PathologyPathologyNURS3518NURS3518

Endocrine System:Endocrine System:Diabetes MellitusDiabetes Mellitus

Nancy Downing, PhD, RN, SANE-ANancy Downing, PhD, RN, SANE-AAssistant ProfessorAssistant Professor

UI College of NursingUI College of Nursing

ObjectivesObjectives

Review endocrine pancreas functionReview endocrine pancreas function Know normal glucose and HgA1c levelsKnow normal glucose and HgA1c levels Understand functions of insulin et glucagonUnderstand functions of insulin et glucagon Compare Type I and Type II DM: pathology, risk Compare Type I and Type II DM: pathology, risk

factors, s/s, acute complicationsfactors, s/s, acute complications Relate how insulin resistance et metabolic Relate how insulin resistance et metabolic

syndrome contribute to DMsyndrome contribute to DM Distinguish between DKA et HHNKSDistinguish between DKA et HHNKS Identify chronic complications of DMIdentify chronic complications of DM

Labs to KnowLabs to Know

Lab Normal Value

What it Tells Us

Blood glucose 75-110mg/dl Glucose level after 8 hrs fasting

HgbA1c <6% Average RBC plasma glucose exposure over its 120-day lifespan

Endocrine PancreasEndocrine Pancreas

Islets of LangerhansIslets of Langerhans αα cells cells

• Synthesize et secrete glucagonSynthesize et secrete glucagon ββ cells cells

• Synthesize et secrete insulinSynthesize et secrete insulin

Insulin et glucagon regulate blood sugarInsulin et glucagon regulate blood sugar

Diabetes MellitusDiabetes Mellitus

Disturbed glucose toleranceDisturbed glucose tolerance Chronic hyperglycemiaChronic hyperglycemia Four categoriesFour categories

Type IType I Type IIType II GestationalGestational Other Other

InsulinInsulin

Facilitates uptake of Facilitates uptake of glucose into most glucose into most cells*cells*

Anabolic hormoneAnabolic hormone Promotes protein, Promotes protein,

lipid, nucleic acid lipid, nucleic acid synthesissynthesis

Insulin SecretionInsulin Secretion

Stimulated byStimulated by ↑ ↑ blood glucose, GI blood glucose, GI

hormones, PNShormones, PNS Diminished byDiminished by

↓ ↓ blood glucose, high levels blood glucose, high levels of insulin (negative of insulin (negative feedback), SNS stimulation feedback), SNS stimulation of of αα cells, prostaglandins cells, prostaglandins

GlucagonGlucagon

↑ ↑ when blood glucose is low or in when blood glucose is low or in response to SNS stimulationresponse to SNS stimulation

GlycogenolysisGlycogenolysis breakdown of glycogen to glucose breakdown of glycogen to glucose

GluconeogenesisGluconeogenesis Generation of glucose from non-Generation of glucose from non-

carb molecules such as lactate, carb molecules such as lactate, pyruvate, amino acids, glycerol pyruvate, amino acids, glycerol

Insulin antagonistInsulin antagonist

Type I DMType I DM Most common pediatric chronic Most common pediatric chronic

diseasedisease Still relatively rare: affects 1:300Still relatively rare: affects 1:300 Diagnosis peaks at age 12Diagnosis peaks at age 12

Most cases autoimmune Most cases autoimmune Loss of ß cellsLoss of ß cells Gene-environment interactionGene-environment interaction

10-13% have a first-degree 10-13% have a first-degree relative affectedrelative affected

HLA variations most commonHLA variations most common

Type I DM: GeneticsType I DM: Genetics

Associated with class II HLA markersAssociated with class II HLA markers HLA-DQ et HLA-DR3/HLA-DR4HLA-DQ et HLA-DR3/HLA-DR4

Heterozygous for one markerHeterozygous for one marker → → 5-8X greater risk5-8X greater risk

Homozygous for two markersHomozygous for two markers → → 20-40X greater risk20-40X greater risk

HLA-DR2 associated with very low riskHLA-DR2 associated with very low risk Mechanism is unclearMechanism is unclear

