Type 1 diabetes: new perspectives on disease pathogenesis and treatment

doi:10.1016/S0140-6736(01)05415-0

The Lancet

Volume 358, Issue 9277, 21 July 2001, Pages 221-229

https://doi.org/10.1016/S0140-6736(01)05415-0 Get rights and content

Summary

As our knowledge of type 1 (insulin-dependent) diabetes increases, so does our appreciation for the pathogenic complexity of this disease and the challenges associated with its treatment. Many new concepts about the pathogenesis of this disorder have arisen. The role of genetics versus environment in disease formation has been questioned, and the basis on which type 1 diabetes is characterised and diagnosed is the subject of much debate. Additionally, the care and treatment of patients with type 1 diabetes has seen a rapid evolution; with genetically engineered insulins, glucose monitoring devices, and algorithms all contributing to a decrease in disease-related complications. We focus this seminar on these changing views, and offer a new perspective on our understanding of the pathogenesis of type 1 diabetes and on principles for therapeutic management of patients with this disorder.

Section snippets

Epidemiology and genetics

The incidence of type 1 disease is rapidly increasing in specific regions and shows a trend towards earlier onset. The incidence of type 1 diabetes is highly variable among different ethnic populations.⁵ The overall age-adjusted incidence of type 1 diabetes varies from 0·1/100 000 per year in the Zunyi region within China to more than 40/100 000 per year in Finland.6, 7 This represents more than a 400-fold variation in the incidence among about 100 populations analysed. Furthermore, the

Pathogenesis

Researchers31, 32, 33, 34 have reported results from investigations of young children (first-degree relatives of patients with type 1 diabetes and individuals from the general population), who were followed from birth to measure expression of autoantibodies and development of type 1 diabetes. Interestingly, despite wide geographical differences in the populations studied (eg, Germany, Finland, Colorado, and USA), the results of the different populations are highly concordant. Transplacental

Prediction and prospects for disease prevention

During the past 10 years, much progress has occurred in determining the biochemical nature of the autoantigens recognised by anti-islet autoantibodies. Historically, the gold-standard assay for anti-islet autoantibodies has been the cytoplasmic islet-cell-antibody test. This assay measures the degree of binding of immunoglobulin with islets compared with acinar pancreas, and uses frozen sections of human pancreas.⁴² Without question, studies of this test have greatly aided our knowledge of the

Diagnosis

The diagnostic criteria for different forms of diabetes are being revised. As our knowledge of the pathogenesis of a disease increases, periodic updates of diagnostic criteria are likely to follow. An expert committee of the American Diabetes Association (ADA) has published aetiological diagnostic criteria.⁵² These criteria recognise that most patients with type 1 diabetes are not children at onset,⁵³ and that not all individuals at onset are insulin dependent⁵⁴ or have an immune-mediated form

Insulin

The 1921 discovery of insulin was initially thought to represent a cure for the disease; a concept that remains common among those unfamiliar with the disorder. However, this is not the case. Acute morbidity and mortality as well as a series of chronic complications still occurs.66, 67 The Diabetes Control and Complications Trial (DCCT) research group4, 70 showed the importance of strict metabolic control for the delay and prevention of chronic complications. However, achieving such control

References (95)

M Bowman et al.
Autoimmune diabetes in NOD mice: a genetic program interruptible by environmental manipulation
Immunol Today
(1994)
A Green et al.
Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE study
Lancet
(1992)
TM Ellis et al.
Early infant diets and insulin-dependent diabetes
Lancet
(1996)
AT Hattersley
Genes versus environment in insulin-dependent diabetes: the phoney war
Lancet
(1997)
R Turner et al.
UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group
Lancet
(1997)
GF Bottazzo et al.
Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies
Lancet
(1974)
A Rabinovitch et al.
Prevention of type 1 diabetes
Med Clin North Am
(1998)
R Turner et al.
UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group
Lancet
(1997)
WJ Riley et al.
Thyroid autoimmunity in insulin-dependent diabetes mellitus: the case for routine screening
J Pediatr
(1981)
E Savilahti et al.
Celiac disease in insulin-dependent diabetes mellitus
J Pediatr
(1986)

F Bao et al.

One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease associated transglutaminase autoantibodies

J Autoimmunity

(1999)

EJ Hoffenberg et al.

Silent celiac disease in children with a genetic risk

J Pediatr

(2000)

GB Bolli et al.

Insulin glargine

Lancet

(2000)

YF Smets et al.

Effect of simultaneous pancreas-kidney transplantation on mortality of patients with type-1 diabetes mellitus and end-stage renal failure

Lancet

(1999)

SE Bursell et al.

Can protein kinase C inhibition and vitamin E prevent the development of diabetic vascular complications?

Diabetes Res Chin Pract

(1999)

L Castano et al.

Type 1 diabetes: a chronic autoimmune disease of human, mouse, and the rat

Annu Rev Immunol

(1990)

MA Atkinson et al.

The pathogenesis of insulin dependent diabetes

N Engl J Med

(1994)

Diabetes Control and Complications Trial Research Group

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

(1993)

RE LaPorte et al.

Geographic differences in the risk of insulin-dependent diabetes mellitus: the importance of registries

Diabetes Care

(1985)

Anonymous

EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe

Lancet

(2000)

P Onkamo et al.

Worldwide increase in incidence of Type 1 diabetes - the analysis of the data on published incidence trends

Diabetologia

(1999)

S Muntoni

New insights into the epidemiology of type 1 diabetes in Mediterranean countries

Diabetes Metab Res Rev

(1999)

JA Todd

From genome to aetiology in a multifactorial disease, type 1 diabetes

BioEssays

(1999)

R Buzzetti et al.

