Nesidioblastosis and Subsequent Diabetes Mellitus in a Dog with Hyperinsulinemic Hypoglycemia Treated with Partial Pancreatectomy.

A 6.5 yr old castrated male mixed-breed dog was presented for clinical signs associated with hypoglycemia. Hyperinsulinemic hypoglycemia was diagnosed as the cause of the persistent hypoglycemia. No obvious pancreatic mass was seen on abdominal computed tomography and exploratory laparotomy. A partial pancreatectomy was performed with the suspicion of an insulinoma-causing hyperinsulinemic hypoglycemia. Nesidioblastosis was diagnosed based clinical, biochemical, and histopathologic findings. There was beta cell hyperplasia and no evidence of neoplasia. The dog was euglycemic postoperatively after a partial pancreatectomy. Long-term follow-up after 2 yr revealed that the dog was diagnosed with diabetes mellitus.

Maltodextrin May Be a Promising Treatment Modality After Near-total Pancreatectomy in Infants Younger Than Six Months with Persistent Hyperinsulinism: A Case Report

Persistent hypoglycemia in infants with congenital hyperinsulinism (CHI) can be challenging in approximately half of these cases, even after undergoing a near-total pancreatectomy. While maltodextrin has been recommended in the nutritional management of CHI cases younger than six months, information regarding its efficacy in managing hypoglycemia are not yet clear. Here, we present a male infant with CHI who experienced persistent hypoglycemia even after undergoing a near-total pancreatectomy and despite multiple medical treatments. The infant's hypoglycemic episodes were successfully controlled by adding maltodextrin to his diet.

Case Report: A Difficult-to-Diagnose Case of Hyperinsulinemic Hypoglycemia Surgically Treated After Developing Acute Pancreatitis.

The patient is a 28-year-old Japanese man diagnosed with severe congenital hyperinsulinemic-hypoglycemia six months after birth. Clinical records revealed no imaging evidence of pancreatic tumor at the time of diagnosis. Subsequently, he had developmental disorders and epilepsy caused by recurrent hypoglycemic attacks. The patient's hypoglycemia improved with oral diazoxide. However, he developed necrotizing acute pancreatitis at 28 years of age, thought to be due to diazoxide. Discontinuation of diazoxide caused persistent hypoglycemia, requiring continuous glucose supplementation by tube feeding and total parenteral nutrition. A selective arterial secretagogue injection test revealed diffuse pancreatic hypersecretion of insulin. He underwent subtotal distal (72%) pancreatectomy and splenectomy. There was no intraoperative visible pancreatic tumor. His hypoglycemia improved after the surgical procedure. The histopathological study revealed a high density of islets of Langerhans in the pancreatic body and tail. There were large islets of Langerhans and multiple neuroendocrine cell nests in the whole pancreas. Nests of neuroendocrine cells were also detected in lymph nodes. The pathological diagnosis was grade 1 neuroendocrine tumor (microinsulinomas) with lymph node metastases. This patient is a difficult-to-diagnose case of hyperinsulinemic hypoglycemia surgically treated after developing acute pancreatitis. We believe this is a unique case of microinsulinomas with lymph metastases diagnosed and treated as congenital hyperinsulinemic hypoglycemia for almost 28 years.

Endogenous hyperinsulinism: diagnostic and therapeutic difficulties.

Endogenous hyperinsulinism is an abnormal clinical condition that involves excessive insulin secretion, related in 55% of cases to insulinoma. Other causes are possible such as islet cell hyperplasia, nesidioblastosis or antibodies to insulin or to the insulin receptor. Differentiation between these diseases may be difficult despite the use of several morphological examinations. We report six patients operated on for endogenous hyperinsulinism from 1st January 2000 to 31st December 2015. Endogenous hyperinsulinism was caused by insulinoma in three cases, endocrine cells hyperplasia in two cases and no pathological lesions were found in the last case. All patients typically presented with adrenergic and neuroglycopenic symptoms with a low blood glucose level concomitant with high insulin and C-peptide levels. Computed tomography showed insulinoma in one case out of two. MRI was carried out four times and succeeded to locate the lesion in the two cases of insulinoma. Endoscopic ultrasound showed one insulinoma and provided false positive findings three times out of four. Intra operative ultrasound succeeded to localize the insulinoma in two cases but was false positive in two cases. Procedures were one duodenopancreatectomy, two left splenopancreatectomy and two enucleations. For the sixth case, no lesion was radiologically objectified. Hence, a left blind pancreatectomy was practised but the pathological examination showed normal pancreatic tissue. Our work showed that even if morphological examinations are suggestive of insulinoma, other causes of endogenous hyperinsulinism must be considered and therefore invasive explorations should be carried out.

