-positive HSCs area ≤ 8% (n = 34) at the same period of time and in the long term (P = 0.03 and P < 0.01, respectively), but not at 3 years (P = 0.8). ASMA expression ≥ 8% at 6 months was found to be an independent risk factor for 7-year fibrosis development by PSR% (r(2) = 0.5; P < 0.01) and by LAFSc (r(2) = 0.3; P = 0.03). Furthermore, ASMA expression ≥ 8% at 3 years showed an association with the development of fibrosis at 7 years (P = 0.02). In conclusion, there is a high proportion of activated HSCs in pediatric LT recipients. ASMA ≥ 8% at 6 months seems to be a risk factor for early and longterm fibrosis development. In addition, activated HSCs showed inverse evolution with respect to fibrosis in the long term. Liver Transplantation 22 822-829 2016 AASLD.

Heterozygous inactivation of plasma membrane Ca(2+)-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability.

AIMS/HYPOTHESIS: Calcium plays an important role in the process of glucose-induced insulin release in pancreatic beta cells. These cells are equipped with a double system responsible for Ca(2+) extrusion--the Na/Ca exchanger (NCX) and the plasma membrane Ca(2+)-ATPase (PMCA). We have shown that heterozygous inactivation of NCX1 in mice increased glucose-induced insulin release and stimulated beta cell proliferation and mass. In the present study, we examined the effects of heterozygous inactivation of the PMCA on beta cell function. METHODS: Biological and morphological methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release and immunohistochemistry) were used to assess beta cell function and proliferation in Pmca2 (also known as Atp2b2) heterozygous mice and control littermates ex vivo. Blood glucose and insulin levels were also measured to assess glucose metabolism in vivo. RESULTS: Pmca (isoform 2) heterozygous inactivation increased intracellular Ca(2+) stores and glucose-induced insulin release. Moreover, increased beta cell proliferation, mass, viability and islet size were observed in Pmca2 heterozygous mice. However, no differences in beta cell glucose metabolism, proinsulin immunostaining and insulin content were observed. CONCLUSIONS/INTERPRETATION: The present data indicates that inhibition of Ca(2+) extrusion from the beta cell and its subsequent intracellular accumulation stimulates beta cell function, proliferation and mass. This is in agreement with our previous results observed in mice displaying heterozygous inactivation of NCX, and indicates that inhibition of Ca(2+) extrusion mechanisms by small molecules in beta cells may represent a new approach in the treatment of type 1 and type 2 diabetes.

Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro.

Insulinomas are ß-cell tumors that cause hypoglycemia through inappropriate secretion of insulin. Characterization of the in vitro dynamics of insulin secretion by perifused fragments of 10 human insulinomas permitted their subdivision into three functional groups with similar insulin content. Group A (four patients with fasting and/or postprandial hypoglycemic episodes) showed qualitatively normal responses to glucose, leucine, diazoxide, tolbutamide, and extracellular CaCl2 omission or excess. The effect of glucose was concentration dependent, but, compared with normal islets, insulin secretion was excessive in both low- and high-glucose conditions. Group B (three patients with fasting hypoglycemic episodes) was mainly characterized by large insulin responses to 1 mmol/L glucose, resulting in very high basal secretion rates that were inhibited by diazoxide and restored by tolbutamide but were not further augmented by other agents except for high levels of CaCl2. Group C (three patients with fasting hypoglycemic episodes) displayed very low rates of insulin secretion and virtually no response to stimuli (including high CaCl2 concentration) and inhibitors (CaCl2 omission being paradoxically stimulatory). In group B, the presence of low-Km hexokinase-I in insulinoma ß-cells (not in adjacent islets) was revealed by immunohistochemistry. Human insulinomas thus show distinct, though not completely heterogeneous, defects in insulin secretion that are attributed to the undue expression of hexokinase-I in 3 of 10 patients.

Cyclin D1 in well differentiated thyroid tumour of uncertain malignant potential.

