EpidemiologyDiabetes Mellitus Type I
(Insulin-Dependent Diabetes Mellitus, IDDM)
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Epidemiology
more frequent in Northern European countries (Finland incidence 40 per 100,000 population)
less frequent among the Oriental (Japen incidence 1-2 per 100,000 population)
US incidence is 12-14 per 100,000 population aged 0-16 years
US prevalence 1 million people affected
more frequent among children that were not breast-fed
33% concordance rate among identical twins
90% of the affected patients do not have an affected first-degree relative
incidence increases with age and peaks around puberty
onset most frequent in late fall and early winter
Genetics
main gene in MHC (major histocompatilibity complex) in chromosome 6
95% of diabetes type 1 patients have HLA-DR3 or -DR4, or combined DR3/DR4 makeup (as compared with only 45% of the American white population)
HLA-DR1, -DR8 and DR16 also correlate with increased susceptibility
HLA-DR11 and -DR15 protect against DM type 1
HLA-DQA1*0102 and -DQB1*0602 have an even stronger predictive power about susceptibility to DM type 1 among subjects with HLA-DR2, but are not as common as the other haplotypes
HLA-DQß1*0302 is a susceptiblity gene and HLA-DQß1*0301 confers a low risk for IDDM; the HLA-DQß1*0602 form is protective and overrides the susceptibility conferred by 0302
all of these MHC haplotypes encode for proteins for constitutive or inducible proteins on the surface of antigen-presenting cells APCs) which immunologically "prime" helper T cells
these proteins may enhance the degree of immune responsiveness of APCs to a pancreatic beta-cell autoantigen thereby triggering an autoimmune reaction when they "facilitate" the presentation of beta-cell antigens to T cells
another gene has been found in chromosome 11, near the gene for insulin and insulin-like growth factor II
TAP Gene- gene for the transporter protein for antigen presentation
at least 20 more genetic regions may increase susceptibility to diabetes mellitus
offspring of affected fathers have 3-5 times higher chance of being diabetic than are offspring of affected mothers
genetic susceptibility to IDDM includes a defect in the nonthymic tolerance to beta-cell autoantigens
Pathology
pancreatic islet beta-cells are 70% of the total islet cell population, thus islets are small
exocrine atrophy of the pancreas
interstitial fibrosis
insulitis
chronic inflammatory infiltrate of the pancreatic islets, worse in those still secreting insulin
consists mainly of T-helper and T-suppressor cells, B cells, NK cells and macrophages
haphazard distribution of islets in the pancreas
Pathophysiology
chronic inflammatory process precedes the clinical presentation by years
autoimmune, antibody-mediated pancreatic islet beta-cell destruction
immunoilogic sparing of glucagon-secreting and pancreatic polypeptide-secreting pancreatic cells
early phase: reduced early insulin response to IV glucose administration
reduced beta-cell response to arginine or tolbutaminde load
progressively elevated plasma glucose
transient variable degree of insulin resistance shortly precedes insulinopenia
Autoantibodies:
islet cell cytoplasmic autoantibody (ICCAAb)
0.5% of the normal population has it
3-4% of the relatives of diabetics have it
70-80% of IDDM patients have it
susceptibility depends on the age and titers
insulin autoantibody (InsAAb)
50% of IDDM patients have it
highly predictive when ICCAAb also present
combined autoantibodies also predict faster progression
Islet cell antigens: pancreatic sialococonjugate, insulin, glutamate decarboxylase* (also known as islet cell protein 64kd), bovine serum albumin**, carboxypeptidase H***, pancreatic sulfatide, beta-cell glucose transporter (GLUT-2), islet cell proteins (37kd, 38kd, 40kd, 52kd****, 69kd)
*most predictive of IDDM; interrupted immunity to Glu decarboxylase prevents IDDM in mice
**theory: early exposure to cow milk may trigger their formation and the development of IDDM
***catalyzes the conversion of pro-insulin to insulin
****great homology with a virus related to congenita IDDM
Cellular Immunity and Mediators of Inflammation
- CD8 cells are the predominant cells in the islets
- antibodies against CD4 cells prevents IDDM in mice
- interleukin-1: inhibits insulin secretion; cytotoxic in large amounts
- interleukin-6: secereted by beta cells; enhances immune reactions
- interferon alpha: found in the pancreas of patients who die of diabetic ketoacidosis; attracts lymphocytes, induced by viruses, stimulates HLA molecule expression. Insulitis develops in mice who have intereferon alpha in their pancreas, but not in those who do not have it.
- cytokines may trigger the production of nitric oxide by beta cells; since beta cells lack SOD they can not get rid of NO or oxygen radicals, which may be lethal to them
Autoimmune Theories of IDDM
- Viral infection theory: this theory holds that a viral infection triggers the production of antibodies that cross react with natural antigens of the beta cells. Viruses that have been implicated include: Cixsackie B4, CMV, rubella, mumps, hepatitis, EBV, and en encephalomyocarditis virus of mice.
- Environmental insult theory: a viral infection or the expression of a beta-cell superantigen causes the generation of cytokines that induce the expression of adhesion molecules on the pancreatic vascular endothelium. These adhesion molecules bind leukocytes that present antigens from the damaged beta cells to the helper T cells, thereby triggering the autoimmune reaction.
Clinical Manifestations
- the 3 P's: polyuria, polyphagia, polydipsia
- slender body habitus as a rule
- honeymoon period may precede frank diabetes
- weight loss
- may make a debut with diabetic ketoacidosis
- hyperglycemia
- insulinopenia
- positive autoantibody tests
Management
Primary Preventive Therapy
- immunosuppressive therapy at the time of onset in diabetic patients (e.g. cyclosporine, azathioprine, anti-CD5 antibodies, antilymphocyte globulin, prednisone, intravenous immunoglobulin)
- immunosuppressive therapy before onset in high-risk subjects (see below)
- insulin administration (intravenous and/or subcutaneous)
- nicotinamide
- bacille Calmette-Gerin vaccine
- avoid cow's milk
Treatment of Diabetes Mellitus Type1
- insulin
- recommended: intensive therapy (Diabetic Complications Control Trial)
- will prevent or delay the onset and progression of complications
- goals of intensive therapy
- three or more injections of insulin SQ or by implanted pump
- adjustments as necessary for changes in diet, illnesses or predicted exercise
- HgbA1C less than 6.05%
- weekly glucose level at 3am of over 65 mg/dl
- fasting glucose level 70-120 mg/dl
- postpandrial glucose not over 180 mg/dl
- balanced diet
- education
- high surveillance intensity for complications (e.g. diabetic ketoacidosis, retinitis, etc)
- attention by multidisciplinary team including a diabetologist, nurse and nurse educator
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