[Choice of surgical approach to insulin-producing pancreatic tumors]. / Vybor metoda khirurgicheskogo lecheniia insulinprodutsiruiushchikh opukholei podzheludochnoi zhelezy.

AIM: To determine the optimal surgical approach to insulin-producing pancreatic tumors via an analysis of early postoperative results. MATERIAL AND METHODS: There were 134 patients with insulin-producing pancreatic tumors followed by organic hyperinsulinism who have undergone surgery in the faculty-based surgical clinic of the Sechenov First Moscow State Medical University for the period 1990-2017. Patients were divided into three groups depending on type of surgical intervention. Surgical procedure was determined after comprehensive preoperative and intraoperative examination including intraoperative ultrasound. RESULTS: Incidence of postoperative complications was 32.8%. Ten (7.5%) patients required redo surgical interventions. Overall postoperative mortality was 4.5%. The best immediate results were observed in patients undergoing distal pancreatectomy. There was a correlation between incidence of early postoperative complications and tumor location depth in the enucleation group. CONCLUSION: Enucleation is advisable for insulinoma of pancreatic head or uncinated process, as well as superficial tumors of the left half of the pancreas. Distal pancreatectomy is indicated for deep tumors of the left half of the pancreas. Indications for pancreatoduodenectomy are individual.

Reversal of Roux en Y gastric bypass: largest single institution experience.

BACKGROUND: There is a paucity of literature on patients who have undergone reversal of Roux-en-Y gastric bypass (RYGB) to normal anatomy. We present the largest single institution experience with reversal of RYGB for serious chronic complications. OBJECTIVE: To describe our experience including indications, outcomes, and complications of RYGB reversal. SETTING: Academic-affiliated private practice. METHODS: Retrospective review of 48 patients who underwent laparoscopic reversal of RYGB between 2012 and 2016. RESULTS: Ninety-six percent (n = 46) of patients were female, and the mean age was 48.6 (range, 23-72). Indications for reversal of RYGB included marginal ulcer (n = 25, 12 of whom were malnourished and 17 had coexisting substance abuse), malnutrition alone (n = 11), chronic pain and nausea (n = 7), and postprandial hyperinsulinemic hypoglycemia (n = 5). Overall 30-day complication rate was 29% (n = 14), including gastrogastric anastomotic leak (n = 5), sepsis (n = 5), and bleeding requiring transfusion (n = 3). Weight gain after surgery increased in all patients, especially those patients deemed severely malnourished. All patients reported resolution of symptoms leading to reversal of RYGB, although 58% of patients were lost to follow-up at 1 year after surgery. CONCLUSIONS: Laparoscopic reversal of Roux-en-Y gastric bypass is a complex revisional operation that can be safely performed in a select group of patients with serious complications. The main indications for reversal of RYGB included malnutrition with and without recalcitrant marginal ulcers. Weight gain and resolution of malnutrition occurred soon after reversal of gastric bypass. Because the complication rates are high, reversal should be considered only after all salvage attempts have failed. Reversal to normal anatomy carries high morbidity, including sepsis, leaks and bleeding, high reoperative rates, and readmission. Although reversal of RYGB has a role in the treatment of a select group of patients, it should be undertaken by surgeons with considerable experience in RYGB revision.

Evidence of unrestrained beta-cell proliferation and neogenesis in a patient with hyperinsulinemic hypoglycemia after gastric bypass surgery.