Type I DM: PathophysiologyType I DM: Pathophysiology

Type I DM: EnvironmentType I DM: Environment

Viral infectionsViral infections Mumps, rubella, cytomegalovirus, EBVMumps, rubella, cytomegalovirus, EBV

DietDiet Cow milk albuminCow milk albumin Nitrosamines (beer, fish, meat, cheese)Nitrosamines (beer, fish, meat, cheese)

RxRx Corticosteroids, thiazide diuretics, Corticosteroids, thiazide diuretics, ββ blockers blockers

StressStress ↑ ↑ cortisol activity, inflammation cortisol activity, inflammation

Type I DM: PathophysiologyType I DM: Pathophysiology

Occurs after 80-90% of Occurs after 80-90% of ββ cells destroyed cells destroyed Hyperglycemia Hyperglycemia

No insulin to escort glucose into cellsNo insulin to escort glucose into cells Glyconeogenesis et production of ketone Glyconeogenesis et production of ketone

bodies (body thinks it needs more glucose)bodies (body thinks it needs more glucose)

↑ ↑ in glycosylated Hgb (HgbAin glycosylated Hgb (HgbA1c1c)) DM diagnosed when HgbADM diagnosed when HgbA1c 1c >6.5%>6.5%

Accumulation of ketones→↓pHAccumulation of ketones→↓pH

Type I DM: s/sType I DM: s/s

DKA can be 1DKA can be 1stst s/s in kids s/s in kids Weight loss d/t impaired Weight loss d/t impaired

anabolic activityanabolic activity ↑ ↑ hunger (polyphagia)hunger (polyphagia) ↑ ↑ urination (polyuria)urination (polyuria)

↑ ↑ glucose in urine glucose in urine produces osmotic diuresisproduces osmotic diuresis

↑ ↑ thirst (polydipsia)thirst (polydipsia)

Type I DM: LabsType I DM: Labs

Normal fasting BG = 75-Normal fasting BG = 75-110mg/dL110mg/dL

Maintenance of HgbAMaintenance of HgbA1c1c

<7% associated with 50-<7% associated with 50-75% reduction in risk of 75% reduction in risk of chronic complications chronic complications after 8-9 years after 8-9 years

Type II DMType II DM

Affects 10.5% ages 45-64; 18.4% 65+Affects 10.5% ages 45-64; 18.4% 65+ Incidence has doubled in past 20 years!!!!Incidence has doubled in past 20 years!!!! Affects 8.8% of black women, 34% 65+Affects 8.8% of black women, 34% 65+

Gene-environment interactionGene-environment interaction Risk factors:Risk factors:

Age, obesity, HTN, inactivity, family hxAge, obesity, HTN, inactivity, family hx ↑ ↑ cytokinescytokines Insulin resistanceInsulin resistance Metabolic syndromeMetabolic syndrome

Correlation b. Obesity and DMIICorrelation b. Obesity and DMII

Metabolic SyndromeMetabolic Syndrome

Waist circumferenceWaist circumference >40 inches men>40 inches men >35 inches women>35 inches women

Triglycerides ≥150mg/dlTriglycerides ≥150mg/dl HDLHDL

<40mg/dl men<40mg/dl men <50mg/dl women<50mg/dl women

Blood pressure ≥130/85 mmHgBlood pressure ≥130/85 mmHg Fasting plasma glucose ≥100mg/dlFasting plasma glucose ≥100mg/dl

Type II DM: PathophysiologyType II DM: Pathophysiology

Amylin: Satiety hormone secreted by Amylin: Satiety hormone secreted by ββ cells cellsIncretins: GI hormones that stimulate insulin secretionIncretins: GI hormones that stimulate insulin secretionGhrelin: Controls appetite, regulates insulin sensitivity Ghrelin: Controls appetite, regulates insulin sensitivity

Insulin ResistanceInsulin Resistance Insufficient response of insulin Insufficient response of insulin

receptorsreceptors High calorie-high fat dietHigh calorie-high fat diet ↓ ↓ responsiveness to adipokines responsiveness to adipokines

