08/11/2010 10:39:00

← Prevalenc eof diabetes in US is 24 million, 8% of the population

← ¼ of them are not diagnosed
← 233,000 deaths a year are secondary to diabetes, 5th leading cause of
death
← $174 billion a years is spent on diabetes (this includes lost productivity
from diabetes) – ¾ is direct medical costs though
← 1/10 health care dollars is spent on diabetes
← 1/5 medicare dollars is spent on diabetes
← 9-11 weeks into gestation islets of langerhans in the panacreas
develop
← islet hyperplasia is seen in infants of diabetic mothers, but ability of
cells to divide is lost after neonatal period
← 1 million islets
← 70% beta cells
← 20% alpha cells
← essentially an endocrine organ embedded in an exocrine organ
← majority of the cells make insulin, the minority make glucagons and
tend to be at the periphery of the islets
← insulin is an anabolic hormone
← increases glucose transport into the cells to make glycogen, etc to
store it
← it is usually done because the target cells have a transporter for
glucose that responds to insulin binding
← this increases glucose phosphorylation (holding it in cells)
← increases glycogen and triglyceride production and storage
← also kind of acts like a growth hormone driving DNA synthesis, cell
growth, protein synthesis, etc
←
← hormones that oppose action of insulin are glucagons, cortisol,
epinephrine, and growth hormone
←
← originally there was juvenile onset and adult onset diabetes
← (also secondary and latent diabetes, but less important)
←
← this was not an ideal classification system, because it wasn’t that
clinically relevant
←
← now there is the insulin-dependent DM (Type I)
← and NIDDM (Type II)
• broken down into obese and non-obese types
• and maturity onset diabetes of the young
←
← this also wasn’t great, because some Type II people ended up needing
insulin
←
← Type I diabetes is due to an auto-immune destruction of the islets
← In Type II, there is insuline resistance and inadequate compensation,
leading to relative insulin deficiency
←
← Type I is a more “brittle” diabetes, they are ketoacidosis prone and
they don’t make any insulin on their own after awhile, highly genetic
← Type II is more “stable”
←
← Type I is more common among the young, but Type II is by far more
common overall
← It is rarer under 20 years old, but it is far far more common in those
over 20, especially in the very old
←
← Type I diabetes is an absolute deficiency in insulin secretion
← This means that the diabetics are extremely sensitive to blood glucose
levels
← So exogenous insulin, changes in diet, changes in fluid, changes in
physical activity, infection, are all problems with them
← They have to adjust insulin they take according to all these things and
it is hard
← Fluctuates rapidly as hypoglycemic and hyperglycemic
←
← the thought is that Type I diabetes does not appear clinically until 75-
90% of beta cell function in your islets is gone
← there is some kind of environmental trigger (we think)
← that begins an autoimmune response against your islets
← you have a “latent” period where you are slowly losing beta cells, but
you don’t know it yet, because you have a lot of extra capacity
← once you have lost like 80% of your capacity, then you will generally
have a stress event that triggers some kind of symptoms that leads to
diagnosis of their diabetes
← 1-5 years – “honeymoon” phase follows where patient capacity is
usually okay, as the aftermath of the stress event the body recovers
← then they will dip into diabetes for the rest of their life after that
←
← it is believed that it is a rare outcome of exposure to a common
environmental factor in genetically susceptibly individual
← risk is directly related to family history/genetics
←
← we think there is an environmental factor because regionally it has
differences
← only 20% of type I diabetics have a family history too
← immigrants have risk closer to country that they go to, rather than
where they come from
← environmental could be something about our lifestyle
← not necessarily like a specific pollen
← some hypotheses have been chemicals, toxins, and viruses
←
← there is linkage to MHC Class II antigens, indicating it has an
autoimmune component
← you can also see inflammatory process in pancreas and you can find
autoantibodies