Hyperinsulinemic hypoglycemia syndrome (HIHG) is a rare complication of roux-en-Y gastric bypass surgery. The pathology is associated with an excessive function of pancreatic beta-cells, and requires pancreas resection in patients that are recalcitrant to nutritional and pharmacological interventions. The exact prevalence is not clearly understood and the underlying mechanisms not yet fully characterized. We herein sought to perform histological and molecular examination of pancreatic sections obtained from a patient who developed HIHG as a complication of gastric bypass compared to 3 weight-matched controls. We studied markers of cellular replication and beta-cell differentiation by immunohistochemistry and immunofluorescence. HIHG after gastric bypass was characterized by a profound increase in beta-cell mass. Cellular proliferation was increased in islets and ducts compared to controls, suggesting unrestrained proliferation in HIHG. We also detected beta-cell differentiation markers in duct cells and occasional duct cells displaying both insulin and glucagon immunoreactivity. These histological observations suggest that beta-cell differentiation from ductal progenitor cells could also underly beta-cell mass expansion in HIHG. Altogether, our results can be construed to demonstrate that HIHG after gastric bypass is characterized by abnormal beta-cell mass expansion, resulting from both unrestrained beta-cell replication and neogenesis.

Selective Arterial Calcium Stimulation with Hepatic Venous Sampling in Patients with Recurrent Endogenous Hyperinsulinemic Hypoglycemia and Metastatic Insulinoma: Evaluation in Five Patients.

Selective arterial calcium stimulation (SACST) with hepatic venous sampling was performed in 5 patients (3 female, 2 male; age range, 53-73 y) with recurrent endogenous hyperinsulinemic hypoglycemia caused by metastatic insulinoma between January 2004 and December 2014. The biochemical results of SACST confirmed functional hepatic metastases alone (n = 3), peripancreatic lymph-node and hepatic metastases (n = 1), and occult insulinoma in the pancreatic bed (n = 1), thereby helping to guide management. SACST may be useful to determine the extent of functional metastatic insulinoma, particularly within the liver, and may provide clinicians with additional information to help guide the multidisciplinary management of patients with recurrent endogenous hyperinsulinemic hypoglycemia.

Long-term incidence of female-specific cancer after bariatric surgery or usual care in the Swedish Obese Subjects Study.

OBJECTIVE: To examine the long-term effects of bariatric surgery on female-specific cancer in women with obesity. METHODS: The prospective, matched Swedish Obese Subjects (SOS) study was designed to examine outcomes after bariatric surgery. This study includes 1420 women from the SOS cohort that underwent bariatric surgery and 1447 contemporaneously matched controls who received conventional obesity treatment. Age was 37-60years and BMI was ≥38kg/m2. Information on cancer events was obtained from the Swedish National Cancer Registry. Median follow-up time was 18.1years (interquartile range 14.8-20.9years, maximum 26years). This study is registered with ClinicalTrials.gov, NCT01479452. RESULTS: Bariatric surgery was associated with reduced risk of overall cancer (hazard ratio=0.71; 95% CI 0.59-0.85; p<0.001). About half of the observed cancers were female-specific, and the incidence of these were lower in the surgery group compared with the control group (hazard ratio=0.68; 95% CI 0.52-0·88; p=0.004). The surgical treatment benefit with respect to female-specific cancer was significantly associated with baseline serum insulin (interaction p value=0.022), with greater relative treatment benefit in patients with medium or high insulin levels. Separate analyses of different types of female-specific cancers showed that bariatric surgery was associated with reduced risk of endometrial cancer (hazard ratio=0.56: 95% CI 0.35-0.89; p=0.014). CONCLUSIONS: In this long-term study, bariatric surgery was associated with reduced risk of female-specific cancer, especially in women with hyperinsulinemia at baseline. FUNDING: This project was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK105948 (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health), the Swedish Research Council K2013-99X-22279-01, K2013-54X-11285-19, Sahlgrenska University Hospital ALF research grant and Swedish Diabetes Foundation.

One-Anastomosis Jejunal Interposition with Gastric Remnant Resection (Branco-Zorron Switch) for Severe Recurrent Hyperinsulinemic Hypoglycemia after Gastric Bypass for Morbid Obesity.

