Diabetes Flashcards
(22 cards)
Type 1 vs. Type 2 and Insulin
Both involve insulin deficiency
From BETA CELL DESTRUCTION (type 1, absolute lack of insulin)
or from INSULIN RESISTANCE (type 2, relative lack of insulin)
Complications arise from the effects of hyperglycemia on endothelial cells, and the subsequent damage to other tissues
Pancreatic Cells
1 million islets that contain a few cell types
Alpha –> GLUCAGON which antagonizes insulin
Beta –> Produce INSULIN
Delta –> Somatostatin, inhibits both alpha and beta cells
Insulin functions
Functions –> lowers blood glucose via action on 3 different tissues –> liver, skeletal muscle and adipose tissue
Alters fatty acid and amino acid metabolism
Increases glucose uptake in adipose tissue and skeletal muscle
In the liver, it decreases gluconeogenesis and alters lipid metabolism; it also increases glycogen synthesis
Stimulates lipogenesis, protein synthesis
Fasting vs. Fed States
When FASTING –> low glucose, low insulin –> glucose preferentially shunted to the BRAIN (insulin dependent) and homeostasis depends on the hepatic processes (gluconeogenesis, glycogenolysis) to prevent hypoglycemia; GLUCAGON is high to make more glucose
When FED –> insulin is secreted, regulated by BLOOD GLUCOSE (most sensitive regulator of insulin release/synthesis)
Insulin is also regulated by GLUCAGON, which is low when glucose is high (stimulates insulin secretion), SOMATOSTATIN (inhibits insulin secretion), CATECHOLAMINES (inhibit insulin release via alpha receptors)
Glucagon RAISES blood glucose
Epidemiology of Diabetes
21 million people, most with type 2
No longer a disease of adults –> more children being diagnosed, on the rise
Diabetes is the LEADING CAUSE OF ESRD, NON-TRAUMATIC LIMB AMPUTATIONS, and ADULT-ONSET BLINDNESS
Only getting worse
Diagnostic Criteria for Diabetes
A random elevated blood glucose OVER 200 mg/dL with signs and symptoms of polyuria, weight loss, polydipsia, hyperglycemia
A fasting glucose level OVER 126 mg/dL on MORE THAN ONE OCCASION
An abnormal oral glucose tolerance test result (> 200 2 hours after a normal carbohydrate load) - this is used to diagnose gestational diabetes
Type 1 Diabetes overview
AUTOIMMUNE DISEASE
occurs as a result of GENETIC predisposition as well as an ENVIRONMENTAL trigger (virus? stress?) - Coxsackie, Mumps, Congenital Rubella?
Biopsy of pancreas shows inflammatory infiltrate of T cells surrounding islets
GRADUAL destruction of the beta cells (> 90%) –> severe LACK of insulin that eventually causes an abrupt onset of symptoms –> when patients come to attention over 90% of their beta cells could already be gone!!
Onset typically YOUNGER (during puberty), but 30% are diagnosed after age 20
Associated with HLA-DR3 and HLA-DR4
Auto-antibodies against islet cells detected in 80% of patients
Symptoms of Type 1 DM
Nausea/vomiting New onset bed wetting Polyuria Polydipsia Polyphagia Weight loss!
Diabetic Ketoacidosis
An important complication of Type 1 DM
SEVERE HYPOGLYCEMIA (> 700) in response to an acute stressor (alcohol, poor compliance, infection, thrombotic episode, stress) results in an INCREASE IN FREE FATTY ACIDS and LIPOLYSIS that OVERWHELMS THE LIVER
As a result, CIRCULATING KETONE BODIES (byproducts of free fatty acid breakdown) and METABOLIC KETOACIDOSIS occur
Findings –> N/V, peri-umbilical pain, polyuria, polydipsia, FRUITY BREATH, hyperventilation; patients look VERY ill
Type 2 Diabetes Overview
Closely associated with CENTRAL OBESITY
More complex, more common
SEDENTARY LIFESTYLE, DIET are contributing factors
Main issue of INSULIN RESISTANCE and BETA CELL DYSFUNCTION
Some insulin (relative deficiency); peripheral organs just don’t respond to it properly
Type 2 DM Pathogenesis
Normally, adipose produces PRO and ANTI hyperglycemia molecules that are usually balanced and in unison –> in T2DM, this balance is lost resulting in insulin insensitivity –> adipose also makes CYTOKINES and PRO-INFLAMMATORY MOLECULES which also contribute
Deposition of FFAs in certain tissues, decreased PPARS expression in adipose tissue both contribute
Early, there is HYPERINSULINEMIA where the beta cells try to compensate for the lack of peripheral resistance
Beta cells will EVENTUALLY BURN OUT and get destroyed/dysfunctional – this is partly mediated by amyloid deposition
Presentation of Type 2 DM
Onset is typically in ADULTHOOD, though many more children are being diagnosed
DON’T generally present with DKA, and are generally ASYMPTOMATIC
Instead of DKA, may present with complications related to DEHYDRATION and SEVERE HYPOGLYCEMIA –> in this situation, stress triggers hyperglycemia with variable ketosis/acidosis and severe dehydration due to OSMOTIC DIURESIS
If the dehydration is severe enough, may show NEURO symptoms (seizure, aphasia)
Osmotic diuresis?