Dissecting the genetics of type 1 diabetes: relevance for familial clustering and differences in incidence

Diabetes Metab Rev

(1998)

A Lernmark et al.

Sometimes it is hot, sometimes it's not

Nat Genet

(1998)

ST Bennett

Human type 1 diabetes and the insulin gene: principles for mapping polygenes

Annu Rev Genet

(1996)

L Nistico et al.

The CTLA-4 gene region on chromosome 2q33 is linked to and associated with type 1 diabetes

Hum Mol Genet

(1996)

GG Dahlquist

Viruses and other perinatal exposures as initiating events for beta-cell destruction

Ann Med

(1997)

M Knip et al.

Environmental factors in the pathogenesis of type 1 diabetes mellitus

Exp Clin Endocrinol Diabetes

(1999)

JM Norris et al.

Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young

JAMA

(1996)

PM Graves et al.

Lack of association between early childhood immunizations and beta-cell autoimmunity

Diabetes Care

(1999)

M Hummel et al.

No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study

Diabetes Care

(2000)

E Hypponen et al.

Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group

Diabetes Care

(1999)

M Lonnrot et al.

Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group

J Med Virol

(2000)

SM Virtanen et al.

Cow's milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes. Childhood diabetes in Finland study group

Diabetes

(2000)

HE Wasmuth et al.

Non-specific viral infections as possible synchronising events of the manifestation of type 1 diabetes

Diabetes Metab Res Rev

(2000)

GS Eisenbarth

Type 1 diabetes mellitus. A chronic autoimmune disease

N Engl J Med

(1986)

PA McKinney et al.

Perinatal and neonatal determinants of childhood type 1 diabetes: a case-control study in Yorkshire, U.K

Diabetes Care

(1999)

GG Dahlquist et al.

Infections and vaccinations as risk factors for childhood type 1 (insulin-dependent) diabetes mellitus: a multicentre case-control investigation. EURODIAB Substudy 2 Study Group

Diabetologia

(2000)

A Pundziute-Lycka et al.

Infections and risk of Type I (insulin-dependent) diabetes mellitus in Lithuanian children

Diabetologia

(2000)

DV Serreze et al.

Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets

Diabetes

(2000)

A-G Ziegler et al.

Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB study

Diabetes

(1999)

T Kimpimaki et al.

Disease-associated autoantibodies as surrogate markers of type 1 diabetes in young children at increased genetic risk. Childhood Diabetes in Finland Study Group

J Clin Endocrinol Metab

(2000)

L Yu et al.

Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes

Proc Natl Acad Sci U S A

(2000)

PG Colman et al.

Islet autoimmunity in infants with a Type 1 diabetic relative is common but is frequently restricted to one autoantibody

Diabetologia

(2000)

SA Litherland et al.

Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus

J Clin Invest

(1999)

PZ Zimmet et al.

Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency

Diabet Med

(1994)

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SeminarType 1 diabetes: new perspectives on disease pathogenesis and treatment

Summary

Section snippets

Epidemiology and genetics

Pathogenesis

Prediction and prospects for disease prevention

Diagnosis

Insulin

Immunol Today

Lancet

Lancet

Lancet

Lancet

Lancet

Med Clin North Am

Lancet

J Pediatr

J Pediatr

J Autoimmunity

J Pediatr

Lancet

Lancet

Diabetes Res Chin Pract

Type 1 diabetes: a chronic autoimmune disease of human, mouse, and the rat

Annu Rev Immunol

The pathogenesis of insulin dependent diabetes

N Engl J Med

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

Geographic differences in the risk of insulin-dependent diabetes mellitus: the importance of registries

Diabetes Care

EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe

Lancet

Worldwide increase in incidence of Type 1 diabetes - the analysis of the data on published incidence trends

Diabetologia

New insights into the epidemiology of type 1 diabetes in Mediterranean countries

Diabetes Metab Res Rev

From genome to aetiology in a multifactorial disease, type 1 diabetes

BioEssays

Dissecting the genetics of type 1 diabetes: relevance for familial clustering and differences in incidence

Diabetes Metab Rev

Sometimes it is hot, sometimes it's not

Nat Genet

Human type 1 diabetes and the insulin gene: principles for mapping polygenes

Annu Rev Genet

The CTLA-4 gene region on chromosome 2q33 is linked to and associated with type 1 diabetes

Hum Mol Genet

Viruses and other perinatal exposures as initiating events for beta-cell destruction

Ann Med

Environmental factors in the pathogenesis of type 1 diabetes mellitus

Exp Clin Endocrinol Diabetes

Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young

JAMA

Lack of association between early childhood immunizations and beta-cell autoimmunity

Diabetes Care

No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study

Diabetes Care

Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group

Diabetes Care

Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group

J Med Virol

Cow's milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes. Childhood diabetes in Finland study group

Diabetes

Non-specific viral infections as possible synchronising events of the manifestation of type 1 diabetes

Diabetes Metab Res Rev

Type 1 diabetes mellitus. A chronic autoimmune disease

N Engl J Med

Perinatal and neonatal determinants of childhood type 1 diabetes: a case-control study in Yorkshire, U.K

Diabetes Care

Infections and vaccinations as risk factors for childhood type 1 (insulin-dependent) diabetes mellitus: a multicentre case-control investigation. EURODIAB Substudy 2 Study Group

Diabetologia

Infections and risk of Type I (insulin-dependent) diabetes mellitus in Lithuanian children

Diabetologia

Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets

Diabetes

Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB study

Diabetes

Disease-associated autoantibodies as surrogate markers of type 1 diabetes in young children at increased genetic risk. Childhood Diabetes in Finland Study Group

J Clin Endocrinol Metab

Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes

Seminar
Type 1 diabetes: new perspectives on disease pathogenesis and treatment