Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

Colombo, Carlo; Porzio, Ottavia; Liu, Ming; Massa, Ornella; Vasta, M; Salardi, S; Beccaria, Luciano; Monciotti, C. M.; Toni, Sonia; Pedersen, Oluf; Hansen, Torben; Federici, L.; Pesavento, R.; Cadario, Francesco; Federici, Giorgio; Ghirri, Paolo; Arvan, Peter; Iafusco, Dario; Barbetti, Fabrizio

doi:10.1172/jci33777

Cited by 146 publications

(262 citation statements)

References 47 publications

Supporting

Mentioning

245

Contrasting

Unclassified

Order By: Relevance

“…Nevertheless, the patient bearing the mutation in the signal peptide shows a milder clinical course, and we cannot exclude that S Signal23 preproinsulin may be partially processed and secreted. Present knowledge indicates that insulin mutations with a proteotoxic effect cause apoptosis of the pancreatic ␤-cell (1), a process that in most patients takes several months after birth (1)(2)(3) (1-4) were diagnosed within the first 4 weeks of birth (i.e., the time interval still in use to define the neonatal period); most of them (more than 40) were diagnosed in the first year of life (infancy). Thus, we believe that classifying these patients as having permanent neonatal diabetes is misleading and that this term should be abandoned in favor of the term "monogenic diabetes of infancy," as previously suggested by our group (1).…”

Section: Methodsmentioning

confidence: 99%

“…Present knowledge indicates that insulin mutations with a proteotoxic effect cause apoptosis of the pancreatic ␤-cell (1), a process that in most patients takes several months after birth (1)(2)(3) (1-4) were diagnosed within the first 4 weeks of birth (i.e., the time interval still in use to define the neonatal period); most of them (more than 40) were diagnosed in the first year of life (infancy). Thus, we believe that classifying these patients as having permanent neonatal diabetes is misleading and that this term should be abandoned in favor of the term "monogenic diabetes of infancy," as previously suggested by our group (1). Indeed, at least 12 patients with insulin gene mutations had the diagnosis of diabetes during childhood or adulthood (1-4 and this report), making the neonatal onset an exception.…”

Section: Methodsmentioning

confidence: 99%

“…M utations of the insulin (INS) gene associated with neonatal-and infancy-onset diabetes cause sustained stress of the endoplasmic reticulum, which in turn triggers apoptosis of the pancreatic ␤-cell (1). In patients with insulin mutations with proteotoxic effect, diabetes presents in isolation and the onset of hyperglycemia may occur well outside the neonatal period (1)(2)(3)(4).…”

Section: Diabetes Care 32:123-125 2009mentioning

confidence: 99%

“…In patients with insulin mutations with proteotoxic effect, diabetes presents in isolation and the onset of hyperglycemia may occur well outside the neonatal period (1)(2)(3)(4). As a consequence, individuals with INS gene mutations may be confused with patients having autoimmune type 1 diabetes (1-4).…”

Section: Diabetes Care 32:123-125 2009mentioning

confidence: 99%

See 3 more Smart Citations

Insulin Gene Mutations as Cause of Diabetes in Children Negative for Five Type 1 Diabetes Autoantibodies

Bonfanti

Colombo

Nocerino³

et al. 2009

Diabetes Care

Self Cite

View full text Add to dashboard Cite

OBJECTIVE—Heterozygous, gain-of-function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood. The aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies. RESEARCH DESIGN AND METHODS—We reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies. We sequenced the INS gene in these seven patients. RESULTS—In two patients whose diabetes onset had been at 2 years 10 months of age and at 6 years 8 months of age, respectively, we identified the mutation GB8S and a novel mutation in the preproinsulin signal peptide (ASignal23S). CONCLUSIONS—Insulin gene mutations are rare in absolute terms in patients classified as type 1 diabetic (0.6%) but can be identified after a thorough screening of type 1 diabetes autoantibodies.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Diabetes Care 32:123-125 2009mentioning

confidence: 99%

Section: Diabetes Care 32:123-125 2009mentioning

confidence: 99%

See 2 more Smart Citations

Insulin Gene Mutations as Cause of Diabetes in Children Negative for Five Type 1 Diabetes Autoantibodies

Bonfanti

Colombo

Nocerino³

et al. 2009

Diabetes Care

Self Cite

View full text Add to dashboard Cite

show abstract

“…The first piece of evidence of the role of ERS in defective insulin secretion came from studies with monogenic forms of diabetes (148,149 was subsequently shown that the increased demand for insulin production in common forms of T2D could also impose perturbations in the ER, leading to the activation of the UPR (150,151). Furthermore, as in other tissues (147), FFAs can act as a trigger of ERS in pancreatic islets, acting in concert with high glucose (19,152).…”

Section: Metabolic Inflammation and Pancreatic Islet Dysfunction In T2dmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Metabolic and inflammatory pathways on the pathogenesis of type 2 diabetes

Coope

Torsoni

Velloso

2016

European Journal of Endocrinology

View full text Add to dashboard Cite

Obesity is the main risk factor for type 2 diabetes (T2D). Studies performed over the last 20 years have identified inflammation as the most important link between these two diseases. During the development of obesity, there is activation of subclinical inflammatory activity in tissues involved in metabolism and energy homeostasis. Intracellular serine/threonine kinases activated in response to inflammatory factors can catalyse the inhibitory phosphorylation of key proteins of the insulin-signalling pathway, leading to insulin resistance. Moreover, during the progression of obesity and insulin resistance, the pancreatic islets are also affected by inflammation, contributing to b-cell failure and leading to the onset of T2D. In this review, we will present the main mechanisms involved in the activation of obesity-associated metabolic inflammation and discuss potential therapeutic opportunities that can be developed to treat obesity-associated metabolic diseases.

show abstract

Role of ferroptosis inhibitors in the management of diabetes

Mohandas

Ramkumar

2022

BioFactors

View full text Add to dashboard Cite

Ferroptosis, the iron‐dependent, lipid peroxide‐mediated cell death, has garnered attention due to its critical involvement in crucial physiological and pathological cellular processes. Indeed, several studies have attributed its role in developing a range of disorders, including diabetes. As accumulating evidence further the understanding of ferroptotic mechanisms, the impact this specialized mode of cell death has on diabetic pathogenesis is still unclear. Several in vivo and in vitro studies have highlighted the association of ferroptosis with beta‐cell death and insulin resistance, supported by observations of marked alterations in ferroptotic markers in experimental diabetes models. The constant improvement in understanding ferroptosis in diabetes has demonstrated it as a potential therapeutic target in diabetic management. In this regard, ferroptosis inhibitors promise to rescue pancreatic beta‐cell function and alleviate diabetes and its complications. This review article elucidates the key ferroptotic pathways that mediate beta‐cell death in diabetes, and its complications. In particular, we share our insight into the cross talk between ferroptosis and other hallmark pathogenic mediators such as oxidative and endoplasmic reticulum stress regulators relevant to diabetes progression. Further, we extensively summarize the recent developments on the role of ferroptosis inhibitors and their therapeutic action in alleviating diabetes and its complications.

show abstract

Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

Cited by 146 publications

References 47 publications

Insulin Gene Mutations as Cause of Diabetes in Children Negative for Five Type 1 Diabetes Autoantibodies

Insulin Gene Mutations as Cause of Diabetes in Children Negative for Five Type 1 Diabetes Autoantibodies

MECHANISMS IN ENDOCRINOLOGY: Metabolic and inflammatory pathways on the pathogenesis of type 2 diabetes

Role of ferroptosis inhibitors in the management of diabetes

Contact Info

Product

Resources

About