← if you immunosuppress diabetics it can actually slow progression of the
disease
← 20% of diabetics have other auto-immune mediated endocrine
disorders
←
← histologically you see the insulin-producing cells in particular
disappear, glucagon-producing cells also seem to increase, but we aren’t
completely sure about that
← islet cell antibodies (ICA) are usually present in 90% of patients at
diagnosis and then it decreases over time (but capacity to destroy pancreas
remains, i.e. after transplant)
← it is often seen in relatives
← the antibody could be etiologic (the cause) or secondary, we don’t
know
← some people think it may be T cell mediated and not antibody
mediated
← if you transfer T cells between mice you can transfer diabetes, but not
if you transfer the antibodies with the serum
← diabetes has been transferred in humans via bone marrow transplant
← if you transfer a good pancreas into a diabetic, it gets destroyed again
←
← insulin replacement and education are the most important treatment
strategies for diabetes
← there is no cure
← you can give a pancreas transplant if you are already giving a kidney
transplant and then immunosuppress the patient (bc you will have to for the
kidney anyway) and then it will allow the pancreas to stick around
←
← Type II diabetes
← Decreased responsiveness of tissues to insulin
← The receptor number/function doesn’t change, but response to
receptor binding decreases
← You also get an impaired compensatory response to this
← The general population prevalence is as high 5%
← Twin of type II diabetes has near 100% chance of developing it
← VERRRY genetic/connected to family history
←
← diabetes type II is increasing worldwide and varies geographically
← native Americans 8% prevalence
← Pima Indians have 50% prevalence
←
← obesity puts you at higher risk
← higher age puts you at higher risk
← hypertension and elevated LDL are also risk factors
←
← lots more obese people these days could account for at least a big part
of the increase in Type 2 diabetes
←
← patients present as older and overweight
← the onset is often insidious
← they don’t realize it
← it gets picked up on and a routine urine test
← 25% of Type 2 diabetics have not been diagnosed
← you see a mild depletion of beta cells
← a unique deposition of amyloid (not always there)
← no insulitis
←
← you see hyaline deposits of pink material in islets
← you give them dietary management, life-style changes, oral
medications, and possibly eventually insulin supplementation
←
←
←
 08/11/2010 10:39:00
← in prep for lab on Friday, review online cases
← acute complications of diabetes
←
← hyperglycemia
← ketoacidosis
← hypoglycemia
← diabetic coma
← death
←
← Type 1 Diabetes
• Increased oxidation of free fatty acids by the liver creates and
releases ketones at a greater rate than they are utilized peripherally
• Metabolic ketoacidosis results in nausea vomiting, kussmaul
breathing
← Type 2
• Presents differently
←
← chronic complications of diabetes are mostly from really high blood
sugar, so they are the same in type 1 and 2
← they are:
• susceptibility to infection
• microvascular diseases
o retinopathy
o nephropathy
 • macrovascular disease
o cardiac
o cerebral peripheral
← more than half of diabetics die of coronary artery disease
← cerebral vascular disease gets another 15%
←
← non-enzymatic glycosylation
← glucose is covalently bound to the beta chain of hemoglobin A
← so you can measure these levels through hemoglobin A1C
← it is a useful test to assess glucose management over last 120 days
← that is the life of a red blood cell
← AGEs are advanced glycosylation end-products
← The formation of them is reversible
← Attach to collagen in basement membrane of vessel walls where they
accumulate over the lifetimes of the vessel
← Binds to receptors on the surface of macrophages and endothelial cells
←
← cellular immunity of diabetics seems to be impaired
← migration of cells is slower
← there is decreased chemotaxis
← and sometimes you don’t get the right T cell response
←
← there are certain organisms you tend to become susceptible to as a
diabetic
←
← poor blood supply further impedes inflammatory response
←
← mucormycosis is pretty much confined to diabetes
← TB, staph, and candida all show increased rates in diabetics
←
← nephropathy
← microalbuminuria
← glomerulosclerosis, etc
←
← you get basement membrane thickening, this is particularly damaging
to kidney function
← 30% increase in thickness in 5 years
← greater than 5 times thicker eventually perhaps
←
← arteriolonephrosclerosis – kidneys get granular appearance
← gives kidney granular appearance
← nephrons die and contract creating microscopic dimples, leading to
granular appearance
← same thing can happen from chronic hypertension
←
← many diabetic patients get to end stage renal disease
← more common in Type 1 diabetics, but more prevalent in type 2
← genetic predisposition to ESRD in diabetes
← African Americas, Hispanic Americans, native Americans at particularly
high risk
← Hypertension accelerates progression to ESRD
←
← retinal capillary microaneurysms occur, when endothelial cells get
killed off by high glucose levels
← you can also get cotton-wool spots – nerve fiber layer infarcts due to
microvascular injury
← neovascularization is the worst thing that can happen to a retina
←
← you can lose your vision through diabetes in a number of ways
← basement membrane thickening can lead to macular edema
← arteriolar hyalinization, neovascularization
← there is a whole big slide of it
← ischemic retina releases angiogenic factor
← now we have some medical therapies that inhibit this that are
intravitreol injections
← there is also pan-retinal photocoagulation – where you destroy
ischemic retina with a lazer
← you will see these as blanched spots that are now there from lost
photoreceptors and RPE
←
← diabetic neuropathy
← sensory neuropathy that affects longer and smaller nerves of hands
and feet
← motor neuropathy, you start having muscle wasting of intrinsic
muscles of hands and feet
← you also have an autonomic neuropathy
← you lose sweating and get drying of the skin
←
← macrovascular disease – you get bad atherosclerosis
← this leads to occlusive problems, MI, stroke, etc
←
← feet are a major problem with diabetics
← they get lower extremity gangrene
← 100x more common in diabetics than nondiabetics
←
←
 08/11/2010 10:39:00
← macrovascular disease kills people
← microvascular disease causes lots of morbidity
← foot amputations, blindness/retinopathy, nephropathy
← the number of people with diabetes is expected to double by 2025
← it is already a worldwide epidemic of almost 200 million people
← fasting hyperglycemia – criteria of diabetes
← glucose test, give a drink of something sugary, see a huge jump in
blood sugar
← measure plasma insulin (not normal)
← normal is like 10, in diabetics you will see insulin levels of 100
← lack of insulin is not the problem
← there is plenty of insulin but blood sugar levels are still high
←
← can deal with this by losing weight
← will go away if person loses weight
← but they will probably gain the weight back
← at first they will be okay on glucose, but insulin levels will start to rise
← eventually the system breaks down and the beta cells stop
overproducing insulin, and you just have straight hyperglycemia and
diabetes
←
← insulin resistance leads to hyperinsulinemia
← you have compensation by beta cells and normal glucose tolerance
← eventually beta cell “failure”
←
← most glucose in fasting state comes from liver, a little from kidney
← 30% of glucose at fast will come from glycogen breakdown, 70% from
gluconeogenesis
← the reason glucose comes from those 2 organs is because those are
the only organs that have G6P enzyme for gluconeogenesis
←
← impaired insulin secretion from pancreas, increased glucose production
in liver, and insulin resistance in muscle – triangle of type 2 diabetes
← in pancreas there is alpha and beta cell dysfunction
← glucose is maintained in a narrow window in the blood
←
← insulin resistance in muscle
← the GLUT4 receptor binds glucose and a pathway follows
← we don’t know where the resistance comes from in this pathway for
sure
← bottom line though is that we think that it has directly to do with
transport
← GLUT4 is not transporting glucose into the cell
←
← increasing free fatty acid levels in blood of healthy people can inhibit
glucose transport in the same way
← how does fat cause this block
← it is possible that intracellular lipids are blocking trafficking of GLUT4 to
the surface
← it is also possible that they are interfering with the insulin signaling
cascade that also activates GLUT4
←