Endo 1-5 Type 1 Diabetes

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Type 1A

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Due to autoimmune destruction of insulin-producing pancreatic beta cells.

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Type 1B

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Idiopathic destruction of beta cells.

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latent autoimmune diabetes in adults

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This is when type 1 presents at adult age.

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Normal age of onset of type 1 diabetes

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10-14

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When are genetic markers present?

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From birth

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When are immune markers present?

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After the onset of the autoimmune process

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When are metabolic markers present?

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Once enough beta cell destruction has occurred.

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Acquisition of type 1 diab

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Genetics most clearly, but also diet, stress, and infectious agents playing a role.

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Timing of presentation of type 1 diabetes

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Beta cell destruction for months-years in a preclinical asymptomatic phase followed by acute/subacute presentation of overt diabetes.

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Hallmark of type 1 diabetes

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Insulitis or islitis - a mononuclear infiltrate of the Islets of Langerhans comprised mainly of CD8 T cells with associated beta cell lysis.

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Triggering of apoptosis in Islets

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Fas expressed on beta cells of the islets and fas-ligand on hte infiltrating mononuclear cells.

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Area most prevalent with type 1 diab

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Highest in the northern-most regions and generally declines in countries that lie in the south.

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Main susceptibility gene of type 1 diab

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HLA-DR3 and 4 - they are both bad, you don't necessarily have both

Within the MHC, there is HLA class II region on chrom 6p21 - formerly called IDDM 1.

This helps present antigenic peptides to T cells.

Also more susc with DQ alpha and beta chains.

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Who is at greatest genetic risk to get type 1 diabetes

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Heterozygote of DR3/DR4.

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Protective MHC haplotypes for type 1 diabetes

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HLA-DR2 or DQB1*0602

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Other susc genes

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IDDM2 (chrom 11)
CTLA-4
PTPN22
interferon-induced helicase
IL-2 receptor
lectin-like gene...

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Lifetime risk of type 1 diabetes if first-deg relative has it

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5-8%

85% of pts with type 1 diabetes don't have an affected first deg relative at time of dx.

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Animal model in non-obese mice - susceptibility gene (MHC)

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MHC H-2Kd allele

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Animal model in non-obese mice - susc gene (non MHC)

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IL-1 receptor and an activating factor of macrophages to make them resistance to parasites.

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Three groups of env agents

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Viral infections
Early infant diet
Toxins

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Viral agents

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Mumps, coxsackie B4, rubella.

They definitely don't present just before onset of disease, but there may be a delayed effect of infection or a modified pancreatic effect of viral infection later in childhood could play a role.

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Early cow milk exposure or breast feeding.

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This falls in the diet/toxins category. Still contradictory evidence abt this.

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Multi-hit theory

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An interaction btwn enterovirus and nutritional factor leads to gradual destruction of the pancreas.

Or a stressful life event causes a person to exceed teh insulin-producing capacity of the pancreas.

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Precipitation model of type 1 diabetes

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During infection, the increased need for insulin is when you finally see the signif beta cell impairment that was there all along.

This theory kinda refutes the causal relationship btwn viral infections and type 1 diabetes

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Why are beta cells bad at dealing with increased oxidative stress?

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Low antioxidant enzyme levels.

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5 markers of autoimmune process

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Islet cell autoantibodies
insulin autoantibodies
glutamic acid decarboxylase
proinsulin
IA-2 autoantibodies

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Islet cell autoantibodies

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Some specific to beta cells, others to alpha cells (glucagon), delta cells (somatostatin), and PP cells (pancreatic polypeptide)

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Anti-insulin antibodies

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just know they exist

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glutamic acid decarboxylase antibodies

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more predictive for SUSC to diabetes than other assays.

data suggests that autoimmunity to this on the islet surface may be the initial step in destruction of beta cells.

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IA-2 (insulinoma-associated-2 antibodies)

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Against a protein tyrosine phophatase

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Relationship with other autoimmune endocrine diseases

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Increased incidence of diab with them.

