Endocrine DI, DM I & II

04/13/2016

Review of Endocrine Pancreas: endocrine and exocrine gland; alpha cells

(glucagon) beta cells (insulin and amylin) delta cells (gastrin and
somatostatin) F/PP cells (pancreatic polypeptide)
Amylin regulates blood glucose by delaying nutrient uptake &
suppressing glucagon secretion after meals
Glucagon - ^ blood glucose by stimulating gluconeogenesis in
muscle & lipolysis in adipose tissue
Somatostatin carb, fat, protein metabolism
Gastrin dont really know, probably islet cell development; Grehlin
stimulates GH secretion & controls appetite; Pancreatic polypeptide
inhibits gallbladder contraction & exocrine pancreas secretion
Diabetes Mellitus: group of metabolic disease characterized by
hyperglycemia resulting in defect in insulin secretion, action, or both;
Four categories:
o Type I beta cell destruction leading to absolute insulin
deficiency
o Type II ranging from insulin resistance to insulin secretory
defects
o Other specific
o Gestational
Diagnosis = HbA1C > 6.5% (glycosylated Hb refers to the
permanent attachment of glucose to Hb and reflects plasma glucose
exposure over the life of an erythrocyte [120d]), FPG >126mg/dl,
2-hr plasma glucose > 200mg/dl during OGTT
DM I: most common pediatric chronic disease; can be autoimmune
(type 1A) or nonautoimmune (type 1B)
Pathophysiology: 1A progressive autoimmune T-cell mediated that
destroys beta cells; associated with HLA class II alleles; geneenvironment reactions result in formation of autoantigens on
surface of pancreatic beta cells & circulating in blood
stream/lymphatics; ultimately beta cell apoptosis, insulin synthesis
decline, and hyperglycemia develops
o Hypoinsulinemia causes ^^ glucagon secretion; also
decreased secretion of amylin, further ^ glucagon
Thus hyperglycemia is a direct result of alpha and beta
cell dysfunction with lack of insulin and ^ glucagon
Manifestations: Long preclinical period
o Glucose accumulates in the blood; when renal threshold is
met - osmotic diuresis, polyuresis, & thirst
o Wide fluctuations in blood glucose levels
o Protein and fat breakdown due to lack of insulin, resulting in
weight loss & ^ circulating ketone bodies

Diabetic ketoacidosis (DKA)

Eval & Treatment: weight loss, polydipsia, polyphagia,
hyperglycemia
o 50% of children diagnosed only when presenting with sign
and symptoms of DKA (hyperventilation and fruity odor on
breath)
o Combination of insulin therapy, meal planning, and exercise

DM II (non-insulin-dependent DM): risk factors are age, obesity,

HTN, physical inactivity, and family history; metabolic syndrome = combo. of
disorder (central obesity, dyslipidemia, pre-HTN, elevated fasting blood
glucose) that confer high risk of developing type 2 later in life
Pathophysiology: genetic defects (esp. in those that code for betacell function); basic mechanisms = insulin resistance & decreased
insulin secretion by beta cells
o Insulin resistance: suboptimal response of insulin-sensitive
tissues (esp. liver, muscle, adipose) and is assoc. w/obesity;
obesity contributes via many mechanisms:
^ serum levels of leptin and decreased adiponectin
assoc. w/inflammation and decreased insulin sensitivity
^ serum FFAs & intracellular deposits of triglycerides &
cholesterol interfere w/intracellular insulin signaling,
thus decreasing tissue responses to insulin; FFAs
contribute to beta cell apoptosis (lipotoxicity)
Inflammatory cytokines (TNF-a, IL-1b, IL-6), released
from adipocytes induce insulin resistance and are toxic
to beta cells
Obesity correlated w hyperinsulinemia and decreased
insulin receptor density
o Compensatory hyperinsulinemia prevent clinical appearance
for years
o Progressive decrease in weight and # of beta cells occur;
remaining cells develop exhaustion
o Alpha cells become less responsive to glucose inhibition,
resulting in ^ glucagon and increased blood glucose (via
gluconeogenesis)
Amylin deficiency furthers this process
o Decreased Ghrelin associated w/insulin resistance; incretins
play a role (released from GI tract in response to food;
increase sensitivity of beta cells to circulating glucose; also
suppress glucagon secretion; are inactivated by DPP-IV)
Incretin analogs (GLP-1) / DPP-IV inhibitors are being
used for treatment of Type 2

Manifestations: HTN, overweight, dyslipidemia, hyperinsulinemia

o Also classic symptoms of polyuria and polydipsia, but
symptoms are often more nonspecific than in Type 1
o Progression w/o treatment may show symptoms related to
CAD, PAD, CVD
Eval & Treatment: triglycerides > 150mg/dl; HDL <40 mg/dl; FPG
>100mg/dl
o Dietary measures and exercise focused on weight loss
Bariatric surgery may be indicated
o Oral hypoglycemic agents; insulin therapy b/c loss of beta cell
function progresses over time