BACKGROUND: Encapsulated follicular tumours with equivocal papillary thyroid carcinoma (PTC) type nuclear features continue to remain a challenge despite the recent attempts to classify these borderline lesions. The term 'well differentiated tumour of uncertain malignant potential (WDT-UMP)' was introduced to classify these tumours. The present study aimed to evaluate the role of a cell cycle regulator like cyclin D1 in these tumours along with assessment of other well established PTC markers like galectin-3, HBME-1, CK19. METHODS: Thirteen cases of metastatic PTC, papillary microcarcinoma and follicular variant of PTC (FVPTC) were identified from a histological review of 510 cases. In addition, 13 cases of a subset of follicular adenomatoid nodules with focal areas showing nuclear features characteristic of PTC, identified as WDT-UMP, were also analyzed. Immunohistochemical analysis of galectin-3, HBME-1, CK19 and the proliferation markers Ki67 and cyclin D1 was performed. Lesions were analyzed for cyclin D1 gene amplification by fluorescent in-situ hybridization. RESULTS: All WDT-UMP lesions showed immunolabelling of cyclin D1, Ki67; 11/ 13 cases showed immunolabelling of CK19; 10/13 cases showed immunolabelling of HBME-1 and 4/13 cases showed immunolabelling of galectin-3. Surrounding benign adenomatoid areas showed no to faint focal staining in all thirteen cases of cyclin D1, HBME-1 and galectin-3. A low rate of cyclin D1 gene amplification was identified in a significant proportion of cells in the WDT-UMP lesions as compared to surrounding benign adenomatoid areas. CONCLUSIONS: Increased expression of cyclin D1 and amplification of its gene along with immunolabelling of HBME-1 in WDT-UMP lesions showing cytological features of papillary thyroid carcinoma within follicular adenomatoid nodules suggest that these areas could correspond to a precursor lesion of follicular variant of PTC. Overexpression of cyclin D1, associated with the amplification of the gene suggests that these WDT-UMP lesions are an intermediate between the benign and malignant groups making this group of lesions a reliable precursor of FVPTC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1851820807142117.

Increased plasma incretin concentrations identifies a subset of patients with persistent congenital hyperinsulinism without KATP channel gene defects.

Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology.

Focal congenital hyperinsulinism managed by medical treatment: a diagnostic algorithm based on molecular genetic screening.

OBJECTIVE: Congenital hyperinsulinism (CHI) requires rapid diagnosis and treatment to avoid irreversible neurological sequelae due to hypoglycaemia. Aetiological diagnosis is instrumental in directing the appropriate therapy. Current diagnostic algorithms provide a complete set of diagnostic tools including (i) biochemical assays, (ii) genetic facility and (iii) state-of-the-art imaging. They consider the response to a therapeutic diazoxide trial an early, crucial step before proceeding (or not) to specific genetic testing and eventually imaging, aimed at distinguishing diffuse vs focal CHI. However, interpretation of the diazoxide test is not trivial and can vary between research groups, which may lead to inappropriate decisions. Objective of this report is proposing a new algorithm in which early genetic screening, rather than diazoxide trial, dictates subsequent clinical decisions. PATIENTS, METHODS AND RESULTS: Two CHI patients weaned from parenteral glucose infusion and glucagon after starting diazoxide. No hypoglycaemia was registered during a 72-h continuous glucose monitoring (CGMS), or hypoglycaemic episodes were present for no longer than 3% of 72-h. Normoglycaemia was obtained by low-medium dose diazoxide combined with frequent carbohydrate feeds for several years. We identified monoallelic, paternally inherited mutations in KATP channel genes, and (18) F-DOPA PET-CT revealed a focal lesion that was surgically resected, resulting in complete remission of hypoglycaemia. CONCLUSIONS: Although rare, some patients with focal lesions may be responsive to diazoxide. As a consequence, we propose an algorithm that is not based on a 'formal' diazoxide response but on genetic testing, in which patients carrying paternally inherited ABCC8 or KCNJ11 mutations should always be subjected to (18) F-DOPA PET-CT.

The expression of dual oxidase, thyroid peroxidase, and caveolin-1 differs according to the type of immune response (TH1/TH2) involved in thyroid autoimmune disorders.

CONTEXT: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are thyroid autoimmune disorders driven by Th1 and Th2 immune responses, respectively. Caveolin-1 (Cav-1), thyroid peroxidase (TPO), and dual oxidase (DUOX) are thought to be part of the thyroxisome, which is essential to maintain thyroid hormone synthesis, at the apical membrane. OBJECTIVES: To analyze the thyroxisome in HT and GD thyroids, we investigated Cav-1, DUOX, and TPO expression as well as markers of oxidative stress (OS), cell proliferation, apoptosis, and antioxidant defenses. The effects of cytokines on Cav-1 expression were analyzed in vitro. RESULTS: In HT, the decrease in Cav-1, DUOX, and TPO expression was marked in follicles having the morphological aspect of active follicles in normal glands and thus called active-like follicles. T4 was not detected in the colloid but in the cytoplasm as well as DUOX and TPO. These abnormalities were associated with increased OS and cell damage. In the hypofunctioning follicles of HT and normal thyroids, Cav-1, DUOX, and TPO were not expressed. In GD, they were expressed at the apical pole of thyrocytes, and T4 accumulated in the colloid of all follicles. Th1 cytokines IL-1α/interferonγ decreased Cav-1 expression in vitro, whereas the Th2 cytokine IL-4 had no effect. CONCLUSION: Th1 cytokine-induced down-regulation of Cav-1 could be responsible for intracytoplasmic T4 synthesis and mislocalization of DUOX and TPO, suggesting an important role for Cav-1 in the preservation of thyroxisome integrity. The thyroxisome's disruption, leading to uncontrolled OS and cell apoptosis, is a key, event in HT pathogenesis.

Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of ß-cells.

Congenital hyperinsulinism causes persistent hypoglycemia in neonates and infants. Most often, uncontrolled insulin secretion (IS) results from a lack of functional K(ATP) channels in all ß-cells or only in ß-cells within a resectable focal lesion. In more rare cases, without K(ATP) channel mutations, hyperfunctional islets are confined within few lobules, whereas hypofunctional islets are present throughout the pancreas. They also can be cured by selective partial pancreatectomy; however, unlike those with a K(ATP) focal lesion, they show clinical sensitivity to diazoxide. Here, we characterized in vitro IS by fragments of pathological and adjacent normal pancreas from six such cases. Responses of normal pancreas were unremarkable. In pathological region, IS was elevated at 1 mmol/L and was further increased by 15 mmol/L glucose. Diazoxide suppressed IS and tolbutamide antagonized the inhibition. The most conspicuous anomaly was a large stimulation of IS by 1 mmol/L glucose. In five of six cases, immunohistochemistry revealed undue presence of low-K(m) hexokinase-I in ß-cells of hyperfunctional islets only. In one case, an activating mutation of glucokinase (I211F) was found in pathological islets only. Both abnormalities, attributed to somatic genetic events, may account for inappropriate IS at low glucose levels by a subset of ß-cells. They represent a novel cause of focal congenital hyperinsulinism.

Commentary: "Cirrhosis or not cirrhosis": should we discontinue the term?

Clinicians and pathologists are moving beyond the term cirrhosis, refining the description of this entity in parallel with a better understanding of its complexity. The objective is to accurately reflect patients' prognosis and consequently determine individual treatment and follow-up appropriately.

Correlation of tacrolimus levels in peripheral blood mononuclear cells with histological staging of rejection after liver transplantation: preliminary results of a prospective study.

Therapeutic drug monitoring of tacrolimus (TAC) is characterized by a complex relationship between trough blood TAC concentrations and therapeutic efficacy. This prospective study evaluates the predictive value of intrahepatic, peripheral blood mononuclear cells (PBMCs) and blood TAC concentrations during the early postliver transplantation (LT) period. In a cohort of 90 adult liver recipients under TAC-based monotherapy, liver biopsies were performed at day 7 post-LT, and PBMCs TAC concentrations were measured at day 1, 3, 5, and 7 post-LT. Both intrahepatic and PBMCs TAC concentrations were determined. All biopsies were graded following the Banff scoring. Intrahepatic, and day 3, 5, 7 PBMCs concentrations correlated very well with day 7 liver Banff rejection scores (P < 0.05). Clinical rejection was characterized by significantly lower mean TAC PBMCs concentrations at day 5 and 7 (P < 0.05) and tended to be associated to lower mean intrahepatic TAC concentrations at day 7 (P = 0.059). Intrahepatic TAC concentrations at day 7 significantly correlated with TAC PBMCs concentrations from day 5 post-LT (P < 0.05). TAC PBMCs concentrations might be reliable markers of immunosuppression efficacy during the early phase after LT. This finding could represent an additional tool to individualize more precisely early immunosuppressive schemes after liver transplantation.

Glucose metabolism in 105 children and adolescents after pancreatectomy for congenital hyperinsulinism.