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Gold standard test for anti-islet autoantibodies

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the cytoplasmic islet-cell antibody test (ICA)

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Progression of antibodies

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Anti-islet autoantibodies dev by 9 months of age and then GAD will develop (most often at least).

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cytokine model of beta cell destruction

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Switch to Th1 cytokines to enhance cellular activities. IFN-gamma and IL-2 promote this shift. IL-4 inhibits this shift.

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Th2 subset

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Not seen with diabetics. A humoral response

It is promoted by IL-4,10.

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Molecular mimicry model of beta cell destruction

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Sequence found on beta cells is being presented after viral exposure.

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Tropic virus-viral superantigen model of beta cell destruction

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Viral infection of beta cells results in expression of a superantigen and many cytokines are released as a result.

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Lymphokine model for beta cell destruction in type 1 diabetes

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Lymphokines produced would impart a limited degree of initial beta cell destruction owing to susceptibility of beta cells to such agents.

Continued cycles of beta cell destruction through the intiation of various cytotoxic agents as well as a lack of adequate cellular or dna repair mechanisms.

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Ways to slow beta cell damage
(primary prevention)

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nicotinamide and insulin
immunization
elimination of dietary antigens
vit d suppp
inhibitors of t cell regen

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Ways to slow beta cell damage
(new onset diabetes)

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Immunosupp
heat shock protein
anti cd3 monoclonal antibodies

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Current strategy to tx type 1 diabetes

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replace insulin or transplant islet cells/whole pancreas with immunosupp

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problem with the virual pancreas

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no way to recognize teh stimulus - can't couple glucose to the release of insulin so pt has to do it themself.

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Breakdown of carbs, prot and fat

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50% carb, 20% prot, 30% fat.

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Typical person needs how much insulin?

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One unit for every 10-15 g of carbs.

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Glycemic index

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Quantifies the abs of carbs relative to pure glucose

Variation is due to fiber, gut glycosidase inhibitors, etc.

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alcohol asisolated calories or with sugar in diabetics leads to...

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hypoglycemia.

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Exercise

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potent way to reduce blood glucose.

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All animal insulin contains...

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some proinsulin.

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Usual insulin secretion in a non-diabetic

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Basal output of small quantities in fasting state and immediate secretion of insulin into portal vein in response to food ingestion.

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brittle diabetes

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wide swings in glycemic control.

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Acute stress leads to...

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specific regimens for controlling diabetes.

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Things more common with pump therapy contrasted with conventional therapy

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Local abscesses at injection sites, hypoglycemia, ketoacidosis.

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Complications due to insulin therapy

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hypoglycemia

insulin allergy
Lipoatrophy or lipohypertrophy can be seen at injection site

immune insulin resistance (IgG)

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Urinary glucose testing

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rarely used now.

but is used to test for ketones.

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Targets for gluc control

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Fasting - 80-140mg/dl (normally 70-100)
2 hour post-meal - <180-200 (normally <140)

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Methods of measuring glycosylated hemoglobin

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RBCs are freely perm to glucose.

Methods are chromatographic, immunoassay or electrophoresis

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Length of detection of a1c

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2-3 months.

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Target of a1c

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<6.5-7%

6% is about 125mg/dL

In kids and adults, want it <8%.
pregnant - <6%

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test of a1c is...

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highly specific but insensitive.

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sources of error for a1c

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hemoglobin variants,

carbamylated hemoglobin in
presence of urea (e.g. renal failure)

altered red cell life span (anemia would make it falsely high, hemolysis would make it falsely low)

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Fructosamine

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To det avg glucose [] over 2-4 weeks.

Must be adj for albumin (is falsely low with rapid albumin turnover)

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1,5-anhydroglucitol -

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gives within day variation of glucose.

renal abs of this molecule is inhibited by glucose.

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contin glucose monitoring system

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every 5 minutes gives a read out.

measures the interstitial fluid.

expensive and has reliability issues.

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Somogyi effect

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If prolonged hypoglycemia is untreated, then stress due to low blood sugar can result in a high blood sugar level rebound.