BACKGROUND: The anatomical and physiological changes after Roux-en-Y gastric bypass for morbid obesity can lead to severe hyperinsulinemic hypoglycemia with neuroglycopenia in a small percentage of patients. The exact physiologic mechanism is not completely understood. Surgical reversal to the original anatomy and distal or total pancreatectomy are current therapeutic options to reverse the hypoglycemic effect, with substantial associated morbidity. Our group reports a pilot clinical series of a novel surgical technique using one-anastomosis jejunal interposition with gastric remnant resection (Branco-Zorron Switch). METHODS: Patients with severe symptomatic hyperinsulinemic hypoglycemia refractory to conservative therapy were treated using the technique. The procedure started with resection of the remnant stomach close to pylorus. The alimentary limb was sectioned at 20 cm from the gastrojejunal anastomosis, and the rest of the alimentary limb was resected until the Y-Roux anastomosis. A hand-sutured anastomosis was then performed with the proximal alimentary limb and the remnant antrum. RESULTS: Four patients were successfully submitted to the procedure with reversal of the symptomatology and normalization of insulin levels, postprandial glucose levels, and oral glucose tolerance test, with a mean follow-up of 24.3 months. Mean operative time was 188 min, and patients recovered without postoperative complications. CONCLUSION: Patients suffering from severe hyperinsulinemic hypoglycemia after gastric bypass may be efficiently treated by this innovative procedure, avoiding extreme surgical therapy such as pancreatectomy or restoring the gastric anatomy, while still maintaining sustained weight loss. Studies with larger series and longer follow-up are still needed to define the role of this therapy in managing this entity.

Vagotomy diminishes obesity in cafeteria rats by decreasing cholinergic potentiation of insulin release

Herein, we investigated whether subdiaphragmatic vagotomy has benefits on obesity, body glucose homeostasis, and insulin secretion in cafeteria (CAF)-obese rats. Wistar rats were fed a standard or CAF diet for 12 weeks. Subsequently, CAF rats were randomly submitted to truncal vagotomy (CAF Vag) or sham operation (CAF Sham). CAF Sham rats were hyperphagic, obese, and presented metabolic disturbances, including hyperinsulinemia, glucose intolerance, insulin resistance, hyperglycemia, and hypertriglyceridemia. Twelve weeks after vagotomy, CAF Vag rats presented reductions in body weight and perigonadal fat stores. Vagotomy did not modify glucose tolerance but normalized fed glycemia, insulinemia, and insulin sensitivity. Isolated islets from CAF Sham rats secreted more insulin in response to the cholinergic agent, carbachol, and when intracellular cyclic adenine monophosphate (cAMP) is enhanced by forskolin or 3-isobutyl-1-methylxanthine. Vagotomy decreased glucose-induced insulin release due to a reduction in the cholinergic action on β-cells. This effect also normalized islet secretion in response to cAMP. Therefore, vagotomy in rats fed on a CAF-style diet effectively decreases adiposity and restores insulin sensitivity. These effects were mainly associated with the lack of cholinergic action on the endocrine pancreas, which decreases insulinemia and may gradually reduce fat storage and improve insulin sensitivity (AU)

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Vagotomy diminishes obesity in cafeteria rats by decreasing cholinergic potentiation of insulin release.

