DSA12 - Pathology of the Endocrine Pancreas

Increase rate of glucose transport into certain cells (decrease Serum Glucose)

What is the main function of Insulin?

GLUT2; GLUT4

(GLUT2/GLUT4) is an Insulin INDEPENDENT Glucose transport; (GLUT2/GLUT4) is an Insulin DEPENDENT Glucose transporter

GPCR (activates AC --> more cAMP)

The Glucagon receptor is what kind of receptor?

Universal inhibitor (Inhibits insulin/glucagon secretion, enzymes & Bile + Stops Motility)

What is the function of Somatostatin?

Type 1 Diabetes Mellitus (T1DM)

Define Condition:

AUTOIMMUNE Metabolic disease involving inappropriately increasing blood glucose - Issue with INSULIN HORMONE LEVELS

-Hx:

> Unknown Etiology

> Genetic Susceptibility w/ Environmental Trigger (ex: Viral Infex via Coxsackievirus)

> Low genetic predisposition

> A/w HLA-DR3 and HLA-DR4

> Onset = Child/Teens --> Adults

-Path: Type IV Hypersensitivity = Failure of T cell self-tolerance -> destruction of beta cells by T cells -> absolute insulin deficiency

-Dx:

Labs

INSULIN LOW

> Autoantibodies =

>> Anti-glutamic acid decarboxylase (Anti GAD-65)

>> Anti-islet cell Autoantibodies

>> Insulin Autoantibodies

Histo

> Autoimmune "Insulitis" - inflammatory (LYMPHOCYTIC) infiltrate in islets

> Late = Beta-cell depletion, islet atrophy, fibrosis

Type 2 Diabetes Mellitus (T2DM)

Define Condition:

End-organ INSULIN RESISTANCE leading to Associated Beta-cell dysfunction leading to Metabolic disease involving inappropriately increasing blood glucose - Issue with INSULIN RECEPTOR

-Hx:

> MC Type (90%)

> A/w...

>> OBESITY

>> GENETIC PREDISPOSITION

> Onset = Adulthood (but more incidence in childhood/teens)

-Path:

> Insulin made, but skeletal muscle/fat and liver don't respond --> Hyperglycemia

> Central Obesity (Abd/Visceral Fat) = More LIPOLYTIC (more adipokines & FFAs --> inflammation --> INSULIN RESISTANCE & BETA CELL DYSFUNCTION)

-Dx:

Labs = INSULIN starts high, then drops with advanced disease

Histo

> Beta-cell hyperplasia & hypertrophy (overcompensation by insulin resistance) --> Less Beta cells --> Less Insulin ==> Hyperglycemia

> Amyloid in islets = Beta-cells also secrete amyloid polypeptide (amylin) --> More insulin = More Amylin accumulation

Gestational Diabetes

Define Condition:

Hyperglycemia that develops during pregnancy

-Path: Pregnancy hormones (ex: human placental lactogen) increases insulin resistance to supply fetus w/ glucose & Amino acids

-Dx:

Histo (in Mother & Fetus)

> Islet Hyperplasia

> Islet Hypertrophy

Hyperglycemia --> Formation of Advanced Glycation End (AGEs) products ==> Damage cells & Promote Atherosclerosis

Describe how Non-enzymatic Glycation occurs and what it can cause

HbA1c (measures avg blood sugar over 3 months)

How is glycated Hb measured?

Coronary Artery Disease; d/t Diabetic Macrovascualr disease as AGEs cause accelerated atherosclerosis

What is the most common cause of death in pts w/ DM?

Diabetic Nephropathy

Define Condition:

MCC of ESRD in U.S.

-Path: AGEs crosslink w/ Collagen IV in Basement Membrane --> DIFFUSE THICKENING, esp of VASCULAR VM ==> HYALINE ARTERIOSCLEROSIS (more of EFFERENT Arteriole) --> More pressure in Glomerulus --> Increased GFR --> Hyperfiltration of Glucose (Pulls water) ==> Polyuria --> Eventually, renal failure & Decrease in GFR

-Sx/PE: Polyuria

-Dx:

Histo = Thickened GBM --> loss of size & charge of barrier

↑ sorbitol accumulation in lens -> osmotic damage -> fluid in lens -> cataract formation (clouding or opacification of the lens)

How does cataracts occur d/t Diabetes Mellitus?

Diabetic Retinopathy (DR)

Define Condition:

-Path: AGEs, oxidative stress, sorbitol accumulation -> damage small blood vessels of the retina

-Dx: Fundoscopy

> Early = Non-Proliferative

>> Microaneurysms

>> Blot Hemorrhages (rupture of microaneurysms)

>> Hard exudates --> Capillary leakage --> lipid deposits

>> Cotton wool spots = areas of retinal ischemia

> Late = Proliferative

>> Neovascularization (attempt to compensate for poor blood supply)

Diabetic Neuropathy

Define Condition:

-Path: ↑ sorbitol accumulation in Schwann cells (myelinate peripheral nerves) -> osmotic damage

-Sx/PE:

> Affects Sensory axons more than motor

>> Paresthesias/Numbness

>> "Sock and Glove" Sensory Loss

> Autonomic Neuropathy

>> Bowel Issues

>> Bladder Issues

>> Issues w/ sexual function

Insulinoma

Define Condition:

Type of Islet Cell Tumor/PanNET

-Hx:

> Usually in ADULTS

> USUALLY BENIGN

-Path: Tumor of Beta cells --> overproduce insulin --> Hypoglycemia

> Functional Tumor

> May be part of MEN1 Syndrome

-Dx:

Labs

> Glucose = LOW

> Insulin = HIGH

> C-Peptide = HIGH

Histo = Cells arranged in NESTS (Monotonous cells demonstrating round nuclei w/ salt + pepper-like chromatin and abundant cytoplasm)

Glucagonoma

Define Condition:

Type of Islet Cell Tumor/PanNET

-Hx:

> Usually in ADULTS

-Path: Tumor of pancreatic alpha cells --> Overproduce glucagon

> Functional Tumor

> May be part of MEN1 Syndrome

-Sx/PE: (6 Ds)

> Dermatitis (Necrolytic migratory erythema = red, blistering, itchy, painful rash; fluctuates in severity; usually seen in genitals, buttocks, groin, and extremities)

> Diabetes

> DVT

> Declining wt

> Depression

> Diarrhea

Somatostatinoma

Define Condition:

Type of Islet Cell Tumor/PanNET

-Hx:

> Usually in ADULTS

-Path: Tumor of pancreatic delta-cells -> overproduce somatostatin ==> Less glucagon/insulin & GI hormones (Secretin, CCK, Gastrin, GIP)

> Functional Tumor

> May be part of MEN1 Syndrome

-Sx/PE:

> Gallstones (Less CCK = bile stasis)

> Steatorrhea (Less GI enzymes & bile secretion)

-Dx:

Labs

> Diabetes/Glucose Intolerance (low Insulin)

> Achlorhydria (less gastrin --Less HCl in stomach)

-Prog: METASTASES