Neurologic Outcomes of 90 Neonates and Infants With Persistent Hyperinsulinemic Hypoglycemia

Menni, Francesca; Lonlay, Pascale de; Sevin, Caroline; Touati, Guy; Peigné, Catherine; Barbier, Valérie; Nihoul‐Feketé, Claire; Saudubray, Jean Marie; Robert, Jean Jacques

doi:10.1542/peds.107.3.476

Cited by 301 publications

(227 citation statements)

References 22 publications

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“…This rate was particularly increased in patients with infancy onset which is different from the patients reported by the French group where mental retardation occurred especially after neonatal onset of hyperinsulinism (25). Differences in the groups of patients in both studies may have contributed to these results.…”

Section: Discussioncontrasting

confidence: 77%

“…It is well known already that transient neonatal hypoglycemia or rare episodes of hypoglycemia of other causes are associated with neurodevelopmental deficits (29,30). However, it is still surprising that despite early treatment in specialized units some patients with CHI develop severe mental deficits (25). Next to the problems that still exist in completely preventing episodes of hypoglycemia, a general influence of the underlying defect on the central nervous system function cannot be completely excluded.…”

Section: Discussionmentioning

confidence: 99%

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Long-term follow-up of 114 patients with congenital hyperinsulinism

Meißner

Wendel

Burgard

et al. 2003

European Journal of Endocrinology

180

144

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Background: The term congenital hyperinsulinism (CHI) comprises a group of different genetic disorders with the common finding of recurrent episodes of hyperinsulinemic hypoglycemia. Objective: To evaluate the clinical presentation, diagnostic criteria, treatment and long-term follow-up in a large cohort of CHI patients. Patients: The data from 114 patients from different hospitals were obtained by a detailed questionnaire. Patients presented neonatally (65%), during infancy (28%) or during childhood (7%). Results: In 20 of 74 (27%) patients with neonatal onset birth weight was greatly increased (group with standard deviation scores (SDS) .2.0) with a mean SDS of 3.2. Twenty-nine percent of neonatal-onset vs 69% of infancy/childhood-onset patients responded to diazoxide and diet or to a carbohydrate-enriched diet alone. Therefore, we observed a high rate of pancreatic surgery performed in the neonatal-onset group (70%) compared with the infancy/childhood-onset group (28%). Partial (3%), subtotal (37%) or near total (15%) pancreatectomy was performed. After pancreatic surgery there appeared a high risk of persistent hypoglycemia (40%). Immediately post-surgery or with a latency of several years insulin-dependent diabetes mellitus was observed in operated patients (27%).

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Long-term follow-up of 114 patients with congenital hyperinsulinism

Meißner

Wendel

Burgard

et al. 2003

European Journal of Endocrinology

180

144

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show abstract

“…PHHI is characterized by dysregulated insulin secretion (19) with a variable clinical phenotype and can be a major cause of severe mental retardation and epilepsy if not treated properly (20)(21)(22). Although symptoms of hypoglycemia can appear during the first postnatal hours or days, some cases involving K ATP mutations are only detected months after birth (9).…”

Section: Normal Islet Morphology Is Maintained In Kir62[aaa]mentioning

confidence: 99%

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

Koster

Remedi

Flagg

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

112

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ATP-sensitive K ؉ (KATP) channels couple cell metabolism to electrical activity. To probe the role of KATP in glucose-induced insulin secretion, we have generated transgenic mice expressing a dominant-negative, GFP-tagged KATP channel subunit in which residues 132-134 (Gly-Tyr-Gly) in the selectivity filter were replaced by Ala-Ala-Ala, under control of the insulin promoter. Transgene expression was confirmed by both beta cell-specific green fluorescence and complete suppression of channel activity in those cells (Ϸ70%) that did fluoresce. Transgenic mice developed normally with no increased mortality and displayed normal body weight, blood glucose levels, and islet architecture. However, hyperinsulinism was evident in adult mice as (i) a disproportionately high level of circulating serum insulin for a given glucose concentration (Ϸ2-fold increase in blood insulin), (ii) enhanced glucose-induced insulin release from isolated islets, and (iii) mild yet significant enhancement in glucose tolerance. Enhanced glucose-induced insulin secretion results from both increased glucose sensitivity and increased release at saturating glucose concentration. The results suggest that incomplete suppression of KATP channel activity can give rise to a maintained hyperinsulinism.T he ATP-sensitive K ϩ channel (K ATP ) has long been proposed as a critical link in glucose-induced insulin release from pancreatic beta cells ( Fig. 1A; refs. 1 and 2). According to this paradigm, a high intracellular [ATP]͞[ADP] ratio in the fed state inhibits K ATP channels, causing membrane depolarization, leading to Ca 2ϩ entry through voltage-dependent Ca 2ϩ channels and insulin exocytosis. A rise in circulating insulin, in turn, leads to an increased peripheral glucose uptake and compensatory drop in blood glucose. Conversely, a falling intracellular [ATP]͞ [ADP] ratio during the fasting state is presumed to relieve inhibition of K ATP channels, resulting in membrane hyperpolarization and cessation of Ca 2ϩ -induced insulin release (3).Direct evidence for this paradigm is provided by the stimulatory and inhibitory effects of the K ATP -specific drugs, sulfonylureas and diazoxide, respectively, on insulin secretion in vivo (4) and the generation of transgenic and knockout mouse models with expression of altered or deficient pancreatic K ATP (5-7) that exhibit beta cell dysfunction. Profound neonatal diabetes due to permanent suppression of insulin release is observed in transgenic mice expressing overactive beta cell K ATP channels, dramatically illustrating the ability of K ATP channels to inhibit secretion (8). Conversely, the recent discovery of numerous mutations in pancreatic K ATP channel subunits (both the poreforming Kir6.2 and SUR1) in human patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) (3) establishes a causative link between suppressed K ATP activity, and the corollary metabolic disorder of hyperinsulinism (3). PHHIassociated K ATP mutations can be classified into two major categories: those that suppress channe...