Herein, we investigated whether subdiaphragmatic vagotomy has benefits on obesity, body glucose homeostasis, and insulin secretion in cafeteria (CAF)-obese rats. Wistar rats were fed a standard or CAF diet for 12 weeks. Subsequently, CAF rats were randomly submitted to truncal vagotomy (CAF Vag) or sham operation (CAF Sham). CAF Sham rats were hyperphagic, obese, and presented metabolic disturbances, including hyperinsulinemia, glucose intolerance, insulin resistance, hyperglycemia, and hypertriglyceridemia. Twelve weeks after vagotomy, CAF Vag rats presented reductions in body weight and perigonadal fat stores. Vagotomy did not modify glucose tolerance but normalized fed glycemia, insulinemia, and insulin sensitivity. Isolated islets from CAF Sham rats secreted more insulin in response to the cholinergic agent, carbachol, and when intracellular cyclic adenine monophosphate (cAMP) is enhanced by forskolin or 3-isobutyl-1-methylxanthine. Vagotomy decreased glucose-induced insulin release due to a reduction in the cholinergic action on ß-cells. This effect also normalized islet secretion in response to cAMP. Therefore, vagotomy in rats fed on a CAF-style diet effectively decreases adiposity and restores insulin sensitivity. These effects were mainly associated with the lack of cholinergic action on the endocrine pancreas, which decreases insulinemia and may gradually reduce fat storage and improve insulin sensitivity.

PROPOSAL OF A REVISIONAL SURGERY TO TREAT NON-INSULINOMA HYPERINSULINEMIC HYPOGLICEMIA POSTGASTRIC BYPASS / PROPOSTA DE CIRURGIA REVISIONAL PARA TRATAMENTO DE HIPOGLICEMIA HIPERINSULINEMICA NÃO INSULINOMA APÓS BYPASS GÁSTRICO

Background : Hyperinsulinemic hypoglicemia with severe neuroglycopenic symptoms has been identified as a late and rare complication in patients submitted to Roux-en-Y gastric bypass. However, the potential gravity of its manifestations requires effective treatment of this condition. The absence of treatment makes it necessary to develop more effective clinical or surgical methods. Aim : To present one surgical option to revisional surgery in the treatment of hyperinsulinemic hypoglicemia Methods : The procedure consists in reconstituting alimentary transit through the duodenum and proximal jejunum, while keeping the restrictive part of the gastric bypass. As an additional strategy to maintain weight loss, is realized gastric fundus resection, aiming to suppress ghrelin production more effectively. Results : It was used in three patients with successful results in one year of follow-up. Conclusion : The procedure to reconstruct the food transit through the duodenum and proximal jejunum, keeping the restrictive component of gastric bypass in the treatment of hyperinsulinemic hypoglycemia showed good initial results and validated its application in other cases with this indication.

Racional : Hipoglicemia hiperinsulinêmica com sintomas neuroglicopênicos severos tem sido identificada como complicação tardia e rara em pacientes submetidos à gastroplastia com bypass em Y-de-Roux. Porém, a gravidade potencial de suas manifestações exige tratamento definitivo desta condição. A falta de tratamento efetivo gera a necessidade de desenvolver métodos clínicos ou cirúrgicos mais eficazes. Objetivo: Apresentar proposta de operação revisional para o tratamento da síndrome de hipoglicemia hiperinsulinêmica. Métodos : O procedimento consiste em reconstituir o trânsito alimentar pelo duodeno e jejuno proximal, mantendo o componente restritivo do by-pass gástrico. Como estratégia adicional de manutenção ponderal, é realizada ressecção do fundo gástrico, visando intensificar a supressão da grelina. Resultado: O procedimento foi realizado em três pacientes com bom resultado em seguimento de um ano. Conclusão : O procedimento de reconstituir o trânsito alimentar pelo duodeno e jejuno proximal, mantendo o componente restritivo do by-pass gástrico no tratamento da hipoglicemia hiperinsulinêmica apresentou bons resultados iniciais podendo validar sua indicação para outros casos.

Refractory hypoglycaemia in patient with gastric outlet obstruction.

A 68-year-old male with a longstanding history of severe gastric outlet obstruction secondary to peptic stricture was found unconscious at home with profound hypoglycaemia. He denied history of fasting, diabetes mellitus or use of hypoglycaemic agents. Systemic examination and metabolic profile were unremarkable. Hypoglycaemic episodes persisted during hospitalisation, requiring continuous intravenous dextrose and eventually diazoxide. Further investigative work up, including 72 h fasting study, revealed a hyperinsulinemic state. MRI and endoscopic ultrasound were unremarkable but mesenteric angiography with hepatic venous sampling revealed a subtle area of hypervascularity in the head of pancreas. An exploratory laparotomy was then performed and resulted in resection of a nodular lesion in the head of pancreas with retrocolic gastrojejunostomy for repair of pyloric stenosis. Histopathology of pancreatic nodule confirmed nesidioblastosis. Postoperatively the patient was weaned of parenteral dextrose and did not have any further episodes of hypoglycaemia.