OBJECTIVE: To describe the long-term metabolic outcome of children with congenital hyperinsulinism after near-total or partial elective pancreatectomy. RESEARCH DESIGN AND METHODS: Patients (n = 105: 58 diffuse and 47 focal congenital hyperinsulinism) received operations between 1984 and 2006. Follow-up consisted of periodic measurements of pre- and postprandial plasma glucose over 24 h, OGTT, and IVGTT. Cumulative incidence of hypo- or hyperglycemia/insulin treatment was estimated by Kaplan-Meier analysis. RESULTS: After near-total pancreatectomy, 59% of children with diffuse congenital hyperinsulinism still presented mild or asymptomatic hypoglycemia that responded to medical treatments and disappeared within 5 years. One-third of the patients had both preprandial hypoglycemia and postprandial hyperglycemia. Hyperglycemia was found in 53% of the patients immediately after surgery; its incidence increased regularly to 100% at 13 years. The cumulative incidence of insulin-treated patients was 42% at 8 years and reached 91% at 14 years, but the progression to insulin dependence was very variable among the patients. Plasma insulin responses to IVGTT and OGTT correlated well with glycemic alterations. In focal congenital hyperinsulinism, hypoglycemia or hyperglycemia were rare, mild, and transient. CONCLUSIONS: Patients with focal congenital hyperinsulinism are cured of hypoglycemia after limited surgery, while the outcome of diffuse congenital hyperinsulinism is very variable after near-total pancreatectomy. The incidence of insulin-dependent diabetes is very high in early adolescence.

In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions.

Congenital hyperinsulinism (CHI) is the major cause of persistent neonatal hypoglycemia. CHI most often occurs due to mutations in the ABCC8 (which encodes sulfonylurea receptor 1) or KCNJ11 (which encodes the potassium channel Kir6.2) gene, which result in a lack of functional KATP channels in pancreatic ß cells. Diffuse forms of CHI (DiCHI), in which all ß cells are abnormal, often require subtotal pancreatectomy, whereas focal forms (FoCHI), which are characterized by localized hyperplasia of abnormal ß cells, can be cured by resection of the lesion. Here, we characterized the in vitro kinetics of insulin secretion by pancreatic fragments from 6 DiCHI patients and by focal lesion and normal adjacent pancreas from 18 FoCHI patients. Responses of normal pancreas were similar to those reported for islets from adult organ donors. Compared with normal pancreas, basal insulin secretion was elevated in both FoCHI and DiCHI tissue. Affected tissues were heterogeneous in their secretory responses, with increased glucose levels often producing a rapid increase in insulin secretion that could be followed by a paradoxical decrease below prestimulatory levels. The KATP channel blocker tolbutamide was consistently ineffective in stimulating insulin secretion; conversely, the KATP channel activator diazoxide often caused an unanticipated increase in insulin secretion. These observed alterations in secretory behavior were similar in focal lesion and DiCHI tissue, and independent of the specific mutation in ABCC8 or KCNJ11. They cannot be explained by classic models of ß cell function. Our results provide insight into the excessive and sometimes paradoxical changes in insulin secretion observed in CHI patients with inactivating mutations of KATP channels.

Heterozygous inactivation of the Na/Ca exchanger increases glucose-induced insulin release, ß-cell proliferation, and mass.

OBJECTIVE: We have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca(2+) extrusion from cells, increases ß-cell programmed cell death (apoptosis) and reduces ß-cell proliferation. To further characterize the role of NCX1 in ß-cells under in vivo conditions, we developed and characterized mice deficient for NCX1. RESEARCH DESIGN AND METHODS: Biologic and morphologic methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release, and point counting morphometry) were used to assess ß-cell function in vitro. Blood glucose and insulin levels were measured to assess glucose metabolism and insulin sensitivity in vivo. Islets were transplanted under the kidney capsule to assess their performance to revert diabetes in alloxan-diabetic mice. RESULTS: Heterozygous inactivation of Ncx1 in mice induced an increase in glucose-induced insulin release, with a major enhancement of its first and second phase. This was paralleled by an increase in ß-cell proliferation and mass. The mutation also increased ß-cell insulin content, proinsulin immunostaining, glucose-induced Ca(2+) uptake, and ß-cell resistance to hypoxia. In addition, Ncx1(+/-) islets showed a two- to four-times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted into diabetic animals. CONCLUSIONS: Downregulation of the Na/Ca exchanger leads to an increase in ß-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in ß-cell function that are opposite to the major abnormalities seen in type 2 diabetes. This provides a unique model for the prevention and treatment of ß-cell dysfunction in type 2 diabetes and after islet transplantation.

Morphologic analysis of focal and diffuse forms of congenital hyperinsulinism.