(regulate appetite)(regulate appetite) Inflammatory cytokines interfere Inflammatory cytokines interfere

w/insulin signaling w/insulin signaling HyperinsulinemiaHyperinsulinemia Eventually may lead to Eventually may lead to ββ cell cell

dysfunction et hypoinsulinemiadysfunction et hypoinsulinemia

Type II DM: GeneticsType II DM: Genetics

Not everyone w/insulin resistance or Not everyone w/insulin resistance or metabolic syndrome will develop DMIImetabolic syndrome will develop DMII

Involves multiple genes that code for:Involves multiple genes that code for: Proinsulin et insulin molecular structureProinsulin et insulin molecular structure Synthesis of glucose, glucagonSynthesis of glucose, glucagon Cellular responsiveness to insulin stimulationCellular responsiveness to insulin stimulation ββ cell mass cell mass ββ cell function cell function Insulin receptorsInsulin receptors

Type II DM: s/sType II DM: s/s

Often nonspecificOften nonspecific FatigueFatigue Pruritus et recurrent infections Pruritus et recurrent infections

• Bacteria et yeast like high-sugar environmentBacteria et yeast like high-sugar environment Visual changes et neuropathyVisual changes et neuropathy

• cellular injury due to build-up of glucosecellular injury due to build-up of glucose

Typically will have s/s metabolic syndromeTypically will have s/s metabolic syndrome May have polyuria et polydipsiaMay have polyuria et polydipsia

Other Types of DMOther Types of DM MODY Maturity onset diabetes of youthMODY Maturity onset diabetes of youth

Genetic mutations of MODY genesGenetic mutations of MODY genes Strong family hx, normal weight, diagnosis Strong family hx, normal weight, diagnosis

before age 25before age 25 Low levels of insulinLow levels of insulin Not associated with weight gainNot associated with weight gain

Gestational diabetesGestational diabetes Glucose intolerance onset in pregnancyGlucose intolerance onset in pregnancy Older age, family hx, hx glucose intolerance, Older age, family hx, hx glucose intolerance,

obesity, non-white, Hispanic, poor OB obesity, non-white, Hispanic, poor OB outcomes, infant born >9 lbsoutcomes, infant born >9 lbs

Complications of DM: AcuteComplications of DM: Acute

HypoglycemiaHypoglycemia DKADKA HHNKSHHNKS Somogyi effectSomogyi effect

Hypoglycemia then rebound hyperglycemiaHypoglycemia then rebound hyperglycemia Makes Type I DM difficult to control in someMakes Type I DM difficult to control in some

Dawn phenomenonDawn phenomenon Early morning rise in BG concentrationEarly morning rise in BG concentration May be r/t nocturnal GH elevationMay be r/t nocturnal GH elevation

Hypoglycemia: BG<60mg/dlHypoglycemia: BG<60mg/dl

More insulin than requiredMore insulin than required ↓ ↓ food intake, ↑ exercise, too much insulinfood intake, ↑ exercise, too much insulin

s/s: vary but occur similarly in each persons/s: vary but occur similarly in each person If BG drop is rapid: tachycardia, palpitations, If BG drop is rapid: tachycardia, palpitations,

diaphoresis, tremors, pallor, arousal anxietydiaphoresis, tremors, pallor, arousal anxiety HA, irritability, fatigue, poor judgment, HA, irritability, fatigue, poor judgment,

confusion, visual changes, hunger, SZ, comaconfusion, visual changes, hunger, SZ, coma Some people don’t feel warning s/sSome people don’t feel warning s/s