PROPOSAL OF A REVISIONAL SURGERY TO TREAT NON-INSULINOMA HYPERINSULINEMIC HYPOGLICEMIA POSTGASTRIC BYPASS.

BACKGROUND: Hyperinsulinemic hypoglicemia with severe neuroglycopenic symptoms has been identified as a late and rare complication in patients submitted to Roux-en-Y gastric bypass. However, the potential gravity of its manifestations requires effective treatment of this condition. The absence of treatment makes it necessary to develop more effective clinical or surgical methods. AIM: To present one surgical option to revisional surgery in the treatment of hyperinsulinemic hypoglicemia Methods : The procedure consists in reconstituting alimentary transit through the duodenum and proximal jejunum, while keeping the restrictive part of the gastric bypass. As an additional strategy to maintain weight loss, is realized gastric fundus resection, aiming to suppress ghrelin production more effectively. RESULTS: It was used in three patients with successful results in one year of follow-up. CONCLUSION: The procedure to reconstruct the food transit through the duodenum and proximal jejunum, keeping the restrictive component of gastric bypass in the treatment of hyperinsulinemic hypoglycemia showed good initial results and validated its application in other cases with this indication.

Histological insights into the pathogenesis of post-Roux-en-Y hyperinsulinaemic hypoglycaemia.

BACKGROUND: ß-cell hyperplasia has been implicated in the aetiology of post Roux-en-Y gastric bypass hyperinsulinaemic hypoglycaemia, but the pathogenesis of this condition is still unclear. CASE REPORT: We report a case of a 52-year-old man with post-Roux-en-Y gastric bypass hyperinsulinaemic hypoglycaemia who underwent distal pancreatectomy to alleviate his symptoms. Pancreatic histopathology showed chronic pancreatitis with a corresponding loss of exocrine tissue and islet retention. Amyloid deposition was found in pancreatic islets. These features are more typically associated with Type 2 diabetes. DISCUSSION: This case highlights the potential multifactorial pathogenesis of symptomatic hypoglycaemia after Roux-en-Y gastric bypass.

Hyperinsulinemic syndrome: the metabolic syndrome is broader than you think.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by hyperinsulinemia. In 2011 we showed that gastric bypass (RYGB) corrects these high levels even though insulin resistance remains high, ie, the operation "dissociates" hyperinsulinemia from insulin resistance. RYGB produces reversal of T2DM along with other diseases associated with the metabolic syndrome. This observation led us to examine whether these illnesses also were characterized by hyperinsulinemia. METHODS: A systematic review was performed to determine whether hyperinsulinemia was present in disorders associated with the metabolic syndrome. We reviewed 423 publications. 58 were selected because of appropriate documentation of insulin measurements. Comparisons were based on whether the studies reported patients as having increased versus normal insulin levels for each metabolic disorder. RESULTS: The presence (+) or absence (-) of hyperinsulinemia was documented in these articles as follows: central obesity (4+ vs 0-), diabetes (5+ vs 0-), hypertension (9+ vs 1-), dyslipidemia (2+ vs 0-), renal failure (4+ vs 0-), nonalcoholic fatty liver disease (5+ vs 0-), polycystic ovary syndrome (7+ vs 1-), sleep apnea (7+ vs 0-), certain cancers (4+ vs 1-), atherosclerosis (4+ vs 0-), and cardiovascular disease (8+ vs 0-). Four articles examined insulin levels in the metabolic syndrome as a whole (4+ vs 0-). CONCLUSION: These data document that disorders linked to the metabolic syndrome are associated with high levels of insulin, suggesting that these diseases share a common etiology that is expressed by high levels of insulin. This leads us to propose the concept of a "hyperinsulinemic syndrome" and question the safety of insulin as a chronic therapy for patients with T2DM.