Congenital hyperinsulinism is clinically characterized by an inappropriate insulin secretion resulting in recurrent severe hypoglycemia. Nesidioblastosis, the proliferation of islet cells budding off from ducts, has been considered for years as the histologic lesion responsible for the syndrome. In our morphologic studies, we demonstrate that nesidioblastosis is not specific of the disease, which is actually not a single entity. Indeed, we recognize the existence of 2 different forms-a diffuse form and a focal form-and demonstrate that they can be differentiated by morphologic criteria, even on frozen sections during surgery. This histologic distinction directs the therapeutic approach because the patients experiencing the focal form of the syndrome can be completely cured by a very limited pancreatectomy. Molecular findings confirmed the reliability of this histologic distinction, showing a specific background for each form.

The surgical management of atypical forms of congenital hyperinsulinism.

Beyond the 2 classical forms of congenital hyperinsulinism, focal and diffuse, we report our experience on the surgical treatment of atypical forms. We define 2 subtypes among these atypical forms of hyperinsulinism: in case of a giant focal form the surgical strategy is the same as in focal forms. In case of hyperinsulinism caused by a mosaic, our experience suggests the benefit of a limited resection from the tail to the body of the pancreas.

Familial focal congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare. AIM: We describe the first familial form of focal CHI in two siblings. PATIENTS AND METHODS: The proband presented with medically unresponsive CHI. He underwent pancreatic venous sampling and Fluorine-18-L-dihydroxyphenylalanine positron emission tomography scan, which localized a 5-mm focal lesion in the isthmus of the pancreas. The sibling presented 8 yr later also with medically unresponsive CHI. An Fluorine-18-L-dihydroxyphenylalanine positron emission-computerised tomography scan showed a 7-mm focal lesion in the posterior section of the head of the pancreas. Both siblings were found to be heterozygous for two paternally inherited ABCC8 mutations, A355T and R1494W. Surgical removal of the focal lesions in both siblings cured the Hyperinsulinaemic hypoglycaemia. CONCLUSION: This is the first report of focal CHI occurring in siblings. Genetic counseling for families of patients with focal CHI should be recommended, despite the rare risk of recurrence of this disease.

Congenital hyperinsulinism.

Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet beta cells. HI has two main characteristics: a high glucose requirement to correct hypoglycemia and a responsiveness of hypoglycemia to exogenous glucagon. HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment. In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis: pancreatic (18)F-fluoro-L-DOPA PET-CT and molecular analysis. Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy. Diffuse HI involves all the pancreatic beta cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable. The genetics of focal islet-cells hyperplasia associates a paternally inherited mutation of the ABCC8 or the KCNJ11 genes, with a loss of the maternal allele specifically in the hyperplasic islet cells. The genetics of diffuse isolated HI is heterogeneous and may be recessively inherited (ABCC8 and KCNJ11) or dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH). Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to potassium channel defect (ABCC8 and KCNJ11), most of these HI are sensitive to diazoxide. The main points sum up the management of HI: i) prevention of brain damages by normalizing glycemia and ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.

Endoplasmic reticulum accumulation of Kir6.2 without activation of ER stress response in islet cells from adult Sur1 knockout mice.

Trafficking of pancreatic K(ATP) channels to the plasma membrane critically depends on masking the endoplasmic reticulum (ER) retention signals of the SUR1 and Kir6.2 subunits upon their proper assembly into functional hetero-octamers. When expressed in the absence of the partner protein, each subunit might accumulate in the ER and trigger beta-cell ER stress and oxidative stress. To test this hypothesis, Kir6.2 localisation, ER ultra-structure and ER-stress- and oxidative-stress-response gene mRNA levels were evaluated in pancreatic endocrine cells from adult wild-type (WT) and Sur1 knockout (Sur1 ( -/- )) mice. As previously reported, Kir6.2 was mainly expressed on secretory granules and at the plasma membrane of WT islet cells. In contrast, like the ER chaperone calreticulin, Kir6.2 was primarily localised in the rough endoplasmic reticulum (RER) of Sur1 ( -/- ) islet cells. ER retention of Kir6.2 was demonstrated (electron microscopy) by a significant increase in the length and Kir6.2 density of RER in Sur1 ( -/- ) vs WT islet cells. Despite Kir6.2 retention in RER, Xbp1 mRNA splicing and mRNA levels of preproinsulin and ER-stress-response genes Bip, Edem and Gadd153 were similar in WT and Sur1 ( -/- ) islets. However, mRNA levels of the antioxidant enzymes Sod1, Sod2, Gpx2 and catalase were significantly up-regulated in Sur1 ( -/- ) islets. Sequestration of Kir6.2 in RER of Sur1 ( -/- ) islet cells is thus associated with an increase in RER length and mild oxidative stress without activation of the classical ER stress response.