ββ blockers block adrenergic s/s blockers block adrenergic s/s

Diabetic KetoacidosisDiabetic Ketoacidosis Occurs w/absence or deficiency of insulinOccurs w/absence or deficiency of insulin More common in Type I DMMore common in Type I DM Often r/t infection trauma, surgery, MIOften r/t infection trauma, surgery, MI ↑ ↑ in counterregulatory hormones designed in counterregulatory hormones designed

to stimulate more insulin production by ↑ to stimulate more insulin production by ↑ glucose levelsglucose levels Catecholamines, cortisol, glucagon, GHCatecholamines, cortisol, glucagon, GH Body relies on gluconeogenesis et ketogenic Body relies on gluconeogenesis et ketogenic

pathways for energy in absence of glucosepathways for energy in absence of glucose

KetonesKetones

Contain HContain H++ atoms so are acidic atoms so are acidic Produced by liver from fatty acid breakdown for Produced by liver from fatty acid breakdown for

energy when body requires glucoseenergy when body requires glucose Impaired ketone activity can’t regenerate bicarbImpaired ketone activity can’t regenerate bicarb

DKA: s/sDKA: s/s

HyperglycemiaHyperglycemia DehydrationDehydration Acetone (sweet) breath Acetone (sweet) breath N/V, anorexia, abdominal painN/V, anorexia, abdominal pain

May be 1May be 1stst s/s DMI in children s/s DMI in children Mental status changes ( e.g. confusion)Mental status changes ( e.g. confusion) PolyuriaPolyuria

Osmotic diuresis pulls out electrolytesOsmotic diuresis pulls out electrolytes• →→Marked ↓ in total body KMarked ↓ in total body K+ + (may be nl in serum)(may be nl in serum)

DKA: LabsDKA: Labs

Glucose >250mg/dlGlucose >250mg/dl Bicarb <18mg/dlBicarb <18mg/dl pH <7.30pH <7.30 Elevated anion gapElevated anion gap Urine et serum ketonesUrine et serum ketones

HHNKS (“Honk”)HHNKS (“Honk”)

Hyperosmolar hyperglycemic nonketonic Hyperosmolar hyperglycemic nonketonic syndromesyndrome

More common in Type II, older peopleMore common in Type II, older people Often r/t infections, Rx, non adherence to Often r/t infections, Rx, non adherence to

DM management, coexisting diseaseDM management, coexisting disease Less insulin deficiency than DKALess insulin deficiency than DKA More dehydration than DKAMore dehydration than DKA Higher BG levels d/t volume depletionHigher BG levels d/t volume depletion

HHNKS: s/sHHNKS: s/s

BG >600mg/dlBG >600mg/dl pH>7.3pH>7.3 Osmolality >320mOsm/kgOsmolality >320mOsm/kg Severe dehydrationSevere dehydration PolyuriaPolyuria

Osmotic diuresis pulls out electrolytesOsmotic diuresis pulls out electrolytes• Marked ↓ in KMarked ↓ in K++

Neurological changes Neurological changes Stupor, confusionStupor, confusion

DKA vs. HHNKSDKA vs. HHNKS

Complications of DM: ChronicComplications of DM: Chronic RetinopathyRetinopathy

Damage to retinaDamage to retina Can progress to blindnessCan progress to blindness

NephropathyNephropathy DM is most common cause of ESRDDM is most common cause of ESRD 30% Type I and 40% Type II will develop30% Type I and 40% Type II will develop

NeuropathyNeuropathy Nerve damage, especially in distal neuronsNerve damage, especially in distal neurons Foot ulcers, amputation, bladder et sexual Foot ulcers, amputation, bladder et sexual

dysfunction dysfunction

Pathophysiology of Chronic Pathophysiology of Chronic ComplicationsComplications

Polyol PathwayPolyol Pathway Some tissues do not require insulin for Some tissues do not require insulin for

glucose transportglucose transport• Kidney, blood vessels, eye lens, nervesKidney, blood vessels, eye lens, nerves

Use alternate metabolic pathway for glucose Use alternate metabolic pathway for glucose metabolism: polyol pathwaymetabolism: polyol pathway

High glucose converted to sorbitol et fructoseHigh glucose converted to sorbitol et fructose Accumulation of sorbitol et fructose →↑ Accumulation of sorbitol et fructose →↑

osmotic pressure, edema, et cell damageosmotic pressure, edema, et cell damage