Intranasally administered insulin intended for prevention of type 1 diabetes—a safety study in healthy adults

Kupila, Antti; Sipilä, Jorma; Keskinen, Päivi; Simell, Tuula; Knip, Mikael; Pulkki, Kari; Simell, Olli

doi:10.1002/dmrr.397

Cited by 62 publications

(58 citation statements)

References 22 publications

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“…N2B insulin delivery appears to be a clinically safe application method for the dissociation of central and peripheral insulin effects [76]. An intranasal insulin spray containing the adsorption enhancer cyclopentadecalactone (CPE-215) was developed as Nasulin™ for the needle-free regimen of diabetes.…”

Section: Intranasal Insulin For Metabolic Diseasesmentioning

confidence: 99%

Nose-to-Brain delivery of insulin for Alzheimer’s disease

Stützle¹,

Flamm²,

Carle

et al. 2015

ADMET DMPK

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The transport of small molecules, peptides and proteins via the olfactory epithelium and along olfactory and trigeminal nerve pathways from the nasal cavity to the brain is very well known and clinically established for central nervous system (CNS) active drugs like oxytocin, sumatriptan or insulin. Insulin is a clinically well-established biopharmaceutical with a validated function in cognition. Central supply with insulin via intranasal administration improves cognition in animal models CNS delivery -an unmet medical needThe World Health Organization (WHO) estimates that more than a billion people worldwide are suffering from diseases of the central nervous system (CNS; [1,2]). Alzheimer's disease (AD) is the most common neurodegenerative dementia in the industrialized world, with prevalence rates well over 30 % in the over 80-years-old population [1,2]. AD causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. Like most neurodegenerative diseases, AD has a poor prognosis and only symptomatic therapy is currently available. Efficient treatment strategies are still limited and an aging society in demographic change presents an enormous challenge to the health systems of industrialized nations. Despite the extensive research and effort to uncover the mechanism of AD pathogenesis, more or less all drug candidates failed to demonstrate significant effects on cognition in clinical trials [3,4].A highly critical point in that context is the low central availability of drugs. The passage of most CNSactive drugs and in particular of biopharmaceuticals is massively hampered by the blood-brain barrier

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Section: Intranasal Insulin For Metabolic Diseasesmentioning

confidence: 99%

Nose-to-Brain delivery of insulin for Alzheimer’s disease

Stützle¹,

Flamm²,

Carle

et al. 2015

ADMET DMPK

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“…Therefore, with the aim of establishing the potential efficacy of mucosal antigen for preventing autoimmune disease, we conducted a randomized, double-blind, crossover study in individuals at risk of type 1 diabetes to determine if intranasal insulin was safe and could induce changes in immunity to insulin consistent with mucosal tolerance. In the absence of absorptionpromoting agents, intranasal insulin has no systemic metabolic effects (21)(22)(23). However, in regard to safety, it is necessary to ensure that mucosal administration of insulin to individuals at risk for type 1 diabetes does not activate pathogenic immunity and accelerate ␤-cell destruction.…”

mentioning

confidence: 99%

Pancreatic β-Cell Function and Immune Responses to Insulin After Administration of Intranasal Insulin to Humans At Risk for Type 1 Diabetes

et al. 2004

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OBJECTIVE -Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate ␤-cell destruction, and could induce immune effects consistent with mucosal tolerance. RESEARCH DESIGN AND METHODS-A total of 38 individuals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was ␤-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly; the secondary outcome was immunity to islet antigens, measured monthly for 12 months.RESULTS -No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible ␤-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as ␤-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin. CONCLUSIONS -Results from this pilot study suggest that intranasal insulin does not accelerate loss of ␤-cell function in individuals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes. Diabetes Care 27:2348 -2355, 2004T ype 1 diabetes is an autoimmune disease in which T-cells mediate destruction of insulin-secreting ␤-cells in the pancreatic islets. Asymptomatic individuals with preclinical type 1 diabetes can be identified by the presence of circulating antibodies (Abs) to insulin, GAD 65-kDa isoform, and tyrosine phosphatase-like insulinoma antigen 2 (IA2) (1-3). Insulin is the only self-antigen specific for ␤-cells, and several lines of evidence indicate that it may play a major role in driving autoimmune ␤-cell destruction (4 -7). In experimental rodent models, administration of self-antigens to mucosa-associated lymphoid tissues can induce immune tolerance and prevent autoimmune disease (8,9). In the nonobese diabetic (NOD) mouse, a spontaneous model of autoimmune type 1 diabetes, oral (10) or naso-respiratory (11) insulin induces regulatory, diabetes-protective Tcells. After naso-respiratory insulin, there was a decrease in T-cell and an increase in Ab responses to insulin (11), conforming to the shift from T-helper (Th)-1 cellular immunity to Th2 humoral immunity that is associated with protection against diabetes in this rodent model (12). In human volunteers, oral (13)...

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“…Therefore, insulin represents the obvious target for antigen-specific intervention in young children. Insulin has been used for decades to treat patients by injection, and more recently it has been given via oral, intranasal, and inhaled routes in patients and healthy subjects [9•, [26][27][28][29]. All studies using oral or intranasal insulin therapy in humans have been reassuring from a safety perspective.…”

Section: Why Antigen-specific Intervention With Insulin?mentioning

confidence: 98%

“…Oral insulin has been given to diabetic and nondiabetic subjects at 2.5, 5, and 7.5 mg/d (corresponding to ~ 0.03-0.8 mg/kg/d for 9-to 85-kg participants) without side effects; among them were children as young as 3 years [9•, 26,27]. Intranasal insulin has been given to islet autoantibody-positive subjects as young as 2 years of age without side effects [28,29]. Immunologic studies suggested some modulation of immune response to insulin in these studies [28,43].…”

Section: Why Mucosal Administration Of Insulin?mentioning

confidence: 99%

Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization

Achenbach

Barker²,

Bonifacio³

2008

Curr Diab Rep

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Mucosal administration of insulin represents an attractive antigen-specific therapeutic approach to preventing type 1 diabetes. It can prevent autoimmune diabetes in animal models, but although it has been shown to be safe, it has not yet been proven effective in human studies. Efficacy may depend on the dose and route at which insulin is administered, the stage in type 1 diabetes pathogenesis at which treatment is initiated, and the study cohort that is treated. We have proposed Pre-POINT (Primary Oral/intranasal INsulin Trial), a dose-finding safety and immune efficacy pilot study for primary mucosal insulin therapy in islet autoantibody-negative children at high genetic risk for type 1 diabetes who naturally first develop autoimmunity to insulin. Pre-POINT aims to identify an optimal insulin dose and route of application (orally or intranasally) that is well tolerated and can induce an immune response to insulin for additional use in a phase II/III primary prevention trial in children at risk.

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Intranasally administered insulin intended for prevention of type 1 diabetes—a safety study in healthy adults

Abstract: Short-term use of intranasal insulin without absorption enhancers was predominantly well tolerated, the risk of hypoglycaemia was minimal and no objective nasal adverse effects were detected.

Cited by 62 publications

References 22 publications

Nose-to-Brain delivery of insulin for Alzheimer’s disease

Nose-to-Brain delivery of insulin for Alzheimer’s disease

Pancreatic β-Cell Function and Immune Responses to Insulin After Administration of Intranasal Insulin to Humans At Risk for Type 1 Diabetes

Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization

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