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Flashcards in Diabetes Deck (22):

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


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


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

New onset bed wetting
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


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



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


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)



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!!!!