Gestation diabetes mellitus (GDM): any degree of glucose

intolerance w/onset or first recognition during pregnancy
Many women w/undiagnosed Type 1 or Type 2 may be
misdiagnosed, and disease will progress after delivery
Women with GDM have a 60% chance of developing DM w/in 10-20
yrs.
Acute Complications of DM
Hypoglycemia: insulin shock; tremor, tachycardia, palpitation;
treatment requires immediate oral or IV glucose replacement
DKA: serum glucose >250 mg/dl; serum bicarb <18 mg/dl; serum
pH >7.3; urine and serum ketones
o Postural dizziness, CNS depression, Kussmaul respirations
Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS):
serum glucose >600mg/dl; pH >7.3; bicarb >15 mg/dl; small or
absent ketones in serum or urine
o Severe dehydration, loss of electrolytes, neurologic changes
(esp. stupor)
Somogyi effect: hypoglycemia followed by rebound hyperglycemia
due to counterregulatory hormones (epinephrine, GH,
corticosteroids) being stimulated by hypoglycemia and producing
gluconeogenesis
Dawn phenomenon: early morning rise in blood glucose related
to nocturnal elevations of GH, which decrease glucose metabolism
by muscle and fat
Chronic Complications of DM: most associated w/chronic
hyperglycemia (also known as glucose toxicity)
Primary Metabolic Mechanisms

o Overactivation of the alternative polyol pathway leads to

excessive accumulation of sorbitol, interfering with ion pumps
and disrupting nerve conduction; RBCs become swollen and
stiff, interfering with perfusion; polyol pathway also reduces
level of glutathione (antioxidant), leading to oxidative injury
to cells and tissue
o Protein kinase C (PKC): family of intracellular signaling
proteins that becomes inappropriately activated by
hyperglycemia
inulin resistance, production of ECM and
proinflammatory cytokines, enhanced contractility and
increased permeability (all contributing to microvascular
complications)
o Nonenzymatic glycation: normal process involving
reversible attachment of glucose to proteins, lipids, and
nucleic acids
W/hyperglycemia, glucose becomes permanently
attached, forming advanced glycation end products
(AGEs); these attach to their receptors and cause
numerous pathologic conditions:
Cross-linking and trapping of proteins
w/thickening of basement membrane or increased
permeability in small blood vessels and nerves
Binding to cell receptors (eg macrophages) and
inducing the release of cytokines and growth
factors that stimulate cellular proliferation in
glomeruli & blood vessel smooth muscle
Inducing lipid oxidation, oxidative stress, &
inflammation
Promotion of platelet adhesion to endothelial cells
Microvascular Complications
o Diabetic retinopathy
Macular edema
o Diabetic nephropathy
o Diabetic neuropathy
Macrovascular Complications
o CAD
o Stroke
o PVD
Infection
o Impaired senses lead to loss of protection w/injury and
repeated trauma, open wounds, etc.

o Hypoxia
o Pathogens proliferated rapidly due to increased glucose in
body fluid
o Decreased blood supply due to vascular changes
o Suppressed immune response
Diabetes insipidus (DI): disorder of insufficient ADH activity, leading
to polyuria and polydipsia
Two forms:
o Neurogenic DI caused by insufficient ADH secretion when any
lesion of hypothalamus, pituitary stalk, or posterior pituitary
interferes w/ADH syntheses
Hereditary disorders that affect ADH genes; closed head
injuries
o Nephrogenic DI: caused by inadequate response of renal
tubules to ADH, which is usually acquired (related to drugs
[loop diuretics, general anesthetics] that damage the renal
tubules or inhibit generation of cAMP) or hereditary disorders
that result in structural changes to the pituitary gland
Often confused w/ pathogenic polydipsia, caused by chronic
ingestion of large quantities of fluid that was out the renal
medullary concentration gradient
o Resolves w/decreased fluid ingestion
Pathophysiology: partial to total inability to concentrate urine
o Insufficient ADH causes excretion of large volumes of dilute
urine, leading to ^ plasma osmolality (urine output of 12L/day to 8-12L/day)
o Dehydration develops; serum hypernatremia and
hyperosmolality
Manifestations: polyuria, nocturia, continuous thirst, polydipsia
o large bladder capacity and hydronephrosis
o Neurogenic = abrupt onset; Nephrogenic = gradual onset
Eval & Treatment: distinguished from other polyuric states;
o Low urine specific gravity & osmolality; hypernatremia;
continued diuresis despite serum sodium >145 mEq/L
o Psychogenic differentiated from Nephrogenic based on plasma
ADH levels
ADH low in psychogenic; normal to high in Nephrogenic
o Treatment: ADH replacement therapy; intranasal
administration of synthetic vasopressin analog DDAV