Occurs when substances such as GLUCOSE enter the kidney tubules and cannot be reabsorbed –> glucose causes an INCREASE in the osmotic pressure within the tubule, causing RETENTION of water within the lumen, thus reduces reabsorption of water and INCREASES URINE OUTPUT
COMPLICATIONS of DIABETES
Primarily has effects on ENDOTHELIAL CELLS (Vasculature!!!)
Macrovasculature (aorta), Microvasculature (capillaries in kidneys, eyes), Peripheral nerves also affected
What do most diabetics DIE from? CV Disease/MI
Pathogenesis of the vasculature attack
Mediated by hyperglycemia, leading to:
ADVANCE GLYCATION END PRODUCTS (AGE’s) –> During HYPERglycemic episodes, intracellular and extracellular proteins are GLYCOSYLATED –> this results in ABNORMAL proteins that have a propensity to aggregate, causing CELL DAMAGE and alterations in permeability (leaky capillaries) –> HEMOGLOBIN A1C is an example of this; also COLLAGEN
These proteins are RESISTANT TO DEGRADATION –> thus they ACCUMULATE and LODGE in different tissues, leading to SEVERE damage –> can further stimulate CYTOKINE release, making it worse –> permeability, coagulation may be altered –> extracellular matrix deposition inreases in the basement membrane of renal structures, further damage
OCCLUSION OF VESSELS/THROMBUS FORMATION
Also PKC activation enhances matrix and smooth muscle deposition through diacylglycerol; important in atherosclerotic patients
Also Polyol pathways –> reactive oxygen species build up in response to hyperglycemia –> anti-oxidants used up –> more damage possible
Biopsy of Diabetics
SOME ISLETS and a T Cell infiltrate that that mediates B cell destruction (type 1)
Amyloid deposition within the islets (type 2) that probably underlies the damage
Macrovascular Disease
Essentially refers to ACCELERATED ATHEROSCLEROSIS or the accumulation of LIPIDS, SMOOTH MUSCLE PROLIFERATION, and INTIMAL THICKENING –> same as normal, just much faster and accentuated
Diabetics have earlier, more severe complications from atherosclerosis than the general population
Peripheral arteries (femoral) can be involved
HYALINE ARTERIOSCLEROSIS underlies chronic HTN and is the result of endothelial vascular wall thickening and stenosis (more prevalent, more severe in diabetics)
GANGRENE is a significant complication
Microvascular Disease
Basement membrane thickening occurs in a variety of organs, like the KIDNEYS and the RETINA
This results in protein leakage and deposition of extracellular matrix in the membranes –> leads to both RENAL and RETINAL problems
Renal Problems in Diabetes
Diabetic NEPHROpathy affects the vessels, glomerulus (Kimmelstiel-Wilson lesions) and increases the risk of PYELONEPHRITIS
Pyelo more commonly progresses to PAPILLARY NECROSIS in these patients and cumulatively, these changes lead to ESRD!!!
25 years into the disease, MOST DIABETICS WILL HAVE ESRD
Retinal Problems in Diabetes
Both pre-proliferative and proliferative stages
BM thickens in the capillaries and vessels, again resulting in LEAKAGE of proteins and macular edema!!
This stimulates NEW VESSEL FORMATION, MICROANEURYSMS, HEMORRHAGE, ISCHEMIC CHANGES that stimulate VEGF (angiogenesis - proliferative phase) and FIBROSIS
This scarring is a MAJOR risk factor for RETINAL DETACHMENT that may cause BLINDNESS (#1 of adult blindness)
Diabetic NEUROPATHY
Hyperglycemia can DIRECTLY damage nerves, change the vascular structure in the periphery, and an autoimmune mech may also contribute
Characterized by SENSORY LOSS initially and MOTOR ABNORMALITIES later on
Sensory deficits –> hard to detect injury like stepping on nails, etc –> increases risk of INFECTIONS –> coupled with poor wound healing from the vasculature problems –> may need AMPUTATIONS
Balance problems, fall risk increases –> fractures –> increased infection risk
EARLY = loss of vibration sense, light touch, thermal sensitivity
Middle = Numbness, tingling, pain
LATE = WASTING of muscles, sensory ataxia
There can also be autonomic dysfunction, leading to bladder infection, sexual dysfunction
Diabetic foot
Characterized by slowly healing, plantar ulcers that result from MINOR trauma
Left untreated, can lead to CELLULITIS, OSTEOMYELITIS
GANGRENE is a feared complication - atherosclerosis (remember it is accelerated) in the peripheral vascular beds cut off blood supply to the foot!
Diabetes accounts for the majority of non-traumatic lower extremity amputations in the US!!!!