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“…The primary concern in this illness is neurologic injury secondary to severe hypoglycemia leading to epilepsy, developmental delay, learning disability, cerebral palsy, or other forms of brain damage [5,6,12]. Medical management deals with maintenance of euglycemia and consists of dietetic measures, parenteral nutrition, diazoxide, glucagon, calcium channel blockers (nifedepine), and octreotide [1,5,8].…”

Section: Discussionmentioning

confidence: 99%

Subtotal Pancreatectomy for Congenital Hyperinsulinism: Our Experience and Review of Literature

et al. 2013

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Congenital hyperinsulinism (HI) is characterized by profound hypoglycemia caused by inappropriate insulin secretion. HI is a heterogeneous disorder with at least two histologic lesions and several implicated genes. If HI is caused by a focal lesion, elective surgery is the treatment of choice because it leads to complete recovery without diabetes. On the contrary, near-total pancreatectomy though recommended for diffuse HI, long-term risks of endocrine and exocrine deficiencies are present. Between the years 2006-2011, three patients of HI were referred to and operated by a single surgeon. The preoperative diagnosis was confirmed by recurrent hypoglycemia, inappropriately high insulin levels, and augmented glucose requirements. The medical records of all three patients were reviewed to study their clinical features, medical and surgical treatment, and postoperative outcome (short-and long-term). There were three patients in this series (male/female ratio, 1:2), all presenting in the neonatal age. All patients failed medical treatment, and radiological imaging did not reveal any pancreatic lesion. All patients underwent subtotal (80 %) pancreatectomy. Two patients had diffuse type of HI and one focal HI. One patient had transient hyperglycemia for 3 months, which needed insulin supplementation. No patient has developed recurrent hypoglycemia, malabsorption syndrome, or any neurological sequelae until the last followup. Doing subtotal or near-total pancreatectomy in diffuse type of HI still remains controversial as one has a higher risk of recurrent hypoglycemia, while the other has a higher rate of insulin dependent diabetes mellitus. Subtotal (80 %) pancreatectomy may be considered as the primary modality of surgical intervention in diffuse type of HI, especially when the diagnostic facilities are limited or diagnosis is not known after preliminary investigations. This minimizes the chances of postoperative diabetes mellitus, and redo surgery can always be considered if there is recurrent hypoglycemia.

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Neurologic Outcomes of 90 Neonates and Infants With Persistent Hyperinsulinemic Hypoglycemia

Abstract: Neonatal hyperinsulinemic hypoglycemia is still a severe disease with an important risk to rapidly develop severe mental retardation and epilepsy.

Cited by 301 publications

References 22 publications

Long-term follow-up of 114 patients with congenital hyperinsulinism

Long-term follow-up of 114 patients with congenital hyperinsulinism

Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels

Subtotal Pancreatectomy for Congenital Hyperinsulinism: Our Experience and Review of Literature

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Neurologic Outcomes of 90 Neonates and Infants With Persistent Hyperinsulinemic Hypoglycemia

Abstract: Neonatal hyperinsulinemic hypoglycemia is still a severe disease with an important risk to rapidly develop severe mental retardation and epilepsy.

Cited by 301 publications

References 22 publications

Long-term follow-up of 114 patients with congenital hyperinsulinism

Long-term follow-up of 114 patients with congenital hyperinsulinism

Hyperinsulinism induced by targeted suppression of beta cell K ATP channels

Subtotal Pancreatectomy for Congenital Hyperinsulinism: Our Experience and Review of Literature

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Product

Resources

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Hyperinsulinism induced by targeted suppression of beta cell